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Sichrovsky M, Lacabanne D, Ruprecht JJ, Rana JJ, Stanik K, Dionysopoulou M, Sowton AP, King MS, Jones SA, Cooper L, Hardwick SW, Paris G, Chirgadze DY, Ding S, Fearnley IM, Palmer SM, Pardon E, Steyaert J, Leone V, Forrest LR, Tavoulari S, Kunji ERS. Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier. SCIENCE ADVANCES 2025; 11:eadw1489. [PMID: 40249800 PMCID: PMC12007569 DOI: 10.1126/sciadv.adw1489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 03/14/2025] [Indexed: 04/20/2025]
Abstract
The mitochondrial pyruvate carrier transports pyruvate, produced by glycolysis from sugar molecules, into the mitochondrial matrix, as a crucial transport step in eukaryotic energy metabolism. The carrier is a drug target for the treatment of cancers, diabetes mellitus, neurodegeneration, and metabolic dysfunction-associated steatotic liver disease. We have solved the structure of the human MPC1L/MPC2 heterodimer in the inward- and outward-open states by cryo-electron microscopy, revealing its alternating access rocker-switch mechanism. The carrier has a central binding site for pyruvate, which contains an essential lysine and histidine residue, important for its ΔpH-dependent transport mechanism. We have also determined the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state by mimicking pyruvate interactions and by using aromatic stacking interactions.
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Affiliation(s)
- Maximilian Sichrovsky
- MRC Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Denis Lacabanne
- MRC Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Jonathan J. Ruprecht
- MRC Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Jessica J. Rana
- Computational Structural Biology Section, National Institutes of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA
| | - Klaudia Stanik
- MRC Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Mariangela Dionysopoulou
- MRC Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Alice P. Sowton
- MRC Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Martin S. King
- MRC Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Scott A. Jones
- MRC Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Lee Cooper
- Department of Biochemistry, University of Cambridge, Sanger Building, Tennis Court Road, Cambridge CB2 1GA, UK
| | - Steven W. Hardwick
- Department of Biochemistry, University of Cambridge, Sanger Building, Tennis Court Road, Cambridge CB2 1GA, UK
| | - Giulia Paris
- Department of Biochemistry, University of Cambridge, Sanger Building, Tennis Court Road, Cambridge CB2 1GA, UK
| | - Dimitri Y. Chirgadze
- Department of Biochemistry, University of Cambridge, Sanger Building, Tennis Court Road, Cambridge CB2 1GA, UK
| | - Shujing Ding
- MRC Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Ian M. Fearnley
- MRC Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Shane M. Palmer
- MRC Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Els Pardon
- VIB-VUB Center for Structural Biology, VIB, Pleinlaan 2, B-1050 Brussels, Belgium
- Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
| | - Jan Steyaert
- VIB-VUB Center for Structural Biology, VIB, Pleinlaan 2, B-1050 Brussels, Belgium
- Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
| | - Vanessa Leone
- Computational Structural Biology Section, National Institutes of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA
- Department of Biophysics and Data Science Institute, Medical College of Wisconsin, Milwaukee, WI 53226-3548, USA
| | - Lucy R. Forrest
- Computational Structural Biology Section, National Institutes of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA
| | - Sotiria Tavoulari
- MRC Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Edmund R. S. Kunji
- MRC Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
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Kurtzeborn K, El-Dahr SS, Pakkasjärvi N, Tortelote GG, Kuure S. Kidney development at a glance: metabolic regulation of renal progenitor cells. Curr Top Dev Biol 2024; 163:15-44. [PMID: 40254344 DOI: 10.1016/bs.ctdb.2024.11.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/22/2025]
Abstract
The aberrant regulation of renal progenitor cells during kidney development leads to congenital kidney anomalies and dysplasia. Recently, significant progress has been made in understanding the metabolic needs of renal progenitor cells during mammalian kidney development, with evidence indicating that multiple metabolic pathways play essential roles in determining the cell fates of distinct renal progenitor populations. This review summarizes recent findings and explores the prospects of integrating this novel information into current diagnostic and treatment strategies for renal diseases. Reciprocal interactions between various embryonic kidney progenitor populations establish the foundation for normal kidney organogenesis, with the three principal kidney structures-the nephrons, the collecting duct network, and the stroma-being generated by nephron progenitor cells, ureteric bud/collecting duct progenitor cells, and interstitial progenitor cells. While energy metabolism is well recognized for its importance in organism development, physiological function regulation, and responses to environmental stimuli, research has primarily focused on nephron progenitor metabolism, highlighting its role in maintaining self-renewal. In contrast, studies on the metabolic requirements of ureteric bud/collecting duct and stromal progenitors remain limited. Given the importance of interactions between progenitor populations during kidney development, further research into the metabolic regulation of self-renewal and differentiation in ureteric bud and stromal progenitor cells will be critical.
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Affiliation(s)
- K Kurtzeborn
- Helsinki Institute of Life Science, University of Helsinki, Finland; Stem Cells and Metabolism Research Program Unit, Faculty of Medicine, University of Helsinki, Finland
| | - S S El-Dahr
- Section of Pediatric Nephrology, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, United States
| | - N Pakkasjärvi
- Stem Cells and Metabolism Research Program Unit, Faculty of Medicine, University of Helsinki, Finland; Department of Pediatric Surgery, Section of Pediatric Urology, New Children's Hospital, Helsinki University Hospital, Helsinki, Finland
| | - G G Tortelote
- Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, United States.
| | - S Kuure
- Helsinki Institute of Life Science, University of Helsinki, Finland; Stem Cells and Metabolism Research Program Unit, Faculty of Medicine, University of Helsinki, Finland; Laboratory Animal Centre, University of Helsinki, Finland.
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3
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Ge H, Malsiu F, Gao Y, Losmanova T, Blank F, Ott J, Medová M, Peng RW, Deng H, Dorn P, Marti TM. Inhibition of LDHB suppresses the metastatic potential of lung cancer by reducing mitochondrial GSH catabolism. Cancer Lett 2024; 611:217353. [PMID: 39615645 DOI: 10.1016/j.canlet.2024.217353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 11/22/2024] [Accepted: 11/23/2024] [Indexed: 12/12/2024]
Abstract
Metastasis, the leading cause of cancer death, is closely linked to lactate metabolism. Our study aimed to investigate the role of lactate dehydrogenase B (LDHB), which mainly catalyzes the conversion of lactate to pyruvate, in the metastatic potential of lung cancer. We found that LDHB silencing reduced the invasion and migration ability of lung cancer cells in vitro. On the molecular level, LDHB silencing decreased the total intracellular levels of the antioxidant glutathione (GSH). Surprisingly, LDHB silencing did not increase cellular or mitochondrial reactive oxygen species (ROS) levels. Furthermore, supplementation with GSH monoethyl ester (GSH-mee), a cell-permeable derivative of GSH, partially restored the reduced in vitro colony formation capacity, the oxygen consumption rate, and the invasion and migration capacity of lung cancer cells after LDHB silencing. Using metabolic inhibitors, we showed that the rescue of colony formation after silencing LDHB by GSH-mee was due to enhanced GSH catabolism by γ-L-Glutamyl transpeptidase (GGT), which was mainly present in the mitochondrial fraction of lung cancer cells. Furthermore, we observed that high GGT expression was a prerequisite for the rescue of migratory capacity by GSH-mee after LDHB silencing. Finally, our in vivo experiments demonstrated that targeting LDHB reduced the metastasis of human and mouse lung cancer cells in immunodeficient and immunocompetent mouse models, respectively. In conclusion, LDHB silencing decreases GSH catabolism mediated by GGT, which is primarily located in the mitochondria of cancer cells. Therefore, targeting LDHB is a promising therapeutic approach for the prevention and treatment of metastatic lung cancer.
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Affiliation(s)
- Huixiang Ge
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland; Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Fatlind Malsiu
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland; Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Yanyun Gao
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Tereza Losmanova
- Institute of Tissue Medicine and Pathology, ITMP, University of Bern, Bern, Switzerland
| | - Fabian Blank
- Department for Pulmonary Medicine, Allergology and Clinical Immunology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Lung Precision Medicine (LPM), Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Julien Ott
- Department of Radiation Oncology, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Michaela Medová
- Department for BioMedical Research, University of Bern, Bern, Switzerland; Department of Radiation Oncology, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Ren-Wang Peng
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Haibin Deng
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland.
| | - Patrick Dorn
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland.
| | - Thomas Michael Marti
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland.
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Huang CY, Chung YH, Wu SY, Wang HY, Lin CY, Yang TJ, Fang JM, Hu CM, Chang ZF. Glutathione determines chronic myeloid leukemia vulnerability to an inhibitor of CMPK and TMPK. Commun Biol 2024; 7:843. [PMID: 38987326 PMCID: PMC11237035 DOI: 10.1038/s42003-024-06547-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 07/04/2024] [Indexed: 07/12/2024] Open
Abstract
Bcr-Abl transformation leads to chronic myeloid leukemia (CML). The acquirement of T315I mutation causes tyrosine kinase inhibitors (TKI) resistance. This study develops a compound, JMF4073, inhibiting thymidylate (TMP) and cytidylate (CMP) kinases, aiming for a new therapy against TKI-resistant CML. In vitro and in vivo treatment of JMF4073 eliminates WT-Bcr-Abl-32D CML cells. However, T315I-Bcr-Abl-32D cells are less vulnerable to JMF4073. Evidence is presented that ATF4-mediated upregulation of GSH causes T315I-Bcr-Abl-32D cells to be less sensitive to JMF4073. Reducing GSH biosynthesis generates replication stress in T315I-Bcr-Abl-32D cells that require dTTP/dCTP synthesis for survival, thus enabling JMF4073 susceptibility. It further shows that the levels of ATF4 and GSH in several human CML blast-crisis cell lines are inversely correlated with JMF4073 sensitivity, and the combinatory treatment of JMF4073 with GSH reducing agent leads to synthetic lethality in these CML blast-crisis lines. Altogether, the investigation indicates an alternative option in CML therapy.
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MESH Headings
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Glutathione/metabolism
- Humans
- Animals
- Mice
- Protein Kinase Inhibitors/pharmacology
- Drug Resistance, Neoplasm/drug effects
- Cell Line, Tumor
- Fusion Proteins, bcr-abl/metabolism
- Fusion Proteins, bcr-abl/genetics
- Fusion Proteins, bcr-abl/antagonists & inhibitors
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Affiliation(s)
- Chang-Yu Huang
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yin-Hsuan Chung
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Sheng-Yang Wu
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hsin-Yen Wang
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chih-Yu Lin
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
| | - Tsung-Jung Yang
- Institute of Chemistry, National Taiwan University, Taipei, Taiwan
| | - Jim-Min Fang
- Institute of Chemistry, National Taiwan University, Taipei, Taiwan
| | - Chun-Mei Hu
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Zee-Fen Chang
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
- Center of Precision Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
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Pye D, Scholey R, Ung S, Dawson M, Shahmalak A, Purba TS. Activation of the integrated stress response in human hair follicles. PLoS One 2024; 19:e0303742. [PMID: 38900734 PMCID: PMC11189182 DOI: 10.1371/journal.pone.0303742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 04/30/2024] [Indexed: 06/22/2024] Open
Abstract
Unravelling how energy metabolism and stress responses are regulated in human scalp hair follicles could reveal novel insights into the controls of hair growth and provide new targets to manage hair loss disorders. The Mitochondrial Pyruvate Carrier (MPC) imports pyruvate, produced via glycolysis, into the mitochondria, fuelling the TCA cycle. Previous work has shown that MPC inhibition promotes lactate generation, which activates murine epithelial hair follicle stem cells (eHFSCs). However, by pharmacologically targeting the MPC in short-term human hair follicle ex vivo organ culture experiments using UK-5099, we induced metabolic stress-responsive proliferative arrest throughout the human hair follicle epithelium, including within Keratin 15+ eHFSCs. Through transcriptomics, MPC inhibition was shown to promote a gene expression signature indicative of disrupted FGF, IGF, TGFβ and WNT signalling, mitochondrial dysfunction, and activation of the integrated stress response (ISR), which can arrest cell cycle progression. The ISR, mediated by the transcription factor ATF4, is activated by stressors including amino acid deprivation and ER stress, consistent with MPC inhibition within our model. Using RNAScope, we confirmed the upregulation of both ATF4 and the highly upregulated ATF4-target gene ADM2 on human hair follicle tissue sections in situ. Moreover, treatment with the ISR inhibitor ISRIB attenuated both the upregulation of ADM2 and the proliferative block imposed via MPC inhibition. Together, this work reveals how the human hair follicle, as a complex and metabolically active human tissue system, can dynamically adapt to metabolic stress.
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Affiliation(s)
- Derek Pye
- Division Musculoskeletal and Dermatological Sciences, Centre for Dermatology Research, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biosciences, The University of Manchester, Manchester, United Kingdom
| | - Rachel Scholey
- Bioinformatics Core Facility, University of Manchester, Manchester, United Kingdom
| | - Sin Ung
- Division Musculoskeletal and Dermatological Sciences, Centre for Dermatology Research, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biosciences, The University of Manchester, Manchester, United Kingdom
| | - Madoc Dawson
- Division Musculoskeletal and Dermatological Sciences, Centre for Dermatology Research, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biosciences, The University of Manchester, Manchester, United Kingdom
| | | | - Talveen S. Purba
- Division Musculoskeletal and Dermatological Sciences, Centre for Dermatology Research, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biosciences, The University of Manchester, Manchester, United Kingdom
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Li YS, Yang RR, Li XY, Liu WW, Zhao YM, Zu MM, Gao YH, Huo MQ, Jiang YT, Li BY. Fluoride impairs vascular smooth muscle A7R5 cell lines via disrupting amino acids metabolism. J Transl Med 2024; 22:528. [PMID: 38824544 PMCID: PMC11143695 DOI: 10.1186/s12967-024-05350-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 05/26/2024] [Indexed: 06/03/2024] Open
Abstract
Given the insidious and high-fatality nature of cardiovascular diseases (CVDs), the emergence of fluoride as a newly identified risk factor demands serious consideration alongside traditional risk factors. While vascular smooth muscle cells (VSMCs) play a pivotal role in the progression of CVDs, the toxicological impact of fluoride on VSMCs remains largely uncharted. In this study, we constructed fluorosis model in SD rats and A7R5 aortic smooth muscle cell lines to confirm fluoride impaired VSMCs. Fluoride aggravated the pathological damage of rat aorta in vivo. Then A7R5 were exposed to fluoride with concentration ranging from 0 to 1200 μmol/L over a 24-h period, revealing a dose-dependent inhibition of cell proliferation and migration. The further metabolomic analysis showed alterations in metabolite profiles induced by fluoride exposure, notably decreasing organic acids and lipid molecules level. Additionally, gene network analysis underscored the frequency of fluoride's interference with amino acids metabolism, potentially impacting the tricarboxylic acid (TCA) cycle. Our results also highlighted the ATP-binding cassette (ABC) transporters pathway as a central element in VSMC impairment. Moreover, we observed a dose-dependent increase in osteopontin (OPN) and α-smooth muscle actin (α-SMA) mRNA level and a dose-dependent decrease in ABC subfamily C member 1 (ABCC1) and bestrophin 1 (BEST1) mRNA level. These findings advance our understanding of fluoride as a CVD risk factor and its influence on VSMCs and metabolic pathways, warranting further investigation into this emerging risk factor.
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MESH Headings
- Animals
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/drug effects
- Fluorides/pharmacology
- Rats, Sprague-Dawley
- Cell Line
- Amino Acids/metabolism
- Cell Proliferation/drug effects
- Rats
- Cell Movement/drug effects
- Male
- Aorta/pathology
- Aorta/drug effects
- Aorta/metabolism
- Metabolomics
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/pathology
- Gene Regulatory Networks/drug effects
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Affiliation(s)
- Yan-Shu Li
- School of Public Health, Shantou University, 243 Daxue Road, Jinping District, Shantou, 515063, Guangdong Province, China
| | - Ru-Ru Yang
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Key Lab of Etiology and Epidemiology, Harbin Medical University, Education Bureau of Heilongjiang Province & Ministry of Health (23618504), Harbin, 150081, China
| | - Xin-Ying Li
- School of Public Health, Shantou University, 243 Daxue Road, Jinping District, Shantou, 515063, Guangdong Province, China
| | - Wei-Wei Liu
- Weihai Municipal Hospital, Weihai, 264299, Shandong Province, China
| | - Yi-Ming Zhao
- Xinyi Center for Disease Control and Prevention, Xinyi, China
| | - Ming-Man Zu
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Key Lab of Etiology and Epidemiology, Harbin Medical University, Education Bureau of Heilongjiang Province & Ministry of Health (23618504), Harbin, 150081, China
| | - Yi-Hong Gao
- School of Public Health, Shantou University, 243 Daxue Road, Jinping District, Shantou, 515063, Guangdong Province, China
| | - Min-Qi Huo
- School of Public Health, Shantou University, 243 Daxue Road, Jinping District, Shantou, 515063, Guangdong Province, China
| | - Yu-Ting Jiang
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Key Lab of Etiology and Epidemiology, Harbin Medical University, Education Bureau of Heilongjiang Province & Ministry of Health (23618504), Harbin, 150081, China
| | - Bing-Yun Li
- School of Public Health, Shantou University, 243 Daxue Road, Jinping District, Shantou, 515063, Guangdong Province, China.
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Ziki RA, Colnot S. Glutamine metabolism, a double agent combating or fuelling hepatocellular carcinoma. JHEP Rep 2024; 6:101077. [PMID: 38699532 PMCID: PMC11063524 DOI: 10.1016/j.jhepr.2024.101077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 02/16/2024] [Accepted: 02/28/2024] [Indexed: 05/05/2024] Open
Abstract
The reprogramming of glutamine metabolism is a key event in cancer more generally and in hepatocellular carcinoma (HCC) in particular. Glutamine consumption supplies tumours with ATP and metabolites through anaplerosis of the tricarboxylic acid cycle, while glutamine production can be enhanced by the overexpression of glutamine synthetase. In HCC, increased glutamine production is driven by activating mutations in the CTNNB1 gene encoding β-catenin. Increased glutamine synthesis or utilisation impacts tumour epigenetics, oxidative stress, autophagy, immunity and associated pathways, such as the mTOR (mammalian target of rapamycin) pathway. In this review, we will discuss studies which emphasise the pro-tumoral or tumour-suppressive effect of glutamine overproduction. It is clear that more comprehensive studies are needed as a foundation from which to develop suitable therapies targeting glutamine metabolic pathways, depending on the predicted pro- or anti-tumour role of dysregulated glutamine metabolism in distinct genetic contexts.
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Affiliation(s)
- Razan Abou Ziki
- INSERM, Sorbonne Université, Centre de Recherche des Cordeliers (CRC), Paris, F-75006, France
- Équipe labellisée Ligue Nationale Contre le Cancer, France
| | - Sabine Colnot
- INSERM, Sorbonne Université, Centre de Recherche des Cordeliers (CRC), Paris, F-75006, France
- Équipe labellisée Ligue Nationale Contre le Cancer, France
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8
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Rauckhorst AJ, Vasquez Martinez G, Mayoral Andrade G, Wen H, Kim JY, Simoni A, Robles-Planells C, Mapuskar KA, Rastogi P, Steinbach EJ, McCormick ML, Allen BG, Pabla NS, Jackson AR, Coleman MC, Spitz DR, Taylor EB, Zepeda-Orozco D. Tubular mitochondrial pyruvate carrier disruption elicits redox adaptations that protect from acute kidney injury. Mol Metab 2024; 79:101849. [PMID: 38056691 PMCID: PMC10733108 DOI: 10.1016/j.molmet.2023.101849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 11/28/2023] [Accepted: 11/30/2023] [Indexed: 12/08/2023] Open
Abstract
OBJECTIVE Energy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Although tubular metabolism changes markedly following acute kidney injury (AKI), it remains unclear which metabolic alterations are beneficial or detrimental. By analyzing large-scale, publicly available datasets, we observed that AKI consistently leads to downregulation of the mitochondrial pyruvate carrier (MPC). This investigation aimed to understand the contribution of the tubular MPC to kidney function, metabolism, and acute injury severity. METHODS We generated tubular epithelial cell-specific Mpc1 knockout (MPC TubKO) mice and employed renal function tests, in vivo renal 13C-glucose tracing, mechanistic enzyme activity assays, and tests of injury and survival in an established rhabdomyolysis model of AKI. RESULTS MPC TubKO mice retained normal kidney function, displayed unchanged markers of kidney injury, but exhibited coordinately increased enzyme activities of the pentose phosphate pathway and the glutathione and thioredoxin oxidant defense systems. Following rhabdomyolysis-induced AKI, compared to WT control mice, MPC TubKO mice showed increased glycolysis, decreased kidney injury and oxidative stress markers, and strikingly increased survival. CONCLUSIONS Our findings suggest that decreased renal tubular mitochondrial pyruvate uptake hormetically upregulates oxidant defense systems before AKI and is a beneficial adaptive response after rhabdomyolysis-induced AKI. This raises the possibility of therapeutically modulating the MPC to attenuate AKI severity.
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Affiliation(s)
- Adam J Rauckhorst
- Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA; Fraternal Order of Eagles Diabetes Research Center (FOEDRC), University of Iowa, Iowa City, IA, USA; FOEDRC Metabolomics Core Research Facility, University of Iowa, Iowa City, IA, USA
| | - Gabriela Vasquez Martinez
- Kidney and Urinary Tract Research Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus OH, USA
| | - Gabriel Mayoral Andrade
- Kidney and Urinary Tract Research Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus OH, USA
| | - Hsiang Wen
- Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA, USA
| | - Ji Young Kim
- Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Aaron Simoni
- Kidney and Urinary Tract Research Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus OH, USA
| | - Claudia Robles-Planells
- Kidney and Urinary Tract Research Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus OH, USA
| | - Kranti A Mapuskar
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
| | - Prerna Rastogi
- Department of Pathology, University of Iowa, Iowa City, IA, USA
| | - Emily J Steinbach
- Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA, USA; Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
| | - Michael L McCormick
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
| | - Bryan G Allen
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
| | - Navjot S Pabla
- Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Ashley R Jackson
- Kidney and Urinary Tract Research Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus OH, USA; Department of Pediatrics, The Ohio State University, Columbus, OH, USA
| | - Mitchell C Coleman
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA; Department of Orthopedics and Rehabilitation, University of Iowa, Iowa City, IA, USA
| | - Douglas R Spitz
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
| | - Eric B Taylor
- Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA; Fraternal Order of Eagles Diabetes Research Center (FOEDRC), University of Iowa, Iowa City, IA, USA; FOEDRC Metabolomics Core Research Facility, University of Iowa, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA; Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA, USA.
| | - Diana Zepeda-Orozco
- Kidney and Urinary Tract Research Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus OH, USA; Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA, USA; Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
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9
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Zhao Y, Zhang X, An M, Zhang J, Liu Y. Recent advancements in nanomedicine based lipid metabolism for tumour immunotherapy. J Drug Target 2023; 31:1050-1064. [PMID: 37962291 DOI: 10.1080/1061186x.2023.2283829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 11/09/2023] [Indexed: 11/15/2023]
Abstract
Therapy on lipid metabolism is emerging as a groundbreaking cancer treatment, offering the unprecedented opportunity to effectively treat and in several cases. Tumorigenesis is inextricably linked to lipid metabolism. In this regard, the features of lipid metabolism include lipid synthesis, decomposition, metabolism and lipid storage and mobilisation from intracellular lipid droplets. Most importantly, the regulation of lipid metabolism is central to the appropriate immune response of tumour cells, and ultimately to exert the immune efforts to realise the perspective of many anti-tumour effects. Different cancers and immune cells have different dependence on lipid metabolism, playing a pivotal role in differentiation and function of immune cells. However, what lies before the immunotherapy targeting lipid metabolism is side effects of systemic toxicity and defects of individual drugs, which strongly highlights that nanodelivery strategy is a magnet for it to enhance drug efficiency, reduce drug toxicity and improve application deficiencies. This review will first focus on emerging research progress of lipid metabolic reprogramming mechanism, and then explore the complex role of lipid metabolism in the tumour cells including the effect on immune cells and their nano-preparations of monotherapy and multiple therapies used in combination, in a shift away from conventional cancer research.HighlightsThe regulation of lipid metabolism is central to the appropriate immune response of tumour cells, and ultimately to exert the immune efforts to realise the perspective of many anti-tumour effects.Preparations of focusing lipid metabolism have side effects of systemic toxicity and defects of individual drugs. It strongly highlights that nanodelivery strategy is a magnet for it to enhance drug efficiency, reduce drug toxicity and improve application deficiencies.This review will first focus on emerging research progress of lipid metabolic reprogramming mechanism, and then explore the complex role of lipid metabolism in the tumour cells including the effect on immune cells as well as their nano-preparations of monotherapy and multiple therapies used in combination, in a shift away from conventional cancer research.
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Affiliation(s)
- Yumeng Zhao
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Xiaojie Zhang
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Min An
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Juntao Zhang
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Yanhua Liu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
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10
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Giafaglione JM, Crowell PD, Delcourt AML, Hashimoto T, Ha SM, Atmakuri A, Nunley NM, Dang RMA, Tian M, Diaz JA, Tika E, Payne MC, Burkhart DL, Li D, Navone NM, Corey E, Nelson PS, Lin NYC, Blanpain C, Ellis L, Boutros PC, Goldstein AS. Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment. Nat Cell Biol 2023; 25:1821-1832. [PMID: 38049604 PMCID: PMC10709144 DOI: 10.1038/s41556-023-01274-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 09/26/2023] [Indexed: 12/06/2023]
Abstract
Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity.
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Affiliation(s)
- Jenna M Giafaglione
- Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA
| | - Preston D Crowell
- Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA
| | - Amelie M L Delcourt
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Takao Hashimoto
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Sung Min Ha
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Aishwarya Atmakuri
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Nicholas M Nunley
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Rachel M A Dang
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA
| | - Mao Tian
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA
| | - Johnny A Diaz
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Elisavet Tika
- Laboratory of Stem Cells and Cancer, WEL Research Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Marie C Payne
- Department of Mechanical & Aerospace Engineering, University of California, Los Angeles, Los Angeles, CA, USA
| | - Deborah L Burkhart
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Dapei Li
- Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Nora M Navone
- Department of GU Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - Eva Corey
- University of Washington, Seattle, WA, USA
| | | | - Neil Y C Lin
- Department of Mechanical & Aerospace Engineering, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA
- Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA, USA
| | - Cedric Blanpain
- Laboratory of Stem Cells and Cancer, WEL Research Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Leigh Ellis
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Paul C Boutros
- Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Vector Institute, Toronto, Ontario, Canada
- Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA
- Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA
| | - Andrew S Goldstein
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA.
- Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA.
- Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA.
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
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11
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Gopal K, Abdualkader AM, Li X, Greenwell AA, Karwi QG, Altamimi TR, Saed C, Uddin GM, Darwesh AM, Jamieson KL, Kim R, Eaton F, Seubert JM, Lopaschuk GD, Ussher JR, Al Batran R. Loss of muscle PDH induces lactic acidosis and adaptive anaplerotic compensation via pyruvate-alanine cycling and glutaminolysis. J Biol Chem 2023; 299:105375. [PMID: 37865313 PMCID: PMC10692893 DOI: 10.1016/j.jbc.2023.105375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 10/03/2023] [Accepted: 10/11/2023] [Indexed: 10/23/2023] Open
Abstract
Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme for glucose oxidation that links glycolysis-derived pyruvate with the tricarboxylic acid (TCA) cycle. Although skeletal muscle is a significant site for glucose oxidation and is closely linked with metabolic flexibility, the importance of muscle PDH during rest and exercise has yet to be fully elucidated. Here, we demonstrate that mice with muscle-specific deletion of PDH exhibit rapid weight loss and suffer from severe lactic acidosis, ultimately leading to early mortality under low-fat diet provision. Furthermore, loss of muscle PDH induces adaptive anaplerotic compensation by increasing pyruvate-alanine cycling and glutaminolysis. Interestingly, high-fat diet supplementation effectively abolishes early mortality and rescues the overt metabolic phenotype induced by muscle PDH deficiency. Despite increased reliance on fatty acid oxidation during high-fat diet provision, loss of muscle PDH worsens exercise performance and induces lactic acidosis. These observations illustrate the importance of muscle PDH in maintaining metabolic flexibility and preventing the development of metabolic disorders.
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Affiliation(s)
- Keshav Gopal
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Abdualrahman Mohammed Abdualkader
- Faculty of Pharmacy, Université de Montréal, Montréal, Quebec, Canada; Montreal Diabetes Research Center, Montréal, Quebec, Canada; Cardiometabolic Health, Diabetes and Obesity Research Network, Montréal, Quebec, Canada
| | - Xiaobei Li
- Faculty of Pharmacy, Université de Montréal, Montréal, Quebec, Canada; Montreal Diabetes Research Center, Montréal, Quebec, Canada; Cardiometabolic Health, Diabetes and Obesity Research Network, Montréal, Quebec, Canada
| | - Amanda A Greenwell
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Qutuba G Karwi
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada; Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, Saint John's, Newfoundland and Labrador, Canada
| | - Tariq R Altamimi
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Christina Saed
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Golam M Uddin
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Ahmed M Darwesh
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - K Lockhart Jamieson
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Ryekjang Kim
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Farah Eaton
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - John M Seubert
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Gary D Lopaschuk
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - John R Ussher
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Rami Al Batran
- Faculty of Pharmacy, Université de Montréal, Montréal, Quebec, Canada; Montreal Diabetes Research Center, Montréal, Quebec, Canada; Cardiometabolic Health, Diabetes and Obesity Research Network, Montréal, Quebec, Canada.
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12
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Yiew NKH, Vazquez JH, Martino MR, Kennon-McGill S, Price JR, Allard FD, Yee EU, Layman AJ, James LP, McCommis KS, Finck BN, McGill MR. Hepatic pyruvate and alanine metabolism are critical and complementary for maintenance of antioxidant capacity and resistance to oxidative insult. Mol Metab 2023; 77:101808. [PMID: 37716594 PMCID: PMC10561123 DOI: 10.1016/j.molmet.2023.101808] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 08/16/2023] [Accepted: 09/12/2023] [Indexed: 09/18/2023] Open
Abstract
OBJECTIVE Mitochondrial pyruvate is a critical intermediary metabolite in gluconeogenesis, lipogenesis, and NADH production. As a result, the mitochondrial pyruvate carrier (MPC) complex has emerged as a promising therapeutic target in metabolic diseases. Clinical trials are currently underway. However, recent in vitro data indicate that MPC inhibition diverts glutamine/glutamate away from glutathione synthesis and toward glutaminolysis to compensate for loss of pyruvate oxidation, possibly sensitizing cells to oxidative insult. Here, we explored this in vivo using the clinically relevant acetaminophen (APAP) overdose model of acute liver injury, which is driven by oxidative stress. METHODS We used pharmacological and genetic approaches to inhibit MPC2 and alanine aminotransferase 2 (ALT2), individually and concomitantly, in mice and cell culture models and determined the effects on APAP hepatotoxicity. RESULTS We found that MPC inhibition sensitizes the liver to APAP-induced injury in vivo only with concomitant loss of alanine aminotransferase 2 (ALT2). Pharmacological and genetic manipulation of neither MPC2 nor ALT2 alone affected APAP toxicity, but liver-specific double knockout (DKO) significantly worsened APAP-induced liver damage. Further investigation indicated that DKO impaired glutathione synthesis and increased urea cycle flux, consistent with increased glutaminolysis, and these results were reproducible in vitro. Finally, induction of ALT2 and post-treatment with dichloroacetate both reduced APAP-induced liver injury, suggesting new therapeutic avenues. CONCLUSIONS Increased susceptibility to APAP toxicity requires loss of both the MPC and ALT2 in vivo, indicating that MPC inhibition alone is insufficient to disrupt redox balance. Furthermore, the results from ALT2 induction and dichloroacetate in the APAP model suggest new metabolic approaches to the treatment of liver damage.
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Affiliation(s)
- Nicole K H Yiew
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Joel H Vazquez
- Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA; Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Michael R Martino
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Stefanie Kennon-McGill
- Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Jake R Price
- Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA; Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Felicia D Allard
- Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Eric U Yee
- Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Alexander J Layman
- Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Laura P James
- Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Kyle S McCommis
- Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Brian N Finck
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Mitchell R McGill
- Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA; Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
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13
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Ammar N, Hildebrandt M, Geismann C, Röder C, Gemoll T, Sebens S, Trauzold A, Schäfer H. Monocarboxylate Transporter-1 (MCT1)-Mediated Lactate Uptake Protects Pancreatic Adenocarcinoma Cells from Oxidative Stress during Glutamine Scarcity Thereby Promoting Resistance against Inhibitors of Glutamine Metabolism. Antioxidants (Basel) 2023; 12:1818. [PMID: 37891897 PMCID: PMC10604597 DOI: 10.3390/antiox12101818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/18/2023] [Accepted: 09/27/2023] [Indexed: 10/29/2023] Open
Abstract
Metabolic compartmentalization of stroma-rich tumors, like pancreatic ductal adenocarcinoma (PDAC), greatly contributes to malignancy. This involves cancer cells importing lactate from the microenvironment (reverse Warburg cells) through monocarboxylate transporter-1 (MCT1) along with substantial phenotype alterations. Here, we report that the reverse Warburg phenotype of PDAC cells compensated for the shortage of glutamine as an essential metabolite for redox homeostasis. Thus, oxidative stress caused by glutamine depletion led to an Nrf2-dependent induction of MCT1 expression in pancreatic T3M4 and A818-6 cells. Moreover, greater MCT1 expression was detected in glutamine-scarce regions within tumor tissues from PDAC patients. MCT1-driven lactate uptake supported the neutralization of reactive oxygen species excessively produced under glutamine shortage and the resulting drop in glutathione levels that were restored by the imported lactate. Consequently, PDAC cells showed greater survival and growth under glutamine depletion when utilizing lactate through MCT1. Likewise, the glutamine uptake inhibitor V9302 and glutaminase-1 inhibitor CB839 induced oxidative stress in PDAC cells, along with cell death and cell cycle arrest that were again compensated by MCT1 upregulation and forced lactate uptake. Our findings show a novel mechanism by which PDAC cells adapt their metabolism to glutamine scarcity and by which they develop resistance against anticancer treatments based on glutamine uptake/metabolism inhibition.
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Affiliation(s)
- Nourhane Ammar
- Institute of Experimental Cancer Research University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Bldg. U30, 24105 Kiel, Germany; (N.A.); (M.H.); (S.S.); (A.T.)
| | - Maya Hildebrandt
- Institute of Experimental Cancer Research University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Bldg. U30, 24105 Kiel, Germany; (N.A.); (M.H.); (S.S.); (A.T.)
| | - Claudia Geismann
- Department of Internal Medicine and Gastroenterology, Carl-von-Ossietzky University Oldenburg, Philosophenweg 36, 26121 Oldenburg, Germany;
| | - Christian Röder
- TriBanK, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Bldg. U30, 24105 Kiel, Germany;
| | - Timo Gemoll
- Section for Translational Surgical Oncology & Biobanking, Department of Surgery, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany;
| | - Susanne Sebens
- Institute of Experimental Cancer Research University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Bldg. U30, 24105 Kiel, Germany; (N.A.); (M.H.); (S.S.); (A.T.)
- TriBanK, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Bldg. U30, 24105 Kiel, Germany;
| | - Ania Trauzold
- Institute of Experimental Cancer Research University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Bldg. U30, 24105 Kiel, Germany; (N.A.); (M.H.); (S.S.); (A.T.)
| | - Heiner Schäfer
- Institute of Experimental Cancer Research University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Bldg. U30, 24105 Kiel, Germany; (N.A.); (M.H.); (S.S.); (A.T.)
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14
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Bullert A, Li X, Chunyun Z, Lee K, Pulliam CF, Cagle BS, Doorn JA, Klingelhutz AJ, Robertson LW, Lehmler HJ. Disposition and metabolomic effects of 2,2',5,5'-tetrachlorobiphenyl in female rats following intraperitoneal exposure. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2023; 102:104245. [PMID: 37572994 PMCID: PMC10562985 DOI: 10.1016/j.etap.2023.104245] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 08/07/2023] [Accepted: 08/09/2023] [Indexed: 08/14/2023]
Abstract
The disposition and toxicity of lower chlorinated PCBs (LC-PCBs) with less than five chlorine substituents have received little attention. This study characterizes the distribution and metabolomic effects of PCB 52, an LC-PCB found in indoor and outdoor air, three weeks after intraperitoneal exposure of female Sprague Dawley rats to 0, 1, 10, or 100 mg/kg BW. PCB 52 exposure did not affect overall body weight. Gas chromatography-tandem mass spectrometry (GC-MS/MS) analysis identified PCB 52 in all tissues investigated. Hydroxylated, sulfated, and methylated PCB metabolites, identified using GC-MS/MS and nontarget liquid chromatography-high resolution mass spectrometry (Nt-LCMS), were primarily found in the serum and liver of rats exposed to 100 mg/kg BW. Metabolomic analysis revealed minor effects on L-cysteine, glycine, cytosine, sphingosine, thymine, linoleic acid, orotic acid, L-histidine, and erythrose serum levels. Thus, the metabolism of PCB 52 and its effects on the metabolome must be considered in toxicity studies.
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Affiliation(s)
- Amanda Bullert
- Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242, USA
| | - Xueshu Li
- Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, USA
| | - Zhang Chunyun
- Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, USA
| | - Kendra Lee
- Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, USA
| | - Casey F Pulliam
- Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA
| | - Brianna S Cagle
- Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, IA 52242, USA
| | - Jonathan A Doorn
- Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA; Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, IA 52242, USA
| | - Aloysius J Klingelhutz
- Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Larry W Robertson
- Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA
| | - Hans-Joachim Lehmler
- Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA.
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15
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Ye Y, Yu B, Wang H, Yi F. Glutamine metabolic reprogramming in hepatocellular carcinoma. Front Mol Biosci 2023; 10:1242059. [PMID: 37635935 PMCID: PMC10452011 DOI: 10.3389/fmolb.2023.1242059] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 08/03/2023] [Indexed: 08/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a lethal disease with limited management strategies and poor prognosis. Metabolism alternations have been frequently unveiled in HCC, including glutamine metabolic reprogramming. The components of glutamine metabolism, such as glutamine synthetase, glutamate dehydrogenase, glutaminase, metabolites, and metabolite transporters, are validated to be potential biomarkers of HCC. Increased glutamine consumption is confirmed in HCC, which fuels proliferation by elevated glutamate dehydrogenase or upstream signals. Glutamine metabolism also serves as a nitrogen source for amino acid or nucleotide anabolism. In addition, more glutamine converts to glutathione as an antioxidant in HCC to protect HCC cells from oxidative stress. Moreover, glutamine metabolic reprogramming activates the mTORC signaling pathway to support tumor cell proliferation. Glutamine metabolism targeting therapy includes glutamine deprivation, related enzyme inhibitors, and transporters inhibitors. Together, glutamine metabolic reprogramming plays a pivotal role in HCC identification, proliferation, and progression.
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Affiliation(s)
- Yanyan Ye
- Department of Ultrasound, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Bodong Yu
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Hua Wang
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, China
| | - Fengming Yi
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, China
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16
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Bullert A, Li X, Zhang C, Lee K, Pulliam CF, Cagle BS, Doorn JA, Klingelhutz AJ, Robertson LW, Lehmler HJ. Disposition and Metabolomic Effects of 2,2',5,5'-Tetrachlorobiphenyl in Female Rats Following Intraperitoneal Exposure. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.19.544952. [PMID: 37609242 PMCID: PMC10441371 DOI: 10.1101/2023.06.19.544952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
The disposition and toxicity of lower chlorinated PCBs (LC-PCBs) with less than five chlorine substituents have received little attention. This study characterizes the distribution and metabolomic effects of PCB 52, an LC-PCB found in indoor and outdoor air, three weeks after intraperitoneal exposure of female Sprague Dawley rats to 0, 1, 10, or 100 mg/kg BW. PCB 52 exposure did not affect overall body weight. Gas chromatography-tandem mass spectrometry (GC-MS/MS) analysis identified PCB 52 in all tissues investigated. Hydroxylated, sulfated, and methylated PCB metabolites, identified using GC-MS/MS and nontarget liquid chromatography-high resolution mass spectrometry (Nt-LCMS), were primarily found in the serum and liver of rats exposed to 100 mg/kg BW. Metabolomic analysis revealed minor effects on L-cysteine, glycine, cytosine, sphingosine, thymine, linoleic acid, orotic acid, L-histidine, and erythrose serum levels. Thus, the metabolism of PCB 52 and its effects on the metabolome must be considered in toxicity studies. Highlights PCB 52 was present in adipose, brain, liver, and serum 3 weeks after PCB exposureLiver and serum contained hydroxylated, sulfated, and methylated PCB 52 metabolitesMetabolomics analysis revealed minor changes in endogenous serum metabolitesLevels of dopamine and its metabolites in the brain were not affected by PCB 52.
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Affiliation(s)
- Amanda Bullert
- Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, USA
- Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242, USA
| | - Xueshu Li
- Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, USA
| | - Chunyun Zhang
- Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, USA
| | - Kendra Lee
- Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, USA
| | - Casey F. Pulliam
- Interdisciplinary Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA
| | - Brianna S. Cagle
- Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, IA 52242, USA
| | - Jonathan A. Doorn
- Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242, USA
- Interdisciplinary Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA
- Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, IA 52242, USA
| | - Aloysius J. Klingelhutz
- Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Larry W. Robertson
- Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, USA
- Interdisciplinary Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA
| | - Hans-Joachim Lehmler
- Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, USA
- Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242, USA
- Interdisciplinary Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA
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17
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Tavoulari S, Sichrovsky M, Kunji ERS. Fifty years of the mitochondrial pyruvate carrier: New insights into its structure, function, and inhibition. Acta Physiol (Oxf) 2023; 238:e14016. [PMID: 37366179 PMCID: PMC10909473 DOI: 10.1111/apha.14016] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/12/2023] [Accepted: 06/14/2023] [Indexed: 06/28/2023]
Abstract
The mitochondrial pyruvate carrier (MPC) resides in the mitochondrial inner membrane, where it links cytosolic and mitochondrial metabolism by transporting pyruvate produced in glycolysis into the mitochondrial matrix. Due to its central metabolic role, it has been proposed as a potential drug target for diabetes, non-alcoholic fatty liver disease, neurodegeneration, and cancers relying on mitochondrial metabolism. Little is known about the structure and mechanism of MPC, as the proteins involved were only identified a decade ago and technical difficulties concerning their purification and stability have hindered progress in functional and structural analyses. The functional unit of MPC is a hetero-dimer comprising two small homologous membrane proteins, MPC1/MPC2 in humans, with the alternative complex MPC1L/MPC2 forming in the testis, but MPC proteins are found throughout the tree of life. The predicted topology of each protomer consists of an amphipathic helix followed by three transmembrane helices. An increasing number of inhibitors are being identified, expanding MPC pharmacology and providing insights into the inhibitory mechanism. Here, we provide critical insights on the composition, structure, and function of the complex and we summarize the different classes of small molecule inhibitors and their potential in therapeutics.
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Affiliation(s)
- Sotiria Tavoulari
- Medical Research Council Mitochondrial Biology UnitUniversity of CambridgeCambridgeUK
| | - Maximilian Sichrovsky
- Medical Research Council Mitochondrial Biology UnitUniversity of CambridgeCambridgeUK
| | - Edmund R. S. Kunji
- Medical Research Council Mitochondrial Biology UnitUniversity of CambridgeCambridgeUK
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18
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Findlay S, Nair R, Merrill RA, Kaiser Z, Cajelot A, Aryanpour Z, Heath J, St-Louis C, Papadopoli D, Topisirovic I, St-Pierre J, Sebag M, Kesarwala AH, Hulea L, Taylor EB, Shanmugam M, Orthwein A. The mitochondrial pyruvate carrier complex potentiates the efficacy of proteasome inhibitors in multiple myeloma. Blood Adv 2023; 7:3485-3500. [PMID: 36920785 PMCID: PMC10362273 DOI: 10.1182/bloodadvances.2022008345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 02/27/2023] [Accepted: 03/02/2023] [Indexed: 03/16/2023] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy that emerges from antibody-producing plasma B cells. Proteasome inhibitors, including the US Food and Drug Administration-approved bortezomib (BTZ) and carfilzomib (CFZ), are frequently used for the treatment of patients with MM. Nevertheless, a significant proportion of patients with MM are refractory or develop resistance to this class of inhibitors, which represents a significant challenge in the clinic. Thus, identifying factors that determine the potency of proteasome inhibitors in MM is of paramount importance to bolster their efficacy in the clinic. Using genome-wide CRISPR-based screening, we identified a subunit of the mitochondrial pyruvate carrier (MPC) complex, MPC1, as a common modulator of BTZ response in 2 distinct human MM cell lines in vitro. We noticed that CRISPR-mediated deletion or pharmacological inhibition of the MPC complex enhanced BTZ/CFZ-induced MM cell death with minimal impact on cell cycle progression. In fact, targeting the MPC complex compromised the bioenergetic capacity of MM cells, which is accompanied by reduced proteasomal activity, thereby exacerbating BTZ-induced cytotoxicity in vitro. Importantly, we observed that the RNA expression levels of several regulators of pyruvate metabolism were altered in advanced stages of MM for which they correlated with poor patient prognosis. Collectively, this study highlights the importance of the MPC complex for the survival of MM cells and their responses to proteasome inhibitors. These findings establish mitochondrial pyruvate metabolism as a potential target for the treatment of MM and an unappreciated strategy to increase the efficacy of proteasome inhibitors in the clinic.
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Affiliation(s)
- Steven Findlay
- Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, Montreal, Canada
- Division of Experimental Medicine, McGill University, Montreal, Canada
| | - Remya Nair
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Ronald A. Merrill
- Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA
| | - Zafir Kaiser
- Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, Montreal, Canada
- Department of Biochemistry, McGill University, Montreal, Canada
| | - Alexandre Cajelot
- Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, Montreal, Canada
- Polytech Nice-Sophia, Université Côte d’Azur, Sophia Antipolis, Nice, France
| | - Zahra Aryanpour
- Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, Montreal, Canada
| | - John Heath
- Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, Montreal, Canada
- Division of Experimental Medicine, McGill University, Montreal, Canada
| | - Catherine St-Louis
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada
- Ottawa Institute of Systems Biology, Ottawa, Canada
| | - David Papadopoli
- Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, Montreal, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada
| | - Ivan Topisirovic
- Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, Montreal, Canada
- Division of Experimental Medicine, McGill University, Montreal, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada
- Department of Biochemistry, McGill University, Montreal, Canada
| | - Julie St-Pierre
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada
- Ottawa Institute of Systems Biology, Ottawa, Canada
| | - Michael Sebag
- The Research Institute of the McGill University Health Center, Montreal, Canada
| | - Aparna H. Kesarwala
- Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Laura Hulea
- Maisonneuve-Rosemont Hospital Research Center, Montreal, Canada
- Département de Biochimie et médecine moléculaire, Université de Montréal, Montreal, Canada
- Département de Médecine, Université de Montréal, Montreal, Canada
| | - Eric B. Taylor
- Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA
| | - Mala Shanmugam
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Alexandre Orthwein
- Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, Montreal, Canada
- Division of Experimental Medicine, McGill University, Montreal, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada
- Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
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19
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Colca JR, Tanis SP, Kletzien RF, Finck BN. Insulin sensitizers in 2023: lessons learned and new avenues for investigation. Expert Opin Investig Drugs 2023; 32:803-811. [PMID: 37755339 DOI: 10.1080/13543784.2023.2263369] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 09/22/2023] [Indexed: 09/28/2023]
Abstract
INTRODUCTION 'Insulin sensitizers' derived discoveries of the Takeda Company in 1970s. Pioglitazone remains the best in class with beneficial pleiotropic pharmacology, although use is limited by tolerability issues. Various attempts to expand out of this class assumed the primary molecular target was the transcription factor, PPARγ. Findings over the last 10 years have identified new targets of thiazolidinediones (TZDs) that should alter the drug discovery paradigm. AREAS COVERED We review structural classes of experimental insulin sensitizer drugs, some of which have attained limited approval in some markets. The TZD pioglitazone, originally approved in 1999 as a secondary treatment for type 2 diabetes, has demonstrated benefit in apparently diverse spectrums of disease from cardiovascular to neurological issues. New TZDs modulate a newly identified mitochondrial target (the mitochondrial pyruvate carrier) to reprogram metabolism and produce insulin sensitizing pharmacology devoid of tolerability issues. EXPERT OPINION Greater understanding of the mechanism of action of insulin sensitizing drugs can expand the rationale for the fields of treatment and potential for treatment combinations. This understanding can facilitate the registration and broader use of agents with that impact the pathophysiology that underlies chronic metabolic diseases as well as host responses to environmental insults including pathogens, insulin sensitizer, MPC, mitochondrial target, metabolic reprogramming, chronic and infectious disease.
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Affiliation(s)
| | | | | | - Brian N Finck
- Department of Medicine, Center for Human Nutrition, Washington University in St Louis, Euclid Ave, MO, USA
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20
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McCommis KS, Finck BN. The Hepatic Mitochondrial Pyruvate Carrier as a Regulator of Systemic Metabolism and a Therapeutic Target for Treating Metabolic Disease. Biomolecules 2023; 13:261. [PMID: 36830630 PMCID: PMC9953669 DOI: 10.3390/biom13020261] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/26/2023] [Accepted: 01/28/2023] [Indexed: 02/03/2023] Open
Abstract
Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product of glycolysis in the cytosol, it must be transported into the mitochondrial matrix for the energy stored in this nutrient to be fully harnessed to generate ATP or to become the building block of new biomolecules. Given the requirement for mitochondrial import, it is not surprising that the mitochondrial pyruvate carrier (MPC) has emerged as a target for therapeutic intervention in a variety of diseases characterized by altered mitochondrial and intermediary metabolism. In this review, we focus on the role of the MPC and related metabolic pathways in the liver in regulating hepatic and systemic energy metabolism and summarize the current state of targeting this pathway to treat diseases of the liver. Available evidence suggests that inhibiting the MPC in hepatocytes and other cells of the liver produces a variety of beneficial effects for treating type 2 diabetes and nonalcoholic steatohepatitis. We also highlight areas where our understanding is incomplete regarding the pleiotropic effects of MPC inhibition.
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Affiliation(s)
- Kyle S. McCommis
- Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA
| | - Brian N. Finck
- Center for Human Nutrition, Washington University School of Medicine, Saint Louis, MO 63110, USA
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21
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Rauckhorst AJ, Martinez GV, Andrade GM, Wen H, Kim JY, Simoni A, Mapuskar KA, Rastogi P, Steinbach EJ, McCormick ML, Allen BG, Pabla NS, Jackson AR, Coleman MC, Spitz DR, Taylor EB, Zepeda-Orozco D. Tubular Mitochondrial Pyruvate Carrier Disruption Elicits Redox Adaptations that Protect from Acute Kidney Injury. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.31.526492. [PMID: 36778297 PMCID: PMC9915694 DOI: 10.1101/2023.01.31.526492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Energy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Tubular metabolism changes markedly following acute kidney injury (AKI), but which changes are adaptive versus maladaptive remain poorly understood. In publicly available data sets, we noticed a consistent downregulation of the mitochondrial pyruvate carrier (MPC) after AKI, which we experimentally confirmed. To test the functional consequences of MPC downregulation, we generated novel tubular epithelial cell-specific Mpc1 knockout (MPC TubKO) mice. 13C-glucose tracing, steady-state metabolomic profiling, and enzymatic activity assays revealed that MPC TubKO coordinately increased activities of the pentose phosphate pathway and the glutathione and thioredoxin oxidant defense systems. Following rhabdomyolysis-induced AKI, MPC TubKO decreased markers of kidney injury and oxidative damage and strikingly increased survival. Our findings suggest that decreased mitochondrial pyruvate uptake is a central adaptive response following AKI and raise the possibility of therapeutically modulating the MPC to attenuate AKI severity.
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Affiliation(s)
- Adam J. Rauckhorst
- Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA
- Fraternal Order of Eagles Diabetes Research Center (FOEDRC), University of Iowa, Iowa City, IA, USA
- FOEDRC Metabolomics Core Research Facility, University of Iowa, Iowa City, IA, USA
| | - Gabriela Vasquez Martinez
- Kidney and Urinary Tract Research Center, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus OH, USA
| | - Gabriel Mayoral Andrade
- Kidney and Urinary Tract Research Center, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus OH, USA
| | - Hsiang Wen
- Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA, USA
| | - Ji Young Kim
- Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Aaron Simoni
- Kidney and Urinary Tract Research Center, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus OH, USA
| | - Kranti A. Mapuskar
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
| | - Prerna Rastogi
- Department of Pathology, University of Iowa, Iowa City, IA, USA
| | - Emily J Steinbach
- Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA, USA
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
| | - Michael L. McCormick
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
| | - Bryan G. Allen
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
| | - Navjot S. Pabla
- Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Ashley R. Jackson
- Kidney and Urinary Tract Research Center, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus OH, USA
- Department of Pediatrics, The Ohio State University, Columbus, OH, USA
| | - Mitchell C. Coleman
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
- Department of Orthopedics and Rehabilitation, University of Iowa, Iowa City, IA, USA
| | - Douglas R. Spitz
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
| | - Eric B. Taylor
- Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA
- Fraternal Order of Eagles Diabetes Research Center (FOEDRC), University of Iowa, Iowa City, IA, USA
- FOEDRC Metabolomics Core Research Facility, University of Iowa, Iowa City, IA, USA
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
- Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA, USA
| | - Diana Zepeda-Orozco
- Kidney and Urinary Tract Research Center, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus OH, USA
- Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA, USA
- Department of Pediatrics, The Ohio State University, Columbus, OH, USA
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22
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Li Y, Zeng X. A novel cuproptosis-related prognostic gene signature and validation of differential expression in hepatocellular carcinoma. Front Pharmacol 2023; 13:1081952. [PMID: 36703728 PMCID: PMC9871247 DOI: 10.3389/fphar.2022.1081952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 12/28/2022] [Indexed: 01/12/2023] Open
Abstract
Background: Cuproptosis is a newly discovered form of programmed cell death, which is characterized by accumulation of intra-cellular copper ion leading to the aggregation of lipoproteins and destabilization of Fe-S cluster proteins in mitochondrial metabolism, thereby affecting the prognosis of patients with cancer. However, the role of cuproptosis-related genes (CRGs) in hepatocellular carcinoma (HCC) remains elusive. Methods: Mutation signature, copy number variation and the expression of 10 CRGs were assessed in HCC from TCGA-LIHC dataset. ICGC-LIRI-JP dataset was used as further validation cohort. The least absolute shrinkage and selection operator (LASSO) was used to construct the prognostic model. Kaplan Meier curves, time-ROC curves, nomogram, univariate and multivariate Cox regression were utilized to evaluate the predictive efficacy of CRGs-score. Immune infiltration was analyzed by CIBERSOFT, ssGSEA algorithm, and TIMER database. The expression of prognostic CRGs was validated by qPCR both in-vitro and in-vivo. Drug sensitivity analysis was performed by pRRophetic. Results: All of the CRGs were differentially expressed in HCC and 5 out of them (CDKN2A, DLAT, GLS, LIPT1, MTF1) correlated with patient survival. These signature genes were selected by LASSO analysis to establish a prognosis model to stratify HCC patients into high and low CRGs-score subgroups. High CRGs-score was associated with a worse prognosis. Subsequently, univariate and multivariate Cox regression verified that CRGs-score was an independent cancer risk factor that correlated with clinical factors including stage and grade. Nomogram integrating the CRGs-score and clinical risk factors performed well to predict patient survival. Immune infiltration analysis further revealed that the expression of immune checkpoint genes was significantly enhanced in high CRGs-score group, especially PD-1 and PD-L1. An independent validation cohort (ICGC) confirmed that CRGs-score as a stable and universally applicable indicator in predicting HCC patient survival. Concordantly, the expression of five confirmed signature genes were also differentially expressed in human HCC cell lines and mouse HCC model. In addition, we also analyzed the sensitivity of 10 clinical targeted therapies between high and low CRGs-score groups. Conclusion: This study elucidated the role of dysregulated CRGs in HCC cohort, with validation with in-vitro and in-vivo models. The CRGs-score might be applied as a novel prognostic factor in HCC.
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Affiliation(s)
- Yaoting Li
- Department of Forensic Science, Guangdong Police College, Guangzhou, Guangdong, China
| | - Xuezhen Zeng
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China,Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China,*Correspondence: Xuezhen Zeng,
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23
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Yuan Y, Song J, Wu Q. Aberrant gene expression pattern in the glycolysis-cholesterol synthesis axis is linked with immune infiltration and prognosis in prostate cancer: A bioinformatics analysis. Medicine (Baltimore) 2022; 101:e31416. [PMID: 36316896 PMCID: PMC9622640 DOI: 10.1097/md.0000000000031416] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Aberrant lipid metabolism is an early event in tumorigenesis and has been found in a variety of tumor types, especially prostate cancer (PCa). Therefore, We hypothesize that PCa can be stratified into metabolic subgroups based on glycolytic and cholesterogenic related genes, and the different subgroups are closely related to the immune microenvironment. Bioinformatics analysis of genomic, transcriptomic, and clinical data from a comprehensive cohort of PCa patients was performed. Datasets included the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) dataset, GSE70768, our previously published PCa cohort. The unsupervised cluster analysis was employed to stratify PCa samples based on the expression of metabolic-related genes. Four molecular subtypes were identified, named Glycolytic, Cholesterogenic, Mixed, and Quiescent. Each metabolic subtype has specific features. Among the 4 subtypes, the cholesterogenic subtype exhibited better median survival, whereas patients with high expression of glycolytic genes showed the shortest survival. The mitochondrial pyruvate carriers (MPC) 1 exhibited expression difference between PCa metabolic subgroups, but not for MPCs 2. Glycolytic subtypes had lower immune cell scores, while Cholesterogenic subgroups had higher immune cell scores. Our results demonstrated that metabolic classifications based on specific glycolytic and cholesterol-producing pathways provide new biological insights into previously established subtypes and may guide develop personalized therapies for unique tumor metabolism characteristics.
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Affiliation(s)
- Yiwen Yuan
- Guizhou Medical University, Guiyang, Guizhou, P.R. China
- Department of Radiology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, P.R. China
| | - Jukun Song
- Department of Oral and Maxillofacial Surgery, the Affiliated Stomatological Hospital of Guizhou Medical University, Guiyang, Guizhou, P.R. China
| | - Qinghua Wu
- Guizhou Medical University, Guiyang, Guizhou, P.R. China
- Department of Radiology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, P.R. China
- *Correspondence: Qinghua Wu, Guizhou Medical University, Guiyang, Guizhou, P.R. China (e-mail: )
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24
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Dong Q, Xiu Y, Wang Y, Hodgson C, Borcherding N, Jordan C, Buchanan J, Taylor E, Wagner B, Leidinger M, Holman C, Thiele DJ, O’Brien S, Xue HH, Zhao J, Li Q, Meyerson H, Boyce BF, Zhao C. HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia. Nat Commun 2022; 13:6107. [PMID: 36245043 PMCID: PMC9573868 DOI: 10.1038/s41467-022-33861-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 10/05/2022] [Indexed: 01/25/2023] Open
Abstract
Acute myeloid leukemia (AML) is maintained by self-renewing leukemic stem cells (LSCs). A fundamental problem in treating AML is that conventional therapy fails to eliminate LSCs, which can reinitiate leukemia. Heat shock transcription factor 1 (HSF1), a central regulator of the stress response, has emerged as an important target in cancer therapy. Using genetic Hsf1 deletion and a direct HSF1 small molecule inhibitor, we show that HSF1 is specifically required for the maintenance of AML, while sparing steady-state and stressed hematopoiesis. Mechanistically, deletion of Hsf1 dysregulates multifaceted genes involved in LSC stemness and suppresses mitochondrial oxidative phosphorylation through downregulation of succinate dehydrogenase C (SDHC), a direct HSF1 target. Forced expression of SDHC largely restores the Hsf1 ablation-induced AML developmental defect. Importantly, the growth and engraftment of human AML cells are suppressed by HSF1 inhibition. Our data provide a rationale for developing efficacious small molecules to specifically target HSF1 in AML.
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Affiliation(s)
- Qianze Dong
- grid.67105.350000 0001 2164 3847Department of Pathology, Case Western Reserve University, Cleveland, OH 44106 USA
| | - Yan Xiu
- grid.67105.350000 0001 2164 3847Department of Pathology, Case Western Reserve University, Cleveland, OH 44106 USA ,grid.410349.b0000 0004 5912 6484Department of Pathology, Louis Stokes Veterans Affairs Medical Center, Cleveland, OH 44106 USA
| | - Yang Wang
- grid.67105.350000 0001 2164 3847Department of Pathology, Case Western Reserve University, Cleveland, OH 44106 USA
| | | | - Nick Borcherding
- grid.4367.60000 0001 2355 7002Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110 USA
| | - Craig Jordan
- grid.241116.10000000107903411Division of Hematology, University of Colorado Anschutz Campus, Denver, CO 80045 USA
| | - Jane Buchanan
- grid.214572.70000 0004 1936 8294Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52240 USA
| | - Eric Taylor
- grid.214572.70000 0004 1936 8294Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52240 USA
| | - Brett Wagner
- grid.214572.70000 0004 1936 8294Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA 52242 USA
| | - Mariah Leidinger
- grid.214572.70000 0004 1936 8294Department of Pathology, University of Iowa, Iowa City, IA 52242 USA
| | - Carol Holman
- grid.214572.70000 0004 1936 8294Department of Pathology, University of Iowa, Iowa City, IA 52242 USA
| | | | | | - Hai-hui Xue
- grid.239835.60000 0004 0407 6328Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, NJ 07110 USA
| | - Jinming Zhao
- grid.67105.350000 0001 2164 3847Department of Pathology, Case Western Reserve University, Cleveland, OH 44106 USA ,grid.412449.e0000 0000 9678 1884Department of Pathology, China Medical University, 77 Puhe Rd, Shenbei Xinqu, Shenyang Shi, 110122 Liaoning Sheng China
| | - Qingchang Li
- grid.412449.e0000 0000 9678 1884Department of Pathology, China Medical University, 77 Puhe Rd, Shenbei Xinqu, Shenyang Shi, 110122 Liaoning Sheng China
| | - Howard Meyerson
- grid.443867.a0000 0000 9149 4843Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH 44106 USA
| | - Brendan F. Boyce
- grid.412750.50000 0004 1936 9166Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642 USA
| | - Chen Zhao
- grid.67105.350000 0001 2164 3847Department of Pathology, Case Western Reserve University, Cleveland, OH 44106 USA ,grid.410349.b0000 0004 5912 6484Department of Pathology, Louis Stokes Veterans Affairs Medical Center, Cleveland, OH 44106 USA ,grid.443867.a0000 0000 9149 4843Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH 44106 USA
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25
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Wei P, Bott AJ, Cluntun AA, Morgan JT, Cunningham CN, Schell JC, Ouyang Y, Ficarro SB, Marto JA, Danial NN, DeBerardinis RJ, Rutter J. Mitochondrial pyruvate supports lymphoma proliferation by fueling a glutamate pyruvate transaminase 2-dependent glutaminolysis pathway. SCIENCE ADVANCES 2022; 8:eabq0117. [PMID: 36179030 PMCID: PMC9524954 DOI: 10.1126/sciadv.abq0117] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 08/04/2022] [Indexed: 06/14/2023]
Abstract
The fate of pyruvate is a defining feature in many cell types. One major fate is mitochondrial entry via the mitochondrial pyruvate carrier (MPC). We found that diffuse large B cell lymphomas (DLBCLs) consume mitochondrial pyruvate via glutamate-pyruvate transaminase 2 to enable α-ketoglutarate production as part of glutaminolysis. This led us to discover that glutamine exceeds pyruvate as a carbon source for the tricarboxylic acid cycle in DLBCLs. As a result, MPC inhibition led to decreased glutaminolysis in DLBCLs, opposite to previous observations in other cell types. We also found that MPC inhibition or genetic depletion decreased DLBCL proliferation in an extracellular matrix (ECM)-like environment and xenografts, but not in a suspension environment. Moreover, the metabolic profile of DLBCL cells in ECM is markedly different from cells in a suspension environment. Thus, we conclude that the synergistic consumption and assimilation of glutamine and pyruvate enables DLBCL proliferation in an extracellular environment-dependent manner.
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Affiliation(s)
- Peng Wei
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Alex J. Bott
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Ahmad A. Cluntun
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Jeffrey T. Morgan
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Corey N. Cunningham
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - John C. Schell
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Yeyun Ouyang
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Scott B. Ficarro
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
- Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Jarrod A. Marto
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
- Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Nika N. Danial
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Ralph J. DeBerardinis
- Children’s Medical Center Research Institute, University of Texas (UT) Southwestern Medical Center, Dallas, TX 75390, USA
- Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jared Rutter
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
- Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
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26
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Zhang CY, Liu S, Yang M. Nutrition deprivation affects the cytotoxic effect of CD8 T cells in hepatocellular carcinoma. World J Gastrointest Oncol 2022; 14:1886-1890. [DOI: 10.4251/wjgo.v14.i9.1886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2023] Open
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27
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Zhang CY, Liu S, Yang M. Nutrition deprivation affects the cytotoxic effect of CD8 T cells in hepatocellular carcinoma. World J Gastrointest Oncol 2022; 14:1887-1891. [PMID: 36187392 PMCID: PMC9516657 DOI: 10.4251/wjgo.v14.i9.1887] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 07/28/2022] [Accepted: 08/16/2022] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the third leading cause of cancer-related death worldwide. Factors including carcinogens, infection of hepatitis viruses, alcohol abuse, and metabolic disorders such as non-alcoholic fatty liver disease mainly contribute to HCC initiation and progression. Immunotherapy is one of the most powerful tools for unresectable HCC treatment in patients. CD8+ T cells are a major immune component in the tumor microenvironment with cytotoxic effects against cancer cells. However, these CD8+ T cells commonly display an exhaustion phenotype with high expression of programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing-3, and/or lymphocyte-activation gene 3, producing low levels of perforin (PRF1) and granzyme B (GZMB), as well as anti-tumor cytokines, such as interferon gamma and tumor necrosis factor alpha. In the referenced study, the authors also showed that deprivation of glutamine decreased the antitumor function of CD8+ T cells, as well as the production of PRF1 and GZMB. However, the role of each amino acid in T cell function and exhaustion may depend on tumor type and tumor microenvironment, including the source of other nutrients. Overall, amino acids or other nutrient metabolites in the tumor microenvironment play a pivotal role in both tumor growth and immune response.
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Affiliation(s)
- Chun-Ye Zhang
- Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, United States
| | - Shuai Liu
- The First Affiliated Hospital, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65211, United States
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28
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Pravda J. Evidence-based pathogenesis and treatment of ulcerative colitis: A causal role for colonic epithelial hydrogen peroxide. World J Gastroenterol 2022; 28:4263-4298. [PMID: 36159014 PMCID: PMC9453768 DOI: 10.3748/wjg.v28.i31.4263] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 04/19/2022] [Accepted: 07/22/2022] [Indexed: 02/06/2023] Open
Abstract
In this comprehensive evidence-based analysis of ulcerative colitis (UC), a causal role is identified for colonic epithelial hydrogen peroxide (H2O2) in both the pathogenesis and relapse of this debilitating inflammatory bowel disease. Studies have shown that H2O2 production is significantly increased in the non-inflamed colonic epithelium of individuals with UC. H2O2 is a powerful neutrophilic chemotactic agent that can diffuse through colonic epithelial cell membranes creating an interstitial chemotactic molecular “trail” that attracts adjacent intravascular neutrophils into the colonic epithelium leading to mucosal inflammation and UC. A novel therapy aimed at removing the inappropriate H2O2 mediated chemotactic signal has been highly effective in achieving complete histologic resolution of colitis in patients experiencing refractory disease with at least one (biopsy-proven) histologic remission lasting 14 years to date. The evidence implies that therapeutic intervention to prevent the re-establishment of a pathologic H2O2 mediated chemotactic signaling gradient will indefinitely preclude neutrophilic migration into the colonic epithelium constituting a functional cure for this disease. Cumulative data indicate that individuals with UC have normal immune systems and current treatment guidelines calling for the suppression of the immune response based on the belief that UC is caused by an underlying immune dysfunction are not supported by the evidence and may cause serious adverse effects. It is the aim of this paper to present experimental and clinical evidence that identifies H2O2 produced by the colonic epithelium as the causal agent in the pathogenesis of UC. A detailed explanation of a novel therapeutic intervention to normalize colonic H2O2, its rationale, components, and formulation is also provided.
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Affiliation(s)
- Jay Pravda
- Disease Pathogenesis, Inflammatory Disease Research Centre, Palm Beach Gardens, FL 33410, United States
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Sun M, Hines N, Scerbo D, Buchanan J, Wu C, Ten Eyck P, Zepeda-Orozco D, Taylor EB, Jalal DI. Allopurinol Lowers Serum Urate but Does Not Reduce Oxidative Stress in CKD. Antioxidants (Basel) 2022; 11:1297. [PMID: 35883787 PMCID: PMC9312025 DOI: 10.3390/antiox11071297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/16/2022] [Accepted: 06/25/2022] [Indexed: 12/31/2022] Open
Abstract
Xanthine oxidase (XO) contributes to oxidative stress and vascular disease. Hyperuricemia and gout are common in patients with chronic kidney disease (CKD), a population at increased risk of vascular disease. We evaluated effects of allopurinol on serum XO activity and metabolome of CKD patients who had participated in a randomized double-blind clinical trial of allopurinol vs. placebo. XO activity was measured in participants' serum. XO expression in venous endothelial cells was evaluated via immunofluorescence. Gas chromatography mass spectrometry (GC/MS) was utilized for metabolomics analysis. We found that in patients with stage 3 CKD and hyperuricemia, allopurinol lowered serum urate while increasing serum xanthine levels. Allopurinol, however, did not significantly suppress measured serum XO activity. Of note, baseline serum XO activity was low. Additionally, neither baseline serum XO activity nor XO protein expression were associated with measures of vascular dysfunction or with systemic or endothelial biomarkers of oxidative stress. Allopurinol affected several pathways, including pentose phosphate, pyrimidine, and tyrosine metabolism. Our findings suggest that circulating XO does not contribute to vascular disease in CKD patients. In addition to inhibition of XO activity, allopurinol was observed to impact other pathways; the implications of which require further study.
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Affiliation(s)
- Mingyao Sun
- Department of Internal Medicine, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (M.S.); (N.H.)
| | - Nicole Hines
- Department of Internal Medicine, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (M.S.); (N.H.)
| | - Diego Scerbo
- Department of Molecular Physiology, University of Iowa, Iowa City, IA 52242, USA; (D.S.); (J.B.); (E.B.T.)
| | - Jane Buchanan
- Department of Molecular Physiology, University of Iowa, Iowa City, IA 52242, USA; (D.S.); (J.B.); (E.B.T.)
| | - Chaorong Wu
- Institute for Clinical and Translational Science, University of Iowa, Iowa City, IA 52242, USA; (C.W.); (P.T.E.)
| | - Patrick Ten Eyck
- Institute for Clinical and Translational Science, University of Iowa, Iowa City, IA 52242, USA; (C.W.); (P.T.E.)
| | - Diana Zepeda-Orozco
- Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Department of Pediatrics, Division of Nephrology and Hypertension, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Eric B. Taylor
- Department of Molecular Physiology, University of Iowa, Iowa City, IA 52242, USA; (D.S.); (J.B.); (E.B.T.)
| | - Diana I. Jalal
- Department of Internal Medicine, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (M.S.); (N.H.)
- Iowa City VA Medical Center, Iowa City, IA 52242, USA
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30
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Tavoulari S, Schirris TJJ, Mavridou V, Thangaratnarajah C, King MS, Jones DTD, Ding S, Fearnley IM, Kunji ERS. Key features of inhibitor binding to the human mitochondrial pyruvate carrier hetero-dimer. Mol Metab 2022; 60:101469. [PMID: 35278701 PMCID: PMC8968063 DOI: 10.1016/j.molmet.2022.101469] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 02/28/2022] [Accepted: 03/01/2022] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE The mitochondrial pyruvate carrier (MPC) has emerged as a promising drug target for metabolic disorders, including non-alcoholic steatohepatitis and diabetes, metabolically dependent cancers and neurodegenerative diseases. A range of structurally diverse small molecule inhibitors have been proposed, but the nature of their interaction with MPC is not understood, and the composition of the functional human MPC is still debated. The goal of this study was to characterise the human MPC protein in vitro, to understand the chemical features that determine binding of structurally diverse inhibitors and to develop novel higher affinity ones. METHODS We recombinantly expressed and purified human MPC hetero-complexes and studied their composition, transport and inhibitor binding properties by establishing in vitro transport assays, high throughput thermostability shift assays and pharmacophore modeling. RESULTS We determined that the functional unit of human MPC is a hetero-dimer. We compared all different classes of MPC inhibitors to find that three closely arranged hydrogen bond acceptors followed by an aromatic ring are shared characteristics of all inhibitors and represent the minimal requirement for high potency. We also demonstrated that high affinity binding is not attributed to covalent bond formation with MPC cysteines, as previously proposed. Following the basic pharmacophore properties, we identified 14 new inhibitors of MPC, one outperforming compound UK5099 by tenfold. Two are the commonly prescribed drugs entacapone and nitrofurantoin, suggesting an off-target mechanism associated with their adverse effects. CONCLUSIONS This work defines the composition of human MPC and the essential MPC inhibitor characteristics. In combination with the functional assays we describe, this new understanding will accelerate the development of clinically relevant MPC modulators.
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Affiliation(s)
- Sotiria Tavoulari
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, United Kingdom.
| | - Tom J J Schirris
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, United Kingdom
| | - Vasiliki Mavridou
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, United Kingdom
| | - Chancievan Thangaratnarajah
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, United Kingdom
| | - Martin S King
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, United Kingdom
| | - Daniel T D Jones
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, United Kingdom
| | - Shujing Ding
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, United Kingdom
| | - Ian M Fearnley
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, United Kingdom
| | - Edmund R S Kunji
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, United Kingdom.
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31
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Sharma S, Agnihotri N, Kumar S. Targeting fuel pocket of cancer cell metabolism: A focus on glutaminolysis. Biochem Pharmacol 2022; 198:114943. [DOI: 10.1016/j.bcp.2022.114943] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/28/2022] [Accepted: 01/31/2022] [Indexed: 12/12/2022]
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32
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Liu F, Ni B, Wei R. Senecavirus A- and Non-Infected Cells at Early Stage of Infection: Comparative Metabolomic Profiles. Front Cell Infect Microbiol 2022; 11:736506. [PMID: 35071028 PMCID: PMC8776658 DOI: 10.3389/fcimb.2021.736506] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 11/08/2021] [Indexed: 11/24/2022] Open
Abstract
Senecavirus A (SVA), classified into the genus Senecavirus in the family Picornaviridae, causes an infectious disease in pigs. This virus can efficiently replicate in some non-pig-derived cells, such as the BHK cell line and its derivative (BSR-T7/5 cell line). We had recovered a wild-type SVA from its cDNA clone previously, and then uncovered the proteomic profile of SVA-infected BSR-T7/5 cells at 12 h post inoculation (hpi). In order to explore the cellular metabolomics further, the SVA-inoculated BSR-T7/5 cell monolayer was collected at 12 hpi for assay via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The resultant data set was comprehensively analyzed using bioinformatics tools. A total of 451 metabolites were identified using in-house and public databases. Out of these metabolites, sixty-one showed significantly differential values (p value < 0.05). The Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to analyze metabolic pathways of the significantly differential metabolites. There were eighty-one identified KEGG pathways, out of which twenty-seven showed their p values < 0.05. The pyrimidine metabolism revealed the minimum p value and the maximum number of significantly differential metabolites, implying the pyrimidine played a key role in cellular metabolism after SVA infection. SVA replication must rely on the cellular metabolism. The present study on metabolomics would shed light on impacts of SVA-induced multiple interactions among metabolites on cells or even on natural hosts.
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Affiliation(s)
- Fuxiao Liu
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, China
| | - Bo Ni
- Surveillance Laboratory of Livestock Diseases, China Animal Health and Epidemiology Center, Qingdao, China
| | - Rong Wei
- Surveillance Laboratory of Livestock Diseases, China Animal Health and Epidemiology Center, Qingdao, China
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33
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Halama A, Suhre K. Advancing Cancer Treatment by Targeting Glutamine Metabolism-A Roadmap. Cancers (Basel) 2022; 14:553. [PMID: 35158820 PMCID: PMC8833671 DOI: 10.3390/cancers14030553] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/19/2022] [Accepted: 01/19/2022] [Indexed: 02/06/2023] Open
Abstract
Tumor growth and metastasis strongly depend on adapted cell metabolism. Cancer cells adjust their metabolic program to their specific energy needs and in response to an often challenging tumor microenvironment. Glutamine metabolism is one of the metabolic pathways that can be successfully targeted in cancer treatment. The dependence of many hematological and solid tumors on glutamine is associated with mitochondrial glutaminase (GLS) activity that enables channeling of glutamine into the tricarboxylic acid (TCA) cycle, generation of ATP and NADPH, and regulation of glutathione homeostasis and reactive oxygen species (ROS). Small molecules that target glutamine metabolism through inhibition of GLS therefore simultaneously limit energy availability and increase oxidative stress. However, some cancers can reprogram their metabolism to evade this metabolic trap. Therefore, the effectiveness of treatment strategies that rely solely on glutamine inhibition is limited. In this review, we discuss the metabolic and molecular pathways that are linked to dysregulated glutamine metabolism in multiple cancer types. We further summarize and review current clinical trials of glutaminolysis inhibition in cancer patients. Finally, we put into perspective strategies that deploy a combined treatment targeting glutamine metabolism along with other molecular or metabolic pathways and discuss their potential for clinical applications.
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Affiliation(s)
- Anna Halama
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Doha 24144, Qatar
| | - Karsten Suhre
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Doha 24144, Qatar
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34
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Ryuge A, Kosugi T, Maeda K, Banno R, Gou Y, Zaitsu K, Ito T, Sato Y, Hirayama A, Tsubota S, Honda T, Nakajima K, Ozaki T, Kondoh K, Takahashi K, Kato N, Ishimoto T, Soga T, Nakagawa T, Koike T, Arima H, Yuzawa Y, Minokoshi Y, Maruyama S, Kadomatsu K. Basigin deficiency prevents anaplerosis and ameliorates insulin resistance and hepatosteatosis. JCI Insight 2021; 6:142464. [PMID: 34676828 PMCID: PMC8564892 DOI: 10.1172/jci.insight.142464] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 09/09/2021] [Indexed: 12/05/2022] Open
Abstract
Monocarboxylates, such as lactate and pyruvate, are precursors for biosynthetic pathways, including those for glucose, lipids, and amino acids via the tricarboxylic acid (TCA) cycle and adjacent metabolic networks. The transportation of monocarboxylates across the cellular membrane is performed primarily by monocarboxylate transporters (MCTs), the membrane localization and stabilization of which are facilitated by the transmembrane protein basigin (BSG). Here, we demonstrate that the MCT/BSG axis sits at a crucial intersection of cellular metabolism. Abolishment of MCT1 in the plasma membrane was achieved by Bsg depletion, which led to gluconeogenesis impairment via preventing the influx of lactate and pyruvate into the cell, consequently suppressing the TCA cycle. This net anaplerosis suppression was compensated in part by the increased utilization of glycogenic amino acids (e.g., alanine and glutamine) into the TCA cycle and by activated ketogenesis through fatty acid β-oxidation. Complementary to these observations, hyperglycemia and hepatic steatosis induced by a high-fat diet were ameliorated in Bsg-deficient mice. Furthermore, Bsg deficiency significantly improved insulin resistance induced by a high-fat diet. Taken together, the plasma membrane–selective modulation of lactate and pyruvate transport through BSG inhibition could potentiate metabolic flexibility to treat metabolic diseases.
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Affiliation(s)
- Akihiro Ryuge
- Departments of Nephrology and.,Molecular Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | | | | | - Ryoichi Banno
- Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya, Japan
| | - Yang Gou
- Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya, Japan
| | - Kei Zaitsu
- Departments of Legal Medicine and Bioethics and
| | - Takanori Ito
- Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | | | - Akiyoshi Hirayama
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan
| | - Shoma Tsubota
- Molecular Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Honda
- Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kazuki Nakajima
- Center for Joint Research Facilities Support, Research Promotion and Support Headquarters, Fujita Health University School of Medicine, Toyoake, Japan
| | - Tomoya Ozaki
- Molecular Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kunio Kondoh
- Division of Endocrinology and Metabolism, National Institute for Physiological Sciences, Okazaki, Japan
| | - Kazuo Takahashi
- Department of Biomedical Molecular Sciences, Fujita Health University School of Medicine, Toyoake, Japan
| | | | | | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan
| | | | - Teruhiko Koike
- Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya, Japan
| | - Hiroshi Arima
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukio Yuzawa
- Nephrology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Yasuhiko Minokoshi
- Division of Endocrinology and Metabolism, National Institute for Physiological Sciences, Okazaki, Japan
| | | | - Kenji Kadomatsu
- Molecular Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan
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35
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Fan C, Kam S, Ramadori P. Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer. Cancers (Basel) 2021; 13:cancers13205250. [PMID: 34680398 PMCID: PMC8534280 DOI: 10.3390/cancers13205250] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/13/2021] [Accepted: 10/16/2021] [Indexed: 12/28/2022] Open
Abstract
Metabolic reprogramming and epigenetic changes have been characterized as hallmarks of liver cancer. Independently of etiology, oncogenic pathways as well as the availability of different energetic substrates critically influence cellular metabolism, and the resulting perturbations often cause aberrant epigenetic alterations, not only in cancer cells but also in the hepatic tumor microenvironment. Metabolic intermediates serve as crucial substrates for various epigenetic modulations, from post-translational modification of histones to DNA methylation. In turn, epigenetic changes can alter the expression of metabolic genes supporting on the one hand, the increased energetic demand of cancer cells and, on the other hand, influence the activity of tumor-associated immune cell populations. In this review, we will illustrate the most recent findings about metabolic reprogramming in liver cancer. We will focus on the metabolic changes characterizing the tumor microenvironment and on how these alterations impact on epigenetic mechanisms involved in the malignant progression. Furthermore, we will report our current knowledge about the influence of cancer-specific metabolites on epigenetic reprogramming of immune cells and we will highlight how this favors a tumor-permissive immune environment. Finally, we will review the current strategies to target metabolic and epigenetic pathways and their therapeutic potential in liver cancer, alone or in combinatorial approaches.
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36
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Le XH, Lee CP, Millar AH. The mitochondrial pyruvate carrier (MPC) complex mediates one of three pyruvate-supplying pathways that sustain Arabidopsis respiratory metabolism. THE PLANT CELL 2021; 33:2776-2793. [PMID: 34137858 PMCID: PMC8408480 DOI: 10.1093/plcell/koab148] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 05/19/2021] [Indexed: 05/03/2023]
Abstract
Malate oxidation by plant mitochondria enables the generation of both oxaloacetate and pyruvate for tricarboxylic acid (TCA) cycle function, potentially eliminating the need for pyruvate transport into mitochondria in plants. Here, we show that the absence of the mitochondrial pyruvate carrier 1 (MPC1) causes the co-commitment loss of its putative orthologs, MPC3/MPC4, and eliminates pyruvate transport into Arabidopsis thaliana mitochondria, proving it is essential for MPC complex function. While the loss of either MPC or mitochondrial pyruvate-generating NAD-malic enzyme (NAD-ME) did not cause vegetative phenotypes, the lack of both reduced plant growth and caused an increase in cellular pyruvate levels, indicating a block in respiratory metabolism, and elevated the levels of branched-chain amino acids at night, a sign of alterative substrate provision for respiration. 13C-pyruvate feeding of leaves lacking MPC showed metabolic homeostasis was largely maintained except for alanine and glutamate, indicating that transamination contributes to the restoration of the metabolic network to an operating equilibrium by delivering pyruvate independently of MPC into the matrix. Inhibition of alanine aminotransferases when MPC1 is absent resulted in extremely retarded phenotypes in Arabidopsis, suggesting all pyruvate-supplying enzymes work synergistically to support the TCA cycle for sustained plant growth.
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Affiliation(s)
- Xuyen H. Le
- School of Molecular Sciences, The University of Western Australia, Crawley, Perth 6009, Australia
- The ARC Centre of Excellence in Plant Energy Biology, The University of Western Australia, Crawley, Perth 6009, Australia
| | - Chun-Pong Lee
- School of Molecular Sciences, The University of Western Australia, Crawley, Perth 6009, Australia
- The ARC Centre of Excellence in Plant Energy Biology, The University of Western Australia, Crawley, Perth 6009, Australia
| | - A. Harvey Millar
- School of Molecular Sciences, The University of Western Australia, Crawley, Perth 6009, Australia
- The ARC Centre of Excellence in Plant Energy Biology, The University of Western Australia, Crawley, Perth 6009, Australia
- Author for correspondence:
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Sheldon RD, Ma EH, DeCamp LM, Williams KS, Jones RG. Interrogating in vivo T-cell metabolism in mice using stable isotope labeling metabolomics and rapid cell sorting. Nat Protoc 2021; 16:4494-4521. [PMID: 34349284 DOI: 10.1038/s41596-021-00586-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 05/31/2021] [Indexed: 11/10/2022]
Abstract
T cells are integral players in the adaptive immune system that readily adapt their metabolism to meet their energetic and biosynthetic needs. A major hurdle to understand physiologic T-cell metabolism has been the differences between in vitro cell culture conditions and the complex in vivo milieu. To address this, we have developed a protocol that merges traditional immunology infection models with whole-body metabolite infusion and mass-spectrometry-based metabolomic profiling to assess T-cell metabolism in vivo. In this protocol, pathogen-infected mice are infused via the tail vein with an isotopically labeled metabolite (2-6 h), followed by rapid magnetic bead isolation to purify T-cell populations (<1 h) and then stable isotope labeling analysis conducted by mass spectrometry (~1-2 d). This procedure enables researchers to evaluate metabolic substrate utilization into central carbon metabolic pathways (i.e., glycolysis and the tricarboxylic acid cycle) by specific T-cell subpopulations in the context of physiological immune responses in vivo.
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Affiliation(s)
- Ryan D Sheldon
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.,Metabolomics and Bioenergetics Core Facility, Van Andel Institute, Grand Rapids, MI, USA
| | - Eric H Ma
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA
| | - Lisa M DeCamp
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA
| | - Kelsey S Williams
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA
| | - Russell G Jones
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.
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Mattox TA, Psaltis C, Weihbrecht K, Robidoux J, Kilburg‐Basnyat B, Murphy MP, Gowdy KM, Anderson EJ. Prohibitin-1 Is a Dynamically Regulated Blood Protein With Cardioprotective Effects in Sepsis. J Am Heart Assoc 2021; 10:e019877. [PMID: 34219469 PMCID: PMC8483490 DOI: 10.1161/jaha.120.019877] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 05/14/2021] [Indexed: 11/25/2022]
Abstract
Background In sepsis, circulating cytokines and lipopolysaccharide elicit mitochondrial dysfunction and cardiomyopathy, a major cause of morbidity and mortality with this condition. Emerging research places the PHB1 (lipid raft protein prohibitin-1) at the nexus of inflammation, metabolism, and oxidative stress. PHB1 has also been reported in circulation, though its function in this compartment is completely unknown. Methods and Results Using a wide-ranging approach across multiple in vitro and in vivo models, we interrogated the functional role of intracellular and circulating PHB1 in the heart during sepsis, and elucidated some of the mechanisms involved. Upon endotoxin challenge or sepsis induction in rodent models, PHB1 translocates from mitochondria to nucleus in cardiomyocytes and is secreted into the circulation from the liver in a manner dependent on nuclear factor (erythroid-derived 2)-like 2, a key transcriptional regulator of the antioxidant response. Overexpression or treatment with recombinant human PHB1 enhances the antioxidant/anti-inflammatory response and protects HL-1 cardiomyocytes from mitochondrial dysfunction and toxicity from cytokine stress. Importantly, administration of recombinant human PHB1 blunted inflammation and restored cardiac contractility and ATP production in mice following lipopolysaccharide challenge. This cardioprotective, anti-inflammatory effect of recombinant human PHB1 was determined to be independent of nuclear factor (erythroid-derived 2)-like 2, but partially dependent on PI3K/AKT signaling in the heart. Conclusions These findings reveal a previously unknown cardioprotective effect of PHB1 during sepsis, and illustrate a pro-survival, protective role for PHB1 in the circulation. Exploitation of circulating PHB1 as a biomarker and/or therapeutic could have widespread benefit in the clinical management of sepsis and other severe inflammatory disorders.
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Affiliation(s)
- Taylor A. Mattox
- Department of Pharmacology & ToxicologyBrody School of MedicineEast Carolina UniversityGreenvilleNC
| | - Christine Psaltis
- Department of Pharmacology & ToxicologyBrody School of MedicineEast Carolina UniversityGreenvilleNC
| | - Katie Weihbrecht
- Fraternal Order of Eagles Diabetes Research CenterUniversity of IowaIowa CityIA
| | - Jacques Robidoux
- Department of Pharmacology & ToxicologyBrody School of MedicineEast Carolina UniversityGreenvilleNC
| | - Brita Kilburg‐Basnyat
- Department of Pharmacology & ToxicologyBrody School of MedicineEast Carolina UniversityGreenvilleNC
| | - Michael P. Murphy
- Medical Research Council Mitochondrial Biology UnitUniversity of CambridgeUnited Kingdom
| | - Kymberly M. Gowdy
- Department of Pharmacology & ToxicologyBrody School of MedicineEast Carolina UniversityGreenvilleNC
| | - Ethan J. Anderson
- Department of Pharmaceutical Sciences & Experimental TherapeuticsCollege of PharmacyIowa CityIA
- Fraternal Order of Eagles Diabetes Research CenterUniversity of IowaIowa CityIA
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You JH, Lee J, Roh JL. Mitochondrial pyruvate carrier 1 regulates ferroptosis in drug-tolerant persister head and neck cancer cells via epithelial-mesenchymal transition. Cancer Lett 2021; 507:40-54. [PMID: 33741422 DOI: 10.1016/j.canlet.2021.03.013] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 03/07/2021] [Accepted: 03/09/2021] [Indexed: 02/06/2023]
Abstract
Cancer cells evolve to survive as 'persister cells' resistant to various chemotherapeutic agents. Persister cancer cells retain mesenchymal traits that are vulnerable to ferroptosis by iron-dependent accumulation of lethal lipid peroxidation. Regulation of the KDM5A-MPC1 axis might shift cancer cells to have mesenchymal traits via epithelial-mesenchymal transition process. Therefore, we examined the therapeutic potentiality of KDM5A-MPC1 axis regulation in promoting ferroptosis in erlotinib-tolerant persister head and neck cancer cells (erPCC). ErPCC acquired mesenchymal traits and disabled antioxidant program that were more vulnerable to ferroptosis inducers of RSL3, ML210, sulfasalazine, and erastin. GPX4 and xCT suppression caused increased sensitivity to ferroptosis in vivo models of GPX4 genetic silencing. KDM5A expression increased and MPC1 expression decreased in erPCC. KDM5A inhibition increased MPC1 expression and decreased sensitivity to ferroptosis inducers in erPCC. MPC1 suppression increased vulnerability to ferroptosis in vitro and in vivo by retaining mesenchymal traits and glutaminolysis. Low expression of MPC1 was associated with low overall survival from the TCGA data. Our data suggest that regulation of the KDM5A-MPC1 axis contributes to promoting cancer ferroptosis susceptibility.
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Affiliation(s)
- Ji Hyeon You
- Department of Otorhinolaryngology-Head Neck Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Jaewang Lee
- Department of Otorhinolaryngology-Head Neck Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Jong-Lyel Roh
- Department of Otorhinolaryngology-Head Neck Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea.
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Sreekumar PG, Ferrington DA, Kannan R. Glutathione Metabolism and the Novel Role of Mitochondrial GSH in Retinal Degeneration. Antioxidants (Basel) 2021; 10:661. [PMID: 33923192 PMCID: PMC8146950 DOI: 10.3390/antiox10050661] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/18/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Glutathione (GSH) is present ubiquitously, and its role as a crucial cellular antioxidant in tissues, including the retina, is well established. GSH's antioxidant function arises from its ability to scavenge reactive oxygen species or to serve as an essential cofactor for GSH S-transferases and peroxidases. This review summarizes the general functions, retinal distribution, disorders linked to GSH deficiency, and the emerging role for mitochondrial GSH (mGSH) in retinal function. Though synthesized only in the cytosol, the presence of GSH in multiple cell organelles suggests the requirement for its active transport across organellar membranes. The localization and distribution of 2-oxoglutarate carrier (OGC) and dicarboxylate carrier (DIC), two recently characterized mitochondrial carrier proteins in RPE and retina, show that these transporters are highly expressed in human retinal pigment epithelium (RPE) cells and retinal layers, and their expression increases with RPE polarity in cultured cells. Depletion of mGSH levels via inhibition of the two transporters resulted in reduced mitochondrial bioenergetic parameters (basal respiration, ATP production, maximal respiration, and spare respiratory capacity) and increased RPE cell death. These results begin to reveal a critical role for mGSH in maintaining RPE bioenergetics and cell health. Thus, augmentation of mGSH pool under GSH-deficient conditions may be a valuable tool in treating retinal disorders, such as age-related macular degeneration and optic neuropathies, whose pathologies have been associated with mitochondrial dysfunction.
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Affiliation(s)
- Parameswaran G. Sreekumar
- The Stephen J. Ryan Initiative for Macular Research (RIMR), Doheny Eye Institute, Los Angeles, CA 90033, USA;
| | - Deborah A. Ferrington
- Department of Ophthalmology and Visual Neurosciences and Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA;
| | - Ram Kannan
- The Stephen J. Ryan Initiative for Macular Research (RIMR), Doheny Eye Institute, Los Angeles, CA 90033, USA;
- Stein Eye Institute, Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
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Longo M, Paolini E, Meroni M, Dongiovanni P. Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC. Int J Mol Sci 2021; 22:4173. [PMID: 33920670 PMCID: PMC8073183 DOI: 10.3390/ijms22084173] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third-leading cause of cancer-related mortality. Currently, the global burden of nonalcoholic fatty liver disease (NAFLD) has dramatically overcome both viral and alcohol hepatitis, thus becoming the main cause of HCC incidence. NAFLD pathogenesis is severely influenced by lifestyle and genetic predisposition. Mitochondria are highly dynamic organelles that may adapt in response to environment, genetics and epigenetics in the liver ("mitochondrial plasticity"). Mounting evidence highlights that mitochondrial dysfunction due to loss of mitochondrial flexibility may arise before overt NAFLD, and from the early stages of liver injury. Mitochondrial failure promotes not only hepatocellular damage, but also release signals (mito-DAMPs), which trigger inflammation and fibrosis, generating an adverse microenvironment in which several hepatocytes select anti-apoptotic programs and mutations that may allow survival and proliferation. Furthermore, one of the key events in malignant hepatocytes is represented by the remodeling of glucidic-lipidic metabolism combined with the reprogramming of mitochondrial functions, optimized to deal with energy demand. In sum, this review will discuss how mitochondrial defects may be translated into causative explanations of NAFLD-driven HCC, emphasizing future directions for research and for the development of potential preventive or curative strategies.
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Affiliation(s)
- Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via Francesco Sforza 35, 20122 Milano, Italy
| | - Erika Paolini
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
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Mitochondrial Pyruvate Carrier Subunits Are Essential for Pyruvate-Driven Respiration, Infectivity, and Intracellular Replication of Trypanosoma cruzi. mBio 2021; 12:mBio.00540-21. [PMID: 33824204 PMCID: PMC8092248 DOI: 10.1128/mbio.00540-21] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Trypanosoma cruzi is the causative agent of Chagas disease. Pyruvate is the end product of glycolysis, and its transport into the mitochondrion is mediated by the mitochondrial pyruvate carrier (MPC) subunits. Pyruvate is the final metabolite of glycolysis and can be converted into acetyl coenzyme A (acetyl-CoA) in mitochondria, where it is used as the substrate for the tricarboxylic acid cycle. Pyruvate availability in mitochondria depends on its active transport through the heterocomplex formed by the mitochondrial pyruvate carriers 1 and 2 (MPC1/MPC2). We report here studies on MPC1/MPC2 of Trypanosoma cruzi, the etiologic agent of Chagas disease. Endogenous tagging of T. cruziMPC1 (TcMPC1) and TcMPC2 with 3×c-Myc showed that both encoded proteins colocalize with MitoTracker to the mitochondria of epimastigotes. Individual knockout (KO) of TcMPC1 and TcMPC2 genes using CRISPR/Cas9 was confirmed by PCR and Southern blot analyses. Digitonin-permeabilized TcMPC1-KO and TcMPC2-KO epimastigotes showed reduced O2 consumption rates when pyruvate, but not succinate, was used as the mitochondrial substrate, while α-ketoglutarate increased their O2 consumption rates due to an increase in α-ketoglutarate dehydrogenase activity. Defective mitochondrial pyruvate import resulted in decreased Ca2+ uptake. The inhibitors UK5099 and malonate impaired pyruvate-driven oxygen consumption in permeabilized control cells. Inhibition of succinate dehydrogenase by malonate indicated that pyruvate needs to be converted into succinate to increase respiration. TcMPC1-KO and TcMPC2-KO epimastigotes showed little growth differences in standard or low-glucose culture medium. However, the ability of trypomastigotes to infect tissue culture cells and replicate as intracellular amastigotes was decreased in TcMPC-KOs. Overall, T. cruzi MPC1 and MPC2 are essential for cellular respiration in the presence of pyruvate, invasion of host cells, and replication of amastigotes.
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Ruiz-Iglesias A, Mañes S. The Importance of Mitochondrial Pyruvate Carrier in Cancer Cell Metabolism and Tumorigenesis. Cancers (Basel) 2021; 13:cancers13071488. [PMID: 33804985 PMCID: PMC8037430 DOI: 10.3390/cancers13071488] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/16/2021] [Accepted: 03/19/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary The characteristic metabolic hallmark of cancer cells is the massive catabolism of glucose by glycolysis, even under aerobic conditions—the so-called Warburg effect. Although energetically unfavorable, glycolysis provides “building blocks” to sustain the unlimited growth of malignant cells. Aberrant glycolysis is also responsible for lactate accumulation and acidosis in the tumor milieu, which fosters hypoxia and immunosuppression. One of the mechanisms used by cancer cells to increase glycolytic flow is the negative regulation of the proteins that conform the mitochondrial pyruvate carrier (MPC) complex, which transports pyruvate into the mitochondrial matrix to be metabolized in the tricarboxylic acid (TCA) cycle. Evidence suggests that MPC downregulation in tumor cells impacts many aspects of tumorigenesis, including cancer cell-intrinsic (proliferation, invasiveness, stemness, resistance to therapy) and -extrinsic (angiogenesis, anti-tumor immune activity) properties. In many cancers, but not in all, MPC downregulation is associated with poor survival. MPC regulation is therefore central to tackling glycolysis in tumors. Abstract Pyruvate is a key molecule in the metabolic fate of mammalian cells; it is the crossroads from where metabolism proceeds either oxidatively or ends with the production of lactic acid. Pyruvate metabolism is regulated by many enzymes that together control carbon flux. Mitochondrial pyruvate carrier (MPC) is responsible for importing pyruvate from the cytosol to the mitochondrial matrix, where it is oxidatively phosphorylated to produce adenosine triphosphate (ATP) and to generate intermediates used in multiple biosynthetic pathways. MPC activity has an important role in glucose homeostasis, and its alteration is associated with diabetes, heart failure, and neurodegeneration. In cancer, however, controversy surrounds MPC function. In some cancers, MPC upregulation appears to be associated with a poor prognosis. However, most transformed cells undergo a switch from oxidative to glycolytic metabolism, the so-called Warburg effect, which, amongst other possibilities, is induced by MPC malfunction or downregulation. Consequently, impaired MPC function might induce tumors with strong proliferative, migratory, and invasive capabilities. Moreover, glycolytic cancer cells secrete lactate, acidifying the microenvironment, which in turn induces angiogenesis, immunosuppression, and the expansion of stromal cell populations supporting tumor growth. This review examines the latest findings regarding the tumorigenic processes affected by MPC.
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Vairetti M, Di Pasqua LG, Cagna M, Richelmi P, Ferrigno A, Berardo C. Changes in Glutathione Content in Liver Diseases: An Update. Antioxidants (Basel) 2021; 10:364. [PMID: 33670839 PMCID: PMC7997318 DOI: 10.3390/antiox10030364] [Citation(s) in RCA: 136] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 02/22/2021] [Accepted: 02/24/2021] [Indexed: 02/07/2023] Open
Abstract
Glutathione (GSH), a tripeptide particularly concentrated in the liver, is the most important thiol reducing agent involved in the modulation of redox processes. It has also been demonstrated that GSH cannot be considered only as a mere free radical scavenger but that it takes part in the network governing the choice between survival, necrosis and apoptosis as well as in altering the function of signal transduction and transcription factor molecules. The purpose of the present review is to provide an overview on the molecular biology of the GSH system; therefore, GSH synthesis, metabolism and regulation will be reviewed. The multiple GSH functions will be described, as well as the importance of GSH compartmentalization into distinct subcellular pools and inter-organ transfer. Furthermore, we will highlight the close relationship existing between GSH content and the pathogenesis of liver disease, such as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), chronic cholestatic injury, ischemia/reperfusion damage, hepatitis C virus (HCV), hepatitis B virus (HBV) and hepatocellular carcinoma. Finally, the potential therapeutic benefits of GSH and GSH-related medications, will be described for each liver disorder taken into account.
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Affiliation(s)
| | - Laura Giuseppina Di Pasqua
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (M.V.); (M.C.); (P.R.); (C.B.)
| | | | | | - Andrea Ferrigno
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (M.V.); (M.C.); (P.R.); (C.B.)
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Li T, Wei Z, Kuang H. UPLC-orbitrap-MS-based metabolic profiling of HaCaT cells exposed to withanolides extracted from Datura metel.L: Insights from an untargeted metabolomics. J Pharm Biomed Anal 2021; 199:113979. [PMID: 33845385 DOI: 10.1016/j.jpba.2021.113979] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 02/12/2021] [Accepted: 02/12/2021] [Indexed: 01/25/2023]
Abstract
In recent decades, more and more attention to the withanolides extracted from Datura metel.L has been paid due to their anti-psoriatic effects. Withanolides have also been reported to exhibit anti-inflammatory and anti-proliferative properties. Thus, withanolides have been considered as a promising candidate of anti-psoriatic drug. The aim of this study was to investigated the metabolic network of HaCaT cells after exposure to withanolides to identify anti-psoriatic mechanism induced by withanolides on skin cells. In this experiment, our results demonstrated that exposure to withanolides at concentrations beyond 50 μg/mL inhibited cell proliferation and induced cell apoptosis in a dose-dependent manner. In addition, withanolides-induced reactive oxygen species (ROS) generation and mitochondrial depolarization in HaCaT cells. In this research, ultra-high performance liquid chromatography coupled with orbitrap mass spectrometry (UPLC-orbitrap-MS) method was applied to profile metabolite changes in HaCaT cells exposed to withanolides. In total, significant variations in 38 differential metabolites were identified between withanolides exposure and untreated groups. The exposure of HaCaT cells to withanolides at the dose of 200 μg/mL for 24 h was revealed by the disturbance of energy metabolism, amino acid metabolism, lipid metabolism and nucleic acid metabolism. UPLC-orbitrap-MS-based cell metabolomics provided a comprehensive method for the identification of withanolides' anti-psoriasis mechanisms in vitro. And above metabolic disorders also reflected potential therapeutic targets for treating psoriasis.
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Affiliation(s)
- Tingting Li
- Guangxi University of Science and Technology, 257 Liu-shi Road, Liuzhou, 545005, China; Heilongjiang University of Traditional Chinese Medicine, Heping Road 24, Harbin, 150040, China.
| | - Zheng Wei
- Ganzhou City People's Hospital, 18 Mei-guan Avenue, Ganzhou, 341000, China.
| | - Haixue Kuang
- Heilongjiang University of Traditional Chinese Medicine, Heping Road 24, Harbin, 150040, China.
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Sun Y, Wang X, Zhou Y, Zhang J, Cui W, Wang E, Du J, Wei B, Xu X. Protective effect of metformin on BPA-induced liver toxicity in rats through upregulation of cystathionine β synthase and cystathionine γ lyase expression. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 750:141685. [PMID: 32862004 DOI: 10.1016/j.scitotenv.2020.141685] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 08/10/2020] [Accepted: 08/11/2020] [Indexed: 06/11/2023]
Abstract
Human exposure to bisphenol A (BPA) is unavoidable in daily life. Recently, research has showen that BPA could induce oxidative imbalance, thereby causing reproductive toxicity and liver dysfunction. Accumulated evidence has demonstrated that metformin possesses strong anti-oxidative properties. This study aimed to study the mechanism underlying the hepatic-protective effect of metformin on liver injury induced by BPA in rats via the UPLC-MS/MS metabolomics approach. Forty-two male rats were randomly divided into six groups (n = 7), namely the saline group (control), the corn oil group (vehicle), the metformin group (Met), the bisphenol A group (BPA), the bisphenol A and metformin group (BPA + Met), and the bisphenol A and diammonium glycyrrhizinate (positive control) group (BPA + DG). Serum was collected for biochemical analysis and metabolomics, and liver tissue was collected for histopathology and metabolomics in each group. We found that metformin could significantly reduce the levels of liver function enzymes (ALT, AST and GGT) and ameliorate inflammatory cell infiltration and hepatocyte necrosis induced by BPA. On the other hand, metformin could significantly enhance the total antioxidant capacity in BPA rats. Notably, metabolomics data indicated that the principal altered metabolic pathways based on the 26 differential metabolites in liver tissue, and 21 in serum among vehicle, BPA and BPA + Met groups, respectively, including cysteine and methionine metabolism, glutathione metabolism, and arginine biosynthesis and purine metabolism. Additionally, metformin significantly increased cystathionine β synthase (CBS) and cystathionine γ lyase (CSE), thus reducing serum levels of homocysteine and increasing hepatic levels of cysteine and glutathione in BPA-treated rats. Overall, this study's results provided new insights into the role and mechanism of metformin in BPA-induced liver injury in rats.
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Affiliation(s)
- Yaxin Sun
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Co-innovation Center of Henan Province for New drug R & D and preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Xinying Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Co-innovation Center of Henan Province for New drug R & D and preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Yuanyuan Zhou
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Co-innovation Center of Henan Province for New drug R & D and preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Junhong Zhang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Co-innovation Center of Henan Province for New drug R & D and preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Weiqi Cui
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Co-innovation Center of Henan Province for New drug R & D and preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Enyin Wang
- Department of Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Juan Du
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Co-innovation Center of Henan Province for New drug R & D and preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, PR China.
| | - Bo Wei
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Co-innovation Center of Henan Province for New drug R & D and preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, PR China.
| | - Xia Xu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Co-innovation Center of Henan Province for New drug R & D and preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, PR China.
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Pirola CJ, Garaycoechea M, Flichman D, Castaño GO, Sookoian S. Liver mitochondrial DNA damage and genetic variability of Cytochrome b - a key component of the respirasome - drive the severity of fatty liver disease. J Intern Med 2021; 289:84-96. [PMID: 32634278 DOI: 10.1111/joim.13147] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 06/04/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS The progression of nonalcoholic fatty liver disease (NAFLD) into severe histological forms (steatohepatitis - NASH) is paralleled by the occurrence of complex molecular processes. Mitochondrial dysfunction is a hallmark feature of advanced disease. Mitochondrially encoded cytochrome B (cytochrome b, MT-CYB), a member of the oxidative phosphorylation system, is a key component of the respirasome supercomplex. Here, we hypothesized that NAFLD severity is associated with liver tissue cytochrome b mutations and damaged mitochondrial DNA (mtDNA). METHODS We included 252 liver specimens of NAFLD patients - in whom histological disease ranged from mild to severe - which were linked to clinical and biochemical information. Tissue molecular explorations included MT-CYB sequencing and analysis of differential mtDNA damage. Profiling of circulating Krebs cycle metabolites and global liver transcriptome was performed in a subsample of patients. Tissue levels of 4-hydroxynonenal - a product of lipid peroxidation and 8-hydroxy-2'-deoxyguanosine, a marker of oxidative damage - were measured. RESULTS Compared to simple steatosis, NASH is associated with a higher level of MT-CYB variance, 12.1 vs. 15.6 substitutions per 103 bp (P = 5.5e-10). The burden of variants was associated with increased levels of 2-hydroxyglutarate, branched-chain amino acids, and glutamate, and changes in the global liver transcriptome. Liver mtDNA damage was associated with advanced disease and inflammation. NAFLD severity was associated with increased tissue levels of DNA oxidative adducts and lipid peroxyl radicals. CONCLUSION NASH is associated with genetic alterations of the liver cellular respirasome, including high cytochrome b variation and mtDNA damage, which may result in broad cellular effects.
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Affiliation(s)
- C J Pirola
- From the, Institute of Medical Research A Lanari, School of Medicine, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.,Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - M Garaycoechea
- Department of Surgery, Hospital de Alta Complejidad en Red 'El Cruce', Florencio Varela, Buenos Aires, Argentina
| | - D Flichman
- Department of Virology, School of Pharmacy and Biochemistry, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - G O Castaño
- Liver Unit, Medicine and Surgery Department, Hospital Abel Zubizarreta, Ciudad Autónoma de Buenos Aires, Argentina
| | - S Sookoian
- From the, Institute of Medical Research A Lanari, School of Medicine, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.,Department of Clinical and Molecular Hepatology, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
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48
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Abstract
Metabolic pathways and redox reactions are at the core of life. In the past decade(s), numerous discoveries have shed light on how metabolic pathways determine the cellular fate and function of lymphoid and myeloid cells, giving rise to an area of research referred to as immunometabolism. Upon activation, however, immune cells not only engage specific metabolic pathways but also rearrange their oxidation-reduction (redox) system, which in turn supports metabolic reprogramming. In fact, studies addressing the redox metabolism of immune cells are an emerging field in immunology. Here, we summarize recent insights revealing the role of reactive oxygen species (ROS) and the differential requirement of the main cellular antioxidant pathways, including the components of the thioredoxin (TRX) and glutathione (GSH) pathways, as well as their transcriptional regulator NF-E2-related factor 2 (NRF2), for proliferation, survival and function of T cells, B cells and macrophages.
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Affiliation(s)
- Jonathan Muri
- Institute of Molecular Health Sciences, Department of Biology, ETH Zürich, Zürich, Switzerland.
| | - Manfred Kopf
- Institute of Molecular Health Sciences, Department of Biology, ETH Zürich, Zürich, Switzerland.
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49
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Metabolic Regulation of Epigenetic Modifications and Cell Differentiation in Cancer. Cancers (Basel) 2020; 12:cancers12123788. [PMID: 33339101 PMCID: PMC7765496 DOI: 10.3390/cancers12123788] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/07/2020] [Accepted: 12/11/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Cancer cells change their metabolism to support a chaotic and uncontrolled growth. In addition to meeting the metabolic needs of the cell, these changes in metabolism also affect the patterns of gene activation, changing the identity of cancer cells. As a consequence, cancer cells become more aggressive and more resistant to treatments. In this article, we present a review of the literature on the interactions between metabolism and cell identity, and we explore the mechanisms by which metabolic changes affect gene regulation. This is important because recent therapies under active investigation target both metabolism and gene regulation. The interactions of these new therapies with existing chemotherapies are not known and need to be investigated. Abstract Metabolic reprogramming is a hallmark of cancer, with consistent rewiring of glucose, glutamine, and mitochondrial metabolism. While these metabolic alterations are adequate to meet the metabolic needs of cell growth and proliferation, the changes in critical metabolites have also consequences for the regulation of the cell differentiation state. Cancer evolution is characterized by progression towards a poorly differentiated, stem-like phenotype, and epigenetic modulation of the chromatin structure is an important prerequisite for the maintenance of an undifferentiated state by repression of lineage-specific genes. Epigenetic modifiers depend on intermediates of cellular metabolism both as substrates and as co-factors. Therefore, the metabolic reprogramming that occurs in cancer likely plays an important role in the process of the de-differentiation characteristic of the neoplastic process. Here, we review the epigenetic consequences of metabolic reprogramming in cancer, with particular focus on the role of mitochondrial intermediates and hypoxia in the regulation of cellular de-differentiation. We also discuss therapeutic implications.
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50
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Veliova M, Ferreira CM, Benador IY, Jones AE, Mahdaviani K, Brownstein AJ, Desousa BR, Acín-Pérez R, Petcherski A, Assali EA, Stiles L, Divakaruni AS, Prentki M, Corkey BE, Liesa M, Oliveira MF, Shirihai OS. Blocking mitochondrial pyruvate import in brown adipocytes induces energy wasting via lipid cycling. EMBO Rep 2020; 21:e49634. [PMID: 33275313 PMCID: PMC7726774 DOI: 10.15252/embr.201949634] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 09/15/2020] [Accepted: 10/07/2020] [Indexed: 12/20/2022] Open
Abstract
Combined fatty acid esterification and lipolysis, termed lipid cycling, is an ATP‐consuming process that contributes to energy expenditure. Therefore, interventions that stimulate energy expenditure through lipid cycling are of great interest. Here we find that pharmacological and genetic inhibition of the mitochondrial pyruvate carrier (MPC) in brown adipocytes activates lipid cycling and energy expenditure, even in the absence of adrenergic stimulation. We show that the resulting increase in ATP demand elevates mitochondrial respiration coupled to ATP synthesis and fueled by lipid oxidation. We identify that glutamine consumption and the Malate‐Aspartate Shuttle are required for the increase in Energy Expenditure induced by MPC inhibition in Brown Adipocytes (MAShEEBA). We thus demonstrate that energy expenditure through enhanced lipid cycling can be activated in brown adipocytes by decreasing mitochondrial pyruvate availability. We present a new mechanism to increase energy expenditure and fat oxidation in brown adipocytes, which does not require adrenergic stimulation of mitochondrial uncoupling.
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Affiliation(s)
- Michaela Veliova
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.,Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Caroline M Ferreira
- Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.,Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Ilan Y Benador
- Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.,Nutrition and Metabolism, Graduate Medical Sciences, Boston University School of Medicine, Boston, MA, USA
| | - Anthony E Jones
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Kiana Mahdaviani
- Nutrition and Metabolism, Graduate Medical Sciences, Boston University School of Medicine, Boston, MA, USA
| | - Alexandra J Brownstein
- Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.,Molecular Cellular Integrative Physiology, University of California, Los Angeles, CA, USA
| | - Brandon R Desousa
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Rebeca Acín-Pérez
- Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Anton Petcherski
- Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Essam A Assali
- Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.,Department of Clinical Biochemistry, School of Medicine, Ben Gurion University of The Negev, Beer-Sheva, Israel
| | - Linsey Stiles
- Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Ajit S Divakaruni
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Marc Prentki
- Department of Nutrition, , Université de Montréal, Montreal Diabetes Research Center and CRCHUM, Montréal, QC, Canada
| | - Barbara E Corkey
- Nutrition and Metabolism, Graduate Medical Sciences, Boston University School of Medicine, Boston, MA, USA
| | - Marc Liesa
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.,Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Marcus F Oliveira
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Orian S Shirihai
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.,Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.,Nutrition and Metabolism, Graduate Medical Sciences, Boston University School of Medicine, Boston, MA, USA
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