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1
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Varghese A, Gusarov I, Gamallo-Lana B, Dolgonos D, Mankan Y, Shamovsky I, Phan M, Jones R, Gomez-Jenkins M, White E, Wang R, Jones DR, Papagiannakopoulos T, Pacold ME, Mar AC, Littman DR, Nudler E. Unravelling cysteine-deficiency-associated rapid weight loss. Nature 2025:10.1038/s41586-025-08996-y. [PMID: 40399674 DOI: 10.1038/s41586-025-08996-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 04/08/2025] [Indexed: 05/23/2025]
Abstract
Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with the incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, have been explored to combat this epidemic3-6. Here we investigated the impact of removing individual amino acids on the weight profiles of mice. We show that conditional cysteine restriction resulted in the most substantial weight loss when compared to essential amino acid restriction, amounting to 30% within 1 week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, partly explaining the phenotype7-9. Notably, we observed lower levels of tissue coenzyme A (CoA), which has been considered to be extremely stable10, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective tricarboxylic acid cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen-rich compounds and amino acids. In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism and stress signalling compared with other amino acid restrictions. These findings suggest strategies for addressing a range of metabolic diseases and the growing obesity crisis.
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Affiliation(s)
- Alan Varghese
- Department of Cell Biology, NYU Grossman School of Medicine, New York, NY, USA
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
| | - Ivan Gusarov
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
| | - Begoña Gamallo-Lana
- Department of Neuroscience and Physiology, Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, USA
| | - Daria Dolgonos
- Department of Cell Biology, NYU Grossman School of Medicine, New York, NY, USA
| | - Yatin Mankan
- Department of Cell Biology, NYU Grossman School of Medicine, New York, NY, USA
| | - Ilya Shamovsky
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
| | - Mydia Phan
- Department of Cell Biology, NYU Grossman School of Medicine, New York, NY, USA
| | - Rebecca Jones
- Division of Advanced Research Technologies, NYU Grossman School of Medicine, New York, NY, USA
| | - Maria Gomez-Jenkins
- Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ, USA
- Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ, USA
| | - Eileen White
- Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ, USA
- Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ, USA
- Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA
| | - Rui Wang
- Department of Biology, York University, Toronto, Ontario, Canada
| | - Drew R Jones
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
| | - Thales Papagiannakopoulos
- Department of Pathology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - Michael E Pacold
- Department of Radiation Oncology and Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - Adam C Mar
- Department of Neuroscience and Physiology, Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, USA
| | - Dan R Littman
- Department of Cell Biology, NYU Grossman School of Medicine, New York, NY, USA.
- Howard Hughes Medical Institute, New York, NY, USA.
| | - Evgeny Nudler
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA.
- Howard Hughes Medical Institute, New York, NY, USA.
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2
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Arif HM, Fu M, Wang R. Hydrogen Sulfide (H 2S) Metabolism, Iron Overload, and Apoptosis-Autophagy Equilibrium in Vascular Smooth Muscle Cells. Antioxidants (Basel) 2025; 14:560. [PMID: 40427442 PMCID: PMC12108171 DOI: 10.3390/antiox14050560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 05/01/2025] [Accepted: 05/06/2025] [Indexed: 05/29/2025] Open
Abstract
Iron overload contributes to proliferative vascular diseases, yet its interplay with hydrogen sulfide (H2S) in vascular smooth muscle cell (VSMC) proliferation remains poorly understood. This study elucidates H2S's role in mitigating iron-overload-induced oxidative stress and cellular damage. Using aortic VSMCs from wildtype (WT) and cystathionine γ-lyase-knockout (CSE-KO) mice treated with ferric ammonium citrate (FAC) at concentrations equivalent to serum levels of iron and citrate, we demonstrate that FAC triggers the integrated stress response (ISR) in WT cells, upregulating CSE to enhance H2S production. The ISR mediator ATF4 activates caspases but simultaneously induces CSE, which inhibits caspase activity and promotes autophagy via AMPK signaling. In CSE-KO cells, iron overload leads to diminished Ferritin upregulation, unchecked Caspase activation, and impaired autophagy compared to WT cells. Exogenous H2S restored iron homeostasis by enhancing Ferritin expression, activating NRF2 antioxidant pathways, and restoring apoptosis-autophagy equilibrium in both WT and KO cells. These findings establish H2S as a critical regulator of iron-induced VSMC dysfunction, highlighting its therapeutic potential in managing vascular pathologies linked to iron dysregulation.
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Affiliation(s)
- Hassan Mustafa Arif
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (H.M.A.); (M.F.)
| | - Ming Fu
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (H.M.A.); (M.F.)
- College of Basic Medicine, Shandong Second Medical University, Weifang 261053, China
| | - Rui Wang
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (H.M.A.); (M.F.)
- College of Basic Medicine, Shandong Second Medical University, Weifang 261053, China
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3
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Le HT, Kim Y, Kim MJ, Hyun SH, Kim H, Chung SW, Joe Y, Chung HT, Shin DM, Back SH. Phosphorylation of eIF2α suppresses the impairment of GSH/NADPH homeostasis and mitigates the activation of cell death pathways, including ferroptosis, during ER stress. Mol Cells 2025; 48:100210. [PMID: 40089158 PMCID: PMC11999272 DOI: 10.1016/j.mocell.2025.100210] [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: 10/10/2024] [Revised: 03/02/2025] [Accepted: 03/07/2025] [Indexed: 03/17/2025] Open
Abstract
eIF2α Phosphorylation helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional and translational reprogramming. This study aims to elucidate the transcriptional regulation of glutathione (GSH) and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) homeostasis through eIF2α phosphorylation and its impact on cell death during ER stress. eIF2α phosphorylation-deficient (A/A) cells exhibited decreased expression of multiple genes involved in GSH synthesis and NADPH production, leading to an exacerbated depletion of both cellular and mitochondrial GSH, as well as mitochondrial NADPH, during ER stress. Impaired GSH homeostasis resulted from deficient expression of ATF4 and/or its dependent factor, Nrf2, which are key transcription factors in the antioxidant response during ER stress. In contrast, the exacerbation of NADPH depletion may primarily be attributed to the dysregulated expression of mitochondrial serine-driven 1-carbon metabolism pathway genes, which are regulated by an unidentified eIF2α phosphorylation-dependent mechanism during ER stress. Moreover, the eIF2α phosphorylation-ATF4 axis was responsible for upregulation of ferroptosis-inhibiting genes and downregulation of ferroptosis-activating genes upon ER stress. Therefore, ER stress strongly induced ferroptosis of A/A cells, which was significantly inhibited by treatments with cell-permeable GSH and the ferroptosis inhibitor ferrostatin-1. ATF4 overexpression suppressed impairment of GSH homeostasis in A/A cells during ER stress by promoting expression of downstream target genes. Consequently, ATF4 overexpression mitigated ferroptosis as well as apoptosis of A/A cells during ER stress. Our findings underscore the importance of eIF2α phosphorylation in maintaining GSH/NADPH homeostasis and inhibiting ferroptosis through ATF4 and unidentified eIF2α phosphorylation-dependent target(s)-mediated transcriptional reprogramming during ER stress.
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Affiliation(s)
- Hien Thi Le
- School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea
| | - Yonghwan Kim
- Department of Cell and Genetic Engineering, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Mi-Jeong Kim
- School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea
| | - Seung Hwa Hyun
- School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea
| | - Hyeeun Kim
- School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea
| | - Su Wol Chung
- School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea
| | - Yeonsoo Joe
- College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Korea
| | - Hun Taeg Chung
- College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Korea
| | - Dong-Myung Shin
- Department of Cell and Genetic Engineering, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Sung Hoon Back
- School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea; Basic-Clinical Convergence Research Center, University of Ulsan, Ulsan 44610, Korea.
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4
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Kelley LP, Hu SH, Boswell SA, Sorger PK, Ringel AE, Haigis MC. Integrated analysis of transcriptional and metabolic responses to mitochondrial stress. CELL REPORTS METHODS 2025; 5:101027. [PMID: 40233762 DOI: 10.1016/j.crmeth.2025.101027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/11/2024] [Accepted: 03/20/2025] [Indexed: 04/17/2025]
Abstract
Mitochondrial stress arises from a variety of sources, including mutations to mitochondrial DNA, the generation of reactive oxygen species, and an insufficient supply of oxygen or fuel. Mitochondrial stress induces a range of dedicated responses that repair damage and restore mitochondrial health. However, a systematic characterization of transcriptional and metabolic signatures induced by distinct types of mitochondrial stress is lacking. Here, we defined how primary human fibroblasts respond to a panel of mitochondrial inhibitors to trigger adaptive stress responses. Using metabolomic and transcriptomic analyses, we established integrated signatures of mitochondrial stress. We developed a tool, stress quantification using integrated datasets (SQUID), to deconvolute mitochondrial stress signatures from existing datasets. Using SQUID, we profiled mitochondrial stress in The Cancer Genome Atlas (TCGA) PanCancer Atlas, identifying a signature of pyruvate import deficiency in IDH1-mutant glioma. Thus, this study defines a tool to identify specific mitochondrial stress signatures, which may be applied to a range of systems.
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Affiliation(s)
- Liam P Kelley
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Song-Hua Hu
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Sarah A Boswell
- Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA 02115, USA; Ginkgo Bioworks, Inc., Boston, MA 02210, USA
| | - Peter K Sorger
- Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA 02115, USA
| | - Alison E Ringel
- Biology Department, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA 02139, USA.
| | - Marcia C Haigis
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
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5
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Hao B, Liu Y, Wang B, Wu H, Chen Y, Zhang L. Hepatitis B surface antigen: carcinogenesis mechanisms and clinical implications in hepatocellular carcinoma. Exp Hematol Oncol 2025; 14:44. [PMID: 40141002 PMCID: PMC11938626 DOI: 10.1186/s40164-025-00642-7] [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: 02/25/2025] [Accepted: 03/11/2025] [Indexed: 03/28/2025] Open
Abstract
Liver cancer is the third leading cause of death globally, with hepatitis B virus (HBV) infection being identified as the primary risk factor for its development. The occurrence of HBV-related hepatocellular carcinoma (HCC) is attributed to various mechanisms, such as chronic inflammation and liver cell regeneration induced by the cytotoxic immune response triggered by the virus, abnormal activation of oncogenes arising from HBV DNA insertion mutations, and epigenetic alterations mediated by viral oncoproteins. The envelope protein of the HBV virus, known as hepatitis B surface antigen (HBsAg), is a key indicator of increased risk for developing HCC in HBsAg-positive individuals. The HBsAg seroclearance status is found to be associated with recurrence in HCC patients undergoing hepatectomy. Additional evidence indicates that HBsAg is essential to the entire process of tumor development, from initiation to advancement, and acts as an oncoprotein involved in accelerating tumor progression. This review comprehensively analyzes the extensive effects and internal mechanisms of HBsAg during the various stages of the initiation and progression of HCC. Furthermore, it highlights the importance and potential applications of HBsAg in the realms of HCC early diagnosis and personalized therapeutic interventions. An in-depth understanding of the molecular mechanism of HBsAg in the occurrence and development of HCC is provided, which is expected to develop more precise and efficient strategies for the prevention and management of HCC in the future.
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Affiliation(s)
- Bingyan Hao
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yachong Liu
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Bohan Wang
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Haofeng Wu
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yan Chen
- Department of Paediatrics, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Lei Zhang
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Tongji Hospital, Tongji Medical College, Shanxi Medical University, Huazhong University of Science and Technology, Taiyuan, 030032, China.
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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6
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Sanfrancesco VC, Hood DA. Acute contractile activity induces the activation of the mitochondrial integrated stress response and the transcription factor ATF4. J Appl Physiol (1985) 2025; 138:857-871. [PMID: 39417830 DOI: 10.1152/japplphysiol.00307.2024] [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: 04/24/2024] [Revised: 09/18/2024] [Accepted: 10/09/2024] [Indexed: 10/19/2024] Open
Abstract
Skeletal muscle relies on mitochondria to produce energy and support its metabolic flexibility. The function of the mitochondrial pool is regulated by quality control (MQC) processes. The integrated stress response (ISR), a MQC pathway, is activated in response to various cellular stressors. The transcription factor ATF4, the main effector of the ISR, ameliorates cellular stress by upregulating protective genes, such as CHOP and ATF5. Recent literature has shown that the ISR is activated upon mitochondrial stress; however, whether this includes acute exercise-induced stress is poorly defined. To investigate this, a mouse in situ hindlimb protocol was utilized to acutely stimulate muscles at 0.25, 0.5, and 1 tetanic contraction/s for 9 min, followed by a 1-h recovery period. CAMKIIα and JNK2 were robustly activated sixfold immediately after the protocol. ISR activation, denoted as the ratio of phosphorylated to total eIF2α protein levels, was also elevated after recovery. Downstream, contractile activity induced an increase in the nuclear localization of ATF4. Robust twofold increases in the mRNA expression of ATF4 and CHOP were also observed after the recovery period. Changes in ATF4 mRNA were independent of transcriptional activation, as assessed with an ATF4 promoter-reporter plasmid. Instead, mRNA decay assays revealed an increase in ATF4 mRNA stability post contractile activity, as a result of enhanced stabilization by the RNA binding protein HuR. Thus, acute contractile activity is sufficient to induce mitochondrial stress and activate the ISR, corresponding to the induction of ATF4 with potential consequences for mitochondrial phenotype adaptations in response to repeated exercise.NEW & NOTEWORTHY The integrated stress response (ISR) is a mitohormetic stress response critical for the maintenance of mitochondrial homeostasis. However, its role in mediating mitochondrial adaptations with exercise-induced stress is not well established. This research demonstrates that acute contractile activity can elicit mitochondrial stress and activate the ISR to maintain mitochondrial homeostasis via the enhancement of the functioning of ATF4, illustrating an early response to exercise that promotes mitochondrial health and adaptations.
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Affiliation(s)
- Victoria C Sanfrancesco
- Muscle Health Research Centre, School of Kinesiology and Health ScienceYork University, Toronto, Ontario, Canada
| | - David A Hood
- Muscle Health Research Centre, School of Kinesiology and Health ScienceYork University, Toronto, Ontario, Canada
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7
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Chanoine JP, Thompson DM, Lehman A. Diabetes Associated With Maternally Inherited Diabetes and Deafness (MIDD): From Pathogenic Variant to Phenotype. Diabetes 2025; 74:153-163. [PMID: 39556456 PMCID: PMC11755681 DOI: 10.2337/db24-0515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 11/13/2024] [Indexed: 11/20/2024]
Abstract
ARTICLE HIGHLIGHTS Maternally inherited diabetes and deafness (MIDD) is a mitochondrial disorder characterized primarily by hearing impairment and diabetes. m.3243A>G, the most common phenotypic variant, causes a complex rewiring of the cell with discontinuous remodeling of both mitochondrial and nuclear genome expressions. We propose that MIDD depends on a combination of insulin resistance and impaired β-cell function that occurs in the presence of high skeletal muscle heteroplasmy (approximately ≥60%) and more moderate cell heteroplasmy (∼25%-72%) for m.3243A>G. Understanding the complex mechanisms of MIDD is necessary to develop disease-specific management guidelines that are presently lacking.
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Affiliation(s)
- Jean-Pierre Chanoine
- Endocrinology and Diabetes Unit, Department of Pediatrics, BC Children’s Hospital and The University of British Columbia, Vancouver, British Columbia, Canada
| | - David M. Thompson
- Division of Endocrinology, Department of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Anna Lehman
- Department of Medical Genetics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
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8
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Le HT, Yu J, Ahn HS, Kim MJ, Chae IG, Cho HN, Kim J, Park HK, Kwon HN, Chae HJ, Kang BH, Seo JK, Kim K, Back SH. eIF2α phosphorylation-ATF4 axis-mediated transcriptional reprogramming mitigates mitochondrial impairment during ER stress. Mol Cells 2025; 48:100176. [PMID: 39756584 PMCID: PMC11786836 DOI: 10.1016/j.mocell.2024.100176] [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: 10/03/2024] [Revised: 12/24/2024] [Accepted: 12/28/2024] [Indexed: 01/07/2025] Open
Abstract
Eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, which regulates all 3 unfolded protein response pathways, helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional and translational reprogramming. However, transcriptional regulation of mitochondrial homeostasis by eIF2α phosphorylation during ER stress is not fully understood. Here, we report that the eIF2α phosphorylation-activating transcription factor 4 (ATF4) axis is required for the expression of multiple transcription factors, including nuclear factor erythroid 2-related factor 2 and its target genes responsible for mitochondrial homeostasis during ER stress. eIF2α phosphorylation-deficient (A/A) cells displayed dysregulated mitochondrial dynamics and mitochondrial DNA replication, decreased expression of oxidative phosphorylation complex proteins, and impaired mitochondrial functions during ER stress. ATF4 overexpression suppressed impairment of mitochondrial homeostasis in A/A cells during ER stress by promoting the expression of downstream transcription factors and their target genes. Our findings underscore the importance of the eIF2α phosphorylation-ATF4 axis for maintaining mitochondrial homeostasis through transcriptional reprogramming during ER stress.
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Affiliation(s)
- Hien Thi Le
- School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea
| | - Jiyoung Yu
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea
| | - Hee Sung Ahn
- AMC Sciences, Asan Medical Center, Seoul 05505, Korea
| | - Mi-Jeong Kim
- School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea
| | - In Gyeong Chae
- School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea
| | - Hyun-Nam Cho
- School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea
| | - Juhee Kim
- School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea
| | - Hye-Kyung Park
- Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea
| | - Hyuk Nam Kwon
- School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea
| | - Han-Jung Chae
- School of Pharmacy, Jeonbuk National University, Jeonju 54896, Korea
| | - Byoung Heon Kang
- Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea
| | - Jeong Kon Seo
- Central Research Facilities (UCRF), Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea.
| | - Kyunggon Kim
- Department of Digital Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
| | - Sung Hoon Back
- Basic-Clinical Convergence Research Center, School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea.
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9
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Zhang W, Cao X. Unfolded protein responses in T cell immunity. Front Immunol 2025; 15:1515715. [PMID: 39845962 PMCID: PMC11750696 DOI: 10.3389/fimmu.2024.1515715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 12/19/2024] [Indexed: 01/24/2025] Open
Abstract
Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are integral to T cell biology, influencing immune responses and associated diseases. This review explores the interplay between the UPR and T cell immunity, highlighting the role of these cellular processes in T cell activation, differentiation, and function. The UPR, mediated by IRE1, PERK, and ATF6, is crucial for maintaining ER homeostasis and supporting T cell survival under stress. However, the precise mechanisms by which ER stress and the UPR regulate T cell-mediated immunity remain incompletely understood. Emerging evidence suggests that the UPR may be a potential therapeutic target for diseases characterized by T cell dysfunction, such as autoimmune disorders and cancer. Further research is needed to elucidate the complex interactions between ER stress, the UPR, and T cell immunity to develop novel therapeutic strategies for T cell-associated diseases.
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Affiliation(s)
- Wencan Zhang
- Shanghai Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China
| | - Xu Cao
- Shanghai Frontiers Science Center for Drug Target Identification and Delivery, and the Engineering Research Center of Cell and Therapeutic Antibody of the Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China
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10
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Hinton A, Neikirk K, Le H, Harris C, Oliver A, Martin P, Gaye A. Estrogen receptors in mitochondrial metabolism: age-related changes and implications for pregnancy complications. AGING ADVANCES 2024; 1:154-171. [PMID: 39839811 PMCID: PMC11748122 DOI: 10.4103/agingadv.agingadv-d-24-00012] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 11/24/2024] [Indexed: 01/23/2025]
Abstract
Estrogen hormones are primarily associated with their role as female sex hormones responsible for primary and secondary sexual development. Estrogen receptors are known to undergo age-dependent decreases due to age-related changes in hormone production. In the mitochondria, estrogen functions by reducing the production of reactive oxygen species in the electron transport chain, inhibiting apoptosis, and regulating mitochondrial DNA content. Moreover, estrogen receptors may be the key components in maintaining mitochondrial membrane potential and structure. Although estrogen plays a crucial role in the development of pregnancy, our understanding of how estrogen receptors change with aging during pregnancy remains limited. During pregnancy, estrogen levels are significantly elevated, with a corresponding upregulation of estrogen receptors, which play various roles in pregnancy. However, the exact role of estrogen receptors in pregnancy complications remains to be further investigated. The paper reviews the role of estrogen receptors in the regulation of mitochondrial metabolism and in pregnancy complications, with a special focus on the effect of age-related changes on estrogen levels and estrogen receptors function. We also address how estrogen maintains mitochondrial function, including reducing the production of reactive oxygen species in the electron transport chain, inhibiting apoptosis, regulating mitochondrial DNA content, and maintaining mitochondrial membrane potential and structure. However, the effects of estrogen on mitochondria-endoplasmic reticulum contacts have not been well studied. Based on these emergent roles in mitochondria, the differential roles of estrogen receptors in pregnancy complications are of great relevance. The paper emphasizes the association between maternal health and estrogen receptors and indicates the need for future research to elucidate the interdependence of estrogen receptor-regulated maternal health with mitochondrial function and their relationship with the gut microbiome. Overall, we summarize the important role of estrogen receptors during pregnancy and highlight the need for further research to better understand the role of estrogen receptors in aging and pregnancy complications. This not only helps to reveal the mechanism underlying the role of estrogen in maternal health but also has potential clinical implications for the development of new therapies targeting age-related diseases and pregnancy complications.
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Affiliation(s)
- Antentor Hinton
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Kit Neikirk
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Han Le
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Chanel Harris
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA
- Department of Biomedical Sciences, Meharry Medical College, Nashville, TN, USA
| | - Ashton Oliver
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA
- Department of Biomedical Sciences, Meharry Medical College, Nashville, TN, USA
| | - Pamela Martin
- Department of Biomedical Sciences, Meharry Medical College, Nashville, TN, USA
| | - Amadou Gaye
- Department of Integrative Genomics and Epidemiology, Meharry Medical College, Nashville, TN, USA
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11
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Yang Z, Wang J, Zhao T, Wang L, Liang T, Zheng Y. Mitochondrial structure and function: A new direction for the targeted treatment of chronic liver disease with Chinese herbal medicine. JOURNAL OF ETHNOPHARMACOLOGY 2024; 334:118461. [PMID: 38908494 DOI: 10.1016/j.jep.2024.118461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/10/2024] [Accepted: 06/13/2024] [Indexed: 06/24/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Excessive fat accumulation, biological clock dysregulation, viral infections, and sustained inflammatory responses can lead to liver inflammation, fibrosis, and cancer, thus promoting the development of chronic liver disease. A comprehensive understanding of the etiological factors leading to chronic liver disease and the intrinsic mechanisms influencing its onset and progression can aid in identifying potential targets for targeted therapy. Mitochondria, as key organelles that maintain the metabolic homeostasis of the liver, provide an important foundation for exploring therapeutic targets for chronic liver disease. Recent studies have shown that active ingredients in herbal medicines and their natural products can modulate chronic liver disease by influencing the structure and function of mitochondria. Therefore, studying how Chinese herbs target mitochondrial structure and function to treat chronic liver diseases is of great significance. AIM OF THE STUDY Investigating the prospects of herbal medicine the Lens of chronic liver disease based on mitochondrial structure and function. MATERIALS AND METHODS A computerized search of PubMed was conducted using the keywords "mitochondrial structure", "mitochondrial function", "mitochondria and chronic liver disease", "botanicals, mitochondria and chronic liver disease".Data from the Web of Science and Science Direct databases were also included. The research findings regarding herbal medicines targeting mitochondrial structure and function for the treatment of chronic liver disease are summarized. RESULTS A computerized search of PubMed using the keywords "mitochondrial structure", "mitochondrial function", "mitochondria and chronic liver disease", "phytopharmaceuticals, mitochondria, and chronic liver disease", as well as the Web of Science and Science Direct databases was conducted to summarize information on studies of mitochondrial structure- and function-based Chinese herbal medicines for the treatment of chronic liver disease and to suggest that the effects of herbal medicines on mitochondrial division and fusion.The study suggested that there is much room for research on the influence of Chinese herbs on mitochondrial division and fusion. CONCLUSIONS Targeting mitochondrial structure and function is crucial for herbal medicine to combat chronic liver disease.
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Affiliation(s)
- Zhihui Yang
- Department of Medicine, Faculty of Chinese Medicine Science Guangxi University of Chinese Medicine, Nanning, Guangxi, 530222, China
| | - Jiahui Wang
- Department of Medicine, Faculty of Chinese Medicine Science Guangxi University of Chinese Medicine, Nanning, Guangxi, 530222, China
| | - Tiejian Zhao
- Department of Medicine, Faculty of Chinese Medicine Science Guangxi University of Chinese Medicine, Nanning, Guangxi, 530222, China
| | - Lei Wang
- Department of Medicine, Faculty of Chinese Medicine Science Guangxi University of Chinese Medicine, Nanning, Guangxi, 530222, China
| | - Tianjian Liang
- Department of Medicine, Faculty of Chinese Medicine Science Guangxi University of Chinese Medicine, Nanning, Guangxi, 530222, China.
| | - Yang Zheng
- Department of Medicine, Faculty of Chinese Medicine Science Guangxi University of Chinese Medicine, Nanning, Guangxi, 530222, China.
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12
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Varghese A, Gusarov I, Gamallo-Lana B, Dolgonos D, Mankan Y, Shamovsky I, Phan M, Jones R, Gomez-Jenkins M, White E, Wang R, Jones D, Papagiannakopoulos T, Pacold ME, Mar AC, Littman DR, Nudler E. Unraveling cysteine deficiency-associated rapid weight loss. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.30.605703. [PMID: 39131293 PMCID: PMC11312522 DOI: 10.1101/2024.07.30.605703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
Forty percent of the US population and 1 in 6 individuals worldwide are obese, and the incidence of this disease is surging globally1,2. Various dietary interventions, including carbohydrate and fat restriction, and more recently amino acid restriction, have been explored to combat this epidemic3-6. We sought to investigate the impact of removing individual amino acids on the weight profiles of mice. Compared to essential amino acid restriction, induction of conditional cysteine restriction resulted in the most dramatic weight loss, amounting to 20% within 3 days and 30% within one week, which was readily reversed. This weight loss occurred despite the presence of substantial cysteine reserves stored in glutathione (GSH) across various tissues7. Further analysis demonstrated that the weight reduction primarily stemmed from an increase in the utilization of fat mass, while locomotion, circadian rhythm and histological appearance of multiple other tissues remained largely unaffected. Cysteine deficiency activated the integrated stress response (ISR) and NRF2-mediated oxidative stress response (OSR), which amplify each other, leading to the induction of GDF15 and FGF21, hormones associated with increased lipolysis, energy homeostasis and food aversion8-10. We additionally observed rapid tissue coenzyme A (CoA) depletion, resulting in energetically inefficient anaerobic glycolysis and TCA cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen rich compounds and amino acids. In summary, our investigation highlights that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism, and stress signaling compared to other amino acid restrictions. These findings may pave the way for innovative strategies for addressing a range of metabolic diseases and the growing obesity crisis.
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Affiliation(s)
- Alan Varghese
- Department of Cell Biology, NYU Grossman School of Medicine, New York, NY 10016, USA
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Ivan Gusarov
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Begoña Gamallo-Lana
- Department of Neuroscience and Physiology, Neuroscience Institute, NYU School of Medicine, New York, NY 10016, USA
| | - Daria Dolgonos
- Department of Cell Biology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Yatin Mankan
- Department of Cell Biology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Ilya Shamovsky
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Mydia Phan
- Department of Cell Biology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Rebecca Jones
- Division of Advanced Research Technologies, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Maria Gomez-Jenkins
- Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08901, USA and Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, USA
| | - Eileen White
- Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08901, USA and Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, USA
- Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544, USA
| | - Rui Wang
- Department of Biology, York University, Toronto, Ontario, M3J 1P3, Canada
| | - Drew Jones
- Division of Advanced Research Technologies, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Thales Papagiannakopoulos
- Department of Pathology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA
| | - Michael E Pacold
- Department of Radiation Oncology and Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, New York, NY 10016, USA
| | - Adam C Mar
- Department of Neuroscience and Physiology, Neuroscience Institute, NYU School of Medicine, New York, NY 10016, USA
| | - Dan R Littman
- Department of Cell Biology, NYU Grossman School of Medicine, New York, NY 10016, USA
- Howard Hughes Medical Institute, New York, NY 10016, USA
| | - Evgeny Nudler
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
- Howard Hughes Medical Institute, New York, NY 10016, USA
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13
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Aranda-Abreu GE, Rojas-Durán F, Hernández-Aguilar ME, Herrera-Covarrubias D, Chí-Castañeda LD, Toledo-Cárdenas MR, Suárez-Medellín JM. Alzheimer's Disease: Cellular and Pharmacological Aspects. Geriatrics (Basel) 2024; 9:86. [PMID: 39051250 PMCID: PMC11270425 DOI: 10.3390/geriatrics9040086] [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: 04/30/2024] [Revised: 05/23/2024] [Accepted: 06/21/2024] [Indexed: 07/27/2024] Open
Abstract
Alzheimer's disease was described more than 100 years ago and despite the fact that several molecules are being tested for its treatment, which are in phase III trials, the disease continues to progress. The main problem is that these molecules function properly in healthy neurons, while neuronal pathology includes plasma membrane disruption, malfunction of various organelles, and hyperphosphorylation of Tau and amyloid plaques. The main objective of this article is the discussion of a neuronal restoration therapy, where molecules designed for the treatment of Alzheimer's disease would probably be more effective, and the quality of life of people would be better.
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Affiliation(s)
- Gonzalo Emiliano Aranda-Abreu
- Instituto de Investigaciones Cerebrales, Universidad Veracruzana, Xalapa 91192, Mexico; (F.R.-D.); (M.E.H.-A.); (D.H.-C.); (L.D.C.-C.); (M.R.T.-C.); (J.M.S.-M.)
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14
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Shrestha P, Ghanwatkar Y, Mahto S, Pramanik N, Mahato RI. Gemcitabine-Lipid Conjugate and ONC201 Combination Therapy Effectively Treats Orthotopic Pancreatic Tumor-Bearing Mice. ACS APPLIED MATERIALS & INTERFACES 2024; 16:29686-29698. [PMID: 38813771 PMCID: PMC11600442 DOI: 10.1021/acsami.4c02626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2024]
Abstract
Gemcitabine (GEM) is a nucleoside analogue approved as a first line of therapy for pancreatic ductal adenocarcinoma (PDAC). However, rapid metabolism by plasma cytidine deaminase leading to the short half-life, intricate intracellular metabolism, ineffective cell uptake, and swift development of chemoresistance downgrades the clinical efficacy of GEM. ONC201 is a small molecule that inhibits the Akt and ERK pathways and upregulates the TNF-related apoptosis-inducing ligand (TRAIL), which leads to the reversal of both intrinsic and acquired GEM resistance in PDAC treatment. Moreover, the pancreatic cancer cells that were able to bypass apoptosis after treatment of ONC201 get arrested in the G1-phase, which makes them highly sensitive to GEM. To enhance the in vivo stability of GEM, we first synthesized a disulfide bond containing stearate conjugated GEM (lipid-GEM), which makes it sensitive to the redox tumor microenvironment (TME) comprising high glutathione levels. In addition, with the help of colipids 1,2-dioleoyl-glycero-3-phosphocholine (DOPC), cholesterol, and 1,2-distearoyl-glycero-3-phosphoethanolamine-poly(ethylene glycol)-2000 (DSPE-PEG 2000), we were able to synthesize the lipid-GEM conjugate and ONC201 releasing liposomes. A cumulative drug release study confirmed that both ONC201 and GEM showed sustained release from the formulation. Since MUC1 is highly expressed in 70-90% PDAC, we conjugated a MUC1 binding peptide in the liposomes which showed higher cytotoxicity, apoptosis, and cellular internalization by MIA PaCa-2 cells. A biodistribution study further confirmed that the systemic delivery of the liposomes through the tail vein resulted in a higher accumulation of drugs in orthotopic PDAC tumors in NSG mice. The IHC of the excised tumor grafts further confirmed the higher apoptosis and lower metastasis and cell proliferation. Thus, our MUC1 targeting binary drug-releasing liposomal formulation showed higher drug payload, enhanced plasma stability, and accumulation of drugs in the pancreatic orthotopic tumor and thus is a promising therapeutic alternative for the treatment of PDAC.
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Affiliation(s)
- Prakash Shrestha
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Yashwardhan Ghanwatkar
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Sohan Mahto
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Nilkamal Pramanik
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
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15
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Lu HJ, Koju N, Sheng R. Mammalian integrated stress responses in stressed organelles and their functions. Acta Pharmacol Sin 2024; 45:1095-1114. [PMID: 38267546 PMCID: PMC11130345 DOI: 10.1038/s41401-023-01225-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 12/30/2023] [Indexed: 01/26/2024]
Abstract
The integrated stress response (ISR) triggered in response to various cellular stress enables mammalian cells to effectively cope with diverse stressful conditions while maintaining their normal functions. Four kinases (PERK, PKR, GCN2, and HRI) of ISR regulate ISR signaling and intracellular protein translation via mediating the phosphorylation of eukaryotic translation initiation factor 2 α (eIF2α) at Ser51. Early ISR creates an opportunity for cells to repair themselves and restore homeostasis. This effect, however, is reversed in the late stages of ISR. Currently, some studies have shown the non-negligible impact of ISR on diseases such as ischemic diseases, cognitive impairment, metabolic syndrome, cancer, vanishing white matter, etc. Hence, artificial regulation of ISR and its signaling with ISR modulators becomes a promising therapeutic strategy for relieving disease symptoms and improving clinical outcomes. Here, we provide an overview of the essential mechanisms of ISR and describe the ISR-related pathways in organelles including mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes. Meanwhile, the regulatory effects of ISR modulators and their potential application in various diseases are also enumerated.
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Affiliation(s)
- Hao-Jun Lu
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences of Soochow University, Suzhou, 215123, China
| | - Nirmala Koju
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences of Soochow University, Suzhou, 215123, China
| | - Rui Sheng
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences of Soochow University, Suzhou, 215123, China.
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16
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Corne A, Adolphe F, Estaquier J, Gaumer S, Corsi JM. ATF4 Signaling in HIV-1 Infection: Viral Subversion of a Stress Response Transcription Factor. BIOLOGY 2024; 13:146. [PMID: 38534416 PMCID: PMC10968437 DOI: 10.3390/biology13030146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 02/13/2024] [Accepted: 02/20/2024] [Indexed: 03/28/2024]
Abstract
Cellular integrated stress response (ISR), the mitochondrial unfolded protein response (UPRmt), and IFN signaling are associated with viral infections. Activating transcription factor 4 (ATF4) plays a pivotal role in these pathways and controls the expression of many genes involved in redox processes, amino acid metabolism, protein misfolding, autophagy, and apoptosis. The precise role of ATF4 during viral infection is unclear and depends on cell hosts, viral agents, and models. Furthermore, ATF4 signaling can be hijacked by pathogens to favor viral infection and replication. In this review, we summarize the ATF4-mediated signaling pathways in response to viral infections, focusing on human immunodeficiency virus 1 (HIV-1). We examine the consequences of ATF4 activation for HIV-1 replication and reactivation. The role of ATF4 in autophagy and apoptosis is explored as in the context of HIV-1 infection programmed cell deaths contribute to the depletion of CD4 T cells. Furthermore, ATF4 can also participate in the establishment of innate and adaptive immunity that is essential for the host to control viral infections. We finally discuss the putative role of the ATF4 paralogue, named ATF5, in HIV-1 infection. This review underlines the role of ATF4 at the crossroads of multiple processes reflecting host-pathogen interactions.
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Affiliation(s)
- Adrien Corne
- Laboratoire de Génétique et Biologie Cellulaire, Université Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, 78000 Versailles, France; (A.C.); (F.A.); (S.G.)
- CHU de Québec Research Center, Laval University, Quebec City, QC G1V 4G2, Canada
| | - Florine Adolphe
- Laboratoire de Génétique et Biologie Cellulaire, Université Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, 78000 Versailles, France; (A.C.); (F.A.); (S.G.)
| | - Jérôme Estaquier
- CHU de Québec Research Center, Laval University, Quebec City, QC G1V 4G2, Canada
- INSERM U1124, Université Paris Cité, 75006 Paris, France
| | - Sébastien Gaumer
- Laboratoire de Génétique et Biologie Cellulaire, Université Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, 78000 Versailles, France; (A.C.); (F.A.); (S.G.)
| | - Jean-Marc Corsi
- Laboratoire de Génétique et Biologie Cellulaire, Université Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, 78000 Versailles, France; (A.C.); (F.A.); (S.G.)
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17
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Liu C, Xu X, He X, Ren J, Chi M, Deng G, Li G, Nasser MI. Activation of the Nrf-2/HO-1 signalling axis can alleviate metabolic syndrome in cardiovascular disease. Ann Med 2023; 55:2284890. [PMID: 38039549 PMCID: PMC10836253 DOI: 10.1080/07853890.2023.2284890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 11/10/2023] [Indexed: 12/03/2023] Open
Abstract
Background: Cardiovascular disease (CVD) is widely observed in modern society. CVDs are responsible for the majority of fatalities, with heart attacks and strokes accounting for approximately 80% of these cases. Furthermore, a significant proportion of these deaths, precisely one-third, occurs in individuals under 70. Metabolic syndrome encompasses a range of diseases characterized by various physiological dysfunctions. These include increased inflammation in adipose tissue, enhanced cholesterol synthesis in the liver, impaired insulin secretion, insulin resistance, compromised vascular tone and integrity, endothelial dysfunction, and atheroma formation. These factors contribute to the development of metabolic disorders and significantly increase the likelihood of experiencing cardiovascular complications.Method: We selected studies that proposed hypotheses regarding metabolic disease syndrome and cardiovascular disease (CVD) and the role of Nrf2/HO-1 and factor regulation in CVD research investigations based on our searches of Medline and PubMed.Results: A total of 118 articles were included in the review, 16 of which exclusively addressed hypotheses about the role of Nrf2 on Glucose regulation, while 16 involved Cholesterol regulation. Likewise, 14 references were used to prove the importance of mitochondria on Nrf2. Multiple studies have provided evidence suggesting the involvement of Nrf2/HO-1 in various physiological processes, including metabolism and immune response. A total of 48 research articles and reviews have been used to highlight the role of metabolic syndrome and CVD.Conclusion: This review provides an overview of the literature on Nrf2/HO-1 and its role in metabolic disease syndrome and CVD.
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Affiliation(s)
- Chi Liu
- Department of Nephrology, Sichuan Clinical Research Center for Kidney Disease, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Xingli Xu
- Ultrasound in Cardiac Electrophysiology and Biomechanics Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Xing He
- School of Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Junyi Ren
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Mingxuan Chi
- Department of Nephrology, Sichuan Clinical Research Center for Kidney Disease, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Gang Deng
- Department of Cardiac Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangdong Cardiovascular Institute, Guangzhou, Guangdong, China
| | - Guisen Li
- Department of Nephrology, Sichuan Clinical Research Center for Kidney Disease, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Moussa Ide Nasser
- Department of Cardiac Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangdong Cardiovascular Institute, Guangzhou, Guangdong, China
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18
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Kasai S, Kokubu D, Mizukami H, Itoh K. Mitochondrial Reactive Oxygen Species, Insulin Resistance, and Nrf2-Mediated Oxidative Stress Response-Toward an Actionable Strategy for Anti-Aging. Biomolecules 2023; 13:1544. [PMID: 37892226 PMCID: PMC10605809 DOI: 10.3390/biom13101544] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/12/2023] [Accepted: 10/15/2023] [Indexed: 10/29/2023] Open
Abstract
Reactive oxygen species (ROS) are produced mainly by mitochondrial respiration and function as signaling molecules in the physiological range. However, ROS production is also associated with the pathogenesis of various diseases, including insulin resistance (IR) and type 2 diabetes (T2D). This review focuses on the etiology of IR and early events, especially mitochondrial ROS (mtROS) production in insulin-sensitive tissues. Importantly, IR and/or defective adipogenesis in the white adipose tissues (WAT) is thought to increase free fatty acid and ectopic lipid deposition to develop into systemic IR. Fatty acid and ceramide accumulation mediate coenzyme Q reduction and mtROS production in IR in the skeletal muscle, while coenzyme Q synthesis downregulation is also involved in mtROS production in the WAT. Obesity-related IR is associated with the downregulation of mitochondrial catabolism of branched-chain amino acids (BCAAs) in the WAT, and the accumulation of BCAA and its metabolites as biomarkers in the blood could reliably indicate future T2D. Transcription factor NF-E2-related factor 2 (Nrf2), which regulates antioxidant enzyme expression in response to oxidative stress, is downregulated in insulin-resistant tissues. However, Nrf2 inducers, such as sulforaphane, could restore Nrf2 and target gene expression and attenuate IR in multiple tissues, including the WAT.
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Affiliation(s)
- Shuya Kasai
- Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan;
| | - Daichi Kokubu
- Department of Vegetable Life Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan;
- Diet & Well-being Research Institute, KAGOME CO., LTD., 17 Nishitomiyama, Nasushiobara 329-2762, Japan
| | - Hiroki Mizukami
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan;
| | - Ken Itoh
- Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan;
- Department of Vegetable Life Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan;
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19
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Yagishita Y, Chartoumpekis DV, Kensler TW, Wakabayashi N. NRF2 and the Moirai: Life and Death Decisions on Cell Fates. Antioxid Redox Signal 2023; 38:684-708. [PMID: 36509429 PMCID: PMC10025849 DOI: 10.1089/ars.2022.0200] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: The transcription factor NRF2 (NF-E2-related factor 2) plays an important role as a master regulator of the cellular defense system by activating transcriptional programs of NRF2 target genes encoding multiple enzymes related to cellular redox balance and xenobiotic detoxication. Comprehensive transcriptional analyses continue to reveal an ever-broadening range of NRF2 target genes, demonstrating the sophistication and diversification of NRF2 biological signatures beyond its canonical cytoprotective roles. Recent Advances: Accumulating evidence indicates that NRF2 has a strong association with the regulation of cell fates by influencing key processes of cellular transitions in the three major phases of the life cycle of the cell (i.e., cell birth, cell differentiation, and cell death). The molecular integration of NRF2 signaling into this regulatory program occurs through a wide range of NRF2 target genes encompassing canonical functions and those manipulating cell fate pathways. Critical Issues: A singular focus on NRF2 signaling for dissecting its actions limits in-depth understanding of its intersection with the molecular machinery of cell fate determinations. Compensatory responses of downstream pathways governed by NRF2 executed by a variety of transcription factors and multifactorial signaling crosstalk require further exploration. Future Directions: Further investigations using optimized in vivo models and active engagement of overarching approaches to probe the interplay of widespread pathways are needed to study the properties and capabilities of NRF2 signaling as a part of a large network within the cell fate regulatory domain. Antioxid. Redox Signal. 38, 684-708.
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Affiliation(s)
- Yoko Yagishita
- Translational Research Program, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Dionysios V Chartoumpekis
- Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
| | - Thomas W Kensler
- Translational Research Program, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Nobunao Wakabayashi
- Translational Research Program, Fred Hutchinson Cancer Center, Seattle, Washington, USA
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20
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Wei CW, Lerdall T, Najjar F, Wei LN. Depleting Cellular Retinoic Acid Binding Protein 1 Impairs UPR mt. JOURNAL OF CELLULAR SIGNALING 2023; 4:151-162. [PMID: 38706516 PMCID: PMC11068023 DOI: 10.33696/signaling.4.102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/07/2024]
Abstract
Mitochondrial dysfunction underlines neurodegenerative diseases which are mostly characterized by progressive degeneration of neurons. We previously reported that Cellular retinoic acid Binding protein 1 (Crabp1) knockout (CKO) mice spontaneously developed age-dependent motor degeneration, with defects accumulated in spinal motor neurons (MNs), the only cell type in spinal cord that expresses CRABP1. Here we uncovered that mitochondrial DNA (mtDNA) content and the expression of genes involved in respiration were significantly reduced in CKO mouse spinal cord, accompanied by significantly elevated reactive oxygen species (ROS) and unfolded protein load, indicating that CRABP1 deficiency caused mitochondrial dysfunction. Further analyses of spinal cord tissues revealed significant reduction in the expression and activity of superoxide dismutase 2 (SOD2), as well as defected mitochondrial unfolded protein response (UPRmt) pathway, specifically an increase in ATF5 mRNA but not its protein level, which suggested failure in the translational response of ATF5 in CKO. Consistently, eukaryotic initiation factor-2α, (eIF2α) phosphorylation was reduced in CKO spinal cord. In a CRABP1 knockdown MN1 model, siCrabp1-MN1, we validated the cell-autonomous function of CRABP1 in modulating the execution of UPRmt. This study reveals a new functional role for CRABP1 in the execution of mitochondrial stress response, that CRABP1 modulates eIF2α phosphorylation thereby contributing to ATF5 translational response that is needed to mitigate mitochondria stress.
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Affiliation(s)
- Chin-Wen Wei
- Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Thomas Lerdall
- Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Fatimah Najjar
- Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Li-Na Wei
- Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
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21
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Induction of ATF4-Regulated Atrogenes Is Uncoupled from Muscle Atrophy during Disuse in Halofuginone-Treated Mice and in Hibernating Brown Bears. Int J Mol Sci 2022; 24:ijms24010621. [PMID: 36614063 PMCID: PMC9820832 DOI: 10.3390/ijms24010621] [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: 10/14/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/31/2022] Open
Abstract
Activating transcription factor 4 (ATF4) is involved in muscle atrophy through the overexpression of some atrogenes. However, it also controls the transcription of genes involved in muscle homeostasis maintenance. Here, we explored the effect of ATF4 activation by the pharmacological molecule halofuginone during hindlimb suspension (HS)-induced muscle atrophy. Firstly, we reported that periodic activation of ATF4-regulated atrogenes (Gadd45a, Cdkn1a, and Eif4ebp1) by halofuginone was not associated with muscle atrophy in healthy mice. Secondly, halofuginone-treated mice even showed reduced atrophy during HS, although the induction of the ATF4 pathway was identical to that in untreated HS mice. We further showed that halofuginone inhibited transforming growth factor-β (TGF-β) signalling, while promoting bone morphogenetic protein (BMP) signalling in healthy mice and slightly preserved protein synthesis during HS. Finally, ATF4-regulated atrogenes were also induced in the atrophy-resistant muscles of hibernating brown bears, in which we previously also reported concurrent TGF-β inhibition and BMP activation. Overall, we show that ATF4-induced atrogenes can be uncoupled from muscle atrophy. In addition, our data also indicate that halofuginone can control the TGF-β/BMP balance towards muscle mass maintenance. Whether halofuginone-induced BMP signalling can counteract the effect of ATF4-induced atrogenes needs to be further investigated and may open a new avenue to fight muscle atrophy. Finally, our study opens the way for further studies to identify well-tolerated chemical compounds in humans that are able to fine-tune the TGF-β/BMP balance and could be used to preserve muscle mass during catabolic situations.
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Zhu MX, Ma XF, Niu X, Fan GB, Li Y. Mitochondrial unfolded protein response in ischemia-reperfusion injury. Brain Res 2022; 1797:148116. [PMID: 36209898 DOI: 10.1016/j.brainres.2022.148116] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/27/2022] [Accepted: 10/02/2022] [Indexed: 11/21/2022]
Abstract
Mitochondrial unfolded protein response (UPRmt) is a mitochondrial stress response that activates the transcriptional program of mitochondrial chaperone proteins and proteases to keep protein homeostasis in mitochondria. Ischemia-reperfusion injury results in multiple severe clinical issues linked to high morbidity and mortality in various disorders. The pathophysiology and pathogenesis of ischemia-reperfusion injury are complex and multifactorial. Emerging evidence showed the roles of UPRmt signaling in ischemia-reperfusion injury. Herein, we discuss the regulatory mechanisms underlying UPRmt signaling in C. elegans and mammals. Furthermore, we review the recent studies into the roles and mechanisms of UPRmt signaling in ischemia-reperfusion injury of the heart, brain, kidney, and liver. Further research of UPRmt signaling will potentially develop novel therapeutic strategies against ischemia-reperfusion injury.
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Affiliation(s)
- Ming-Xi Zhu
- Department of Anatomy, School of Basic Medicine and Life Science, Hainan Medical University, Hainan, China
| | - Xiao-Fei Ma
- Department of ICU, The 4th Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xing Niu
- Department of Second Clinical College, Shengjing Hospital of China Medical University, Shenyang, China
| | - Gui-Bo Fan
- Department of Anesthesiology, The 4th Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Yan Li
- Department of Anesthesiology, The 4th Affiliated Hospital of Harbin Medical University, Harbin, China.
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Ei ZZ, Hutamekalin P, Prommeenate P, Singh A, Benjakul S, Visuttijai K, Chanvorachote P. Chitooligosaccharide prevents vascular endothelial cell apoptosis by attenuation of endoplasmic reticulum stress via suppression of oxidative stress through Nrf2-SOD1 up-regulation. PHARMACEUTICAL BIOLOGY 2022; 60:2155-2166. [PMID: 36300849 PMCID: PMC9621211 DOI: 10.1080/13880209.2022.2133150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 08/22/2022] [Accepted: 10/01/2022] [Indexed: 06/16/2023]
Abstract
CONTEXT Endoplasmic reticulum (ER) stress contributes to endothelium pathological conditions. Chitooligosaccharides (COS) have health benefits, but their effect on endothelial cells is unknown. We demonstrate for the first time a protective effect of COS against ER-induced endothelial cell damage. OBJECTIVE To evaluate the protective effect of COS on ER stress-induced apoptosis in endothelial cells. MATERIAL AND METHODS Endothelial (EA.hy926) cells were pre-treated with COS (250 or 500 μg/mL) for 24 h, and then treated with 0.16 μg/mL of Tg for 24 h and compared to the untreated control. Apoptosis and necrosis were detected by Annexin V-FITC/propidium iodide co-staining. Reactive oxygen species (ROS) were measured with the DCFH2-DA and DHE probes. The protective pathway and ER stress markers were evaluated by reverse transcription-polymerase chain reaction, western blot, and immunofluorescence analyses. RESULTS COS attenuated ER stress-induced cell death. The viability of EA.hy926 cells treated with Tg alone was 44.97 ± 1% but the COS pre-treatment increased cells viability to 74.74 ± 3.95% in the 250 μg/mL COS and 75.34 ± 2.4% in the 500 μg/mL COS treatments. Tg induced ER stress and ROS, which were associated with ER stress-mediated death. Interestingly, COS reduced ROS by upregulating nuclear factor-E2-related factor 2 (Nrf2), and the oxidative enzymes, superoxide dismutase1 (SOD1) and catalase. COS also suppressed up-regulation of the ER-related apoptosis protein, CHOP induced by Tg. CONCLUSIONS COS protected against ER stress-induced apoptosis in endothelial cells by suppressing ROS and up-regulation Nrf2 and SOD1. These findings support the use of COS to protect endothelial cells.
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Affiliation(s)
- Zin Zin Ei
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Pilaiwanwadee Hutamekalin
- Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Songkhla, Thailand
| | - Peerada Prommeenate
- Biochemical Engineering and Systems Biology Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency at King Mongkut’s University of Technology Thonburi, Bangkok, Thailand
| | - Avtar Singh
- International Center of Excellence in Seafood Science and Innovation (ICE-SSI), Faculty of Agro-Industry, Prince of Songkla University, Songkhla, Thailand
| | - Soottawat Benjakul
- International Center of Excellence in Seafood Science and Innovation (ICE-SSI), Faculty of Agro-Industry, Prince of Songkla University, Songkhla, Thailand
| | - Kittichate Visuttijai
- Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Pithi Chanvorachote
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
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Nrf2 Regulates Oxidative Stress and Its Role in Cerebral Ischemic Stroke. Antioxidants (Basel) 2022; 11:antiox11122377. [PMID: 36552584 PMCID: PMC9774301 DOI: 10.3390/antiox11122377] [Citation(s) in RCA: 134] [Impact Index Per Article: 44.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/23/2022] [Accepted: 11/27/2022] [Indexed: 12/05/2022] Open
Abstract
Cerebral ischemic stroke is characterized by acute ischemia in a certain part of the brain, which leads to brain cells necrosis, apoptosis, ferroptosis, pyroptosis, etc. At present, there are limited effective clinical treatments for cerebral ischemic stroke, and the recovery of cerebral blood circulation will lead to cerebral ischemia-reperfusion injury (CIRI). Cerebral ischemic stroke involves many pathological processes such as oxidative stress, inflammation, and mitochondrial dysfunction. Nuclear factor erythroid 2-related factor 2 (Nrf2), as one of the most critical antioxidant transcription factors in cells, can coordinate various cytoprotective factors to inhibit oxidative stress. Targeting Nrf2 is considered as a potential strategy to prevent and treat cerebral ischemia injury. During cerebral ischemia, Nrf2 participates in signaling pathways such as Keap1, PI3K/AKT, MAPK, NF-κB, and HO-1, and then alleviates cerebral ischemia injury or CIRI by inhibiting oxidative stress, anti-inflammation, maintaining mitochondrial homeostasis, protecting the blood-brain barrier, and inhibiting ferroptosis. In this review, we have discussed the structure of Nrf2, the mechanisms of Nrf2 in cerebral ischemic stroke, the related research on the treatment of cerebral ischemia through the Nrf2 signaling pathway in recent years, and expounded the important role and future potential of the Nrf2 pathway in cerebral ischemic stroke.
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25
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Habeos GI, Filippopoulou F, Habeos EE, Kalaitzopoulou E, Skipitari M, Papadea P, Lagoumintzis G, Niarchos A, Georgiou CD, Chartoumpekis DV. Maternal Calorie Restriction Induces a Transcriptional Cytoprotective Response in Embryonic Liver Partially Dependent on Nrf2. Antioxidants (Basel) 2022; 11:2274. [PMID: 36421460 PMCID: PMC9687455 DOI: 10.3390/antiox11112274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/07/2022] [Accepted: 11/15/2022] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND Calorie restriction is known to enhance Nrf2 signaling and longevity in adult mice, partially by reducing reactive oxygen species, but calorie restriction during pregnancy leads to intrauterine growth retardation. The latter is associated with fetal reprogramming leading to increased incidence of obesity, metabolic syndrome and diabetes in adult life. Transcription factor Nrf2 is a central regulator of the antioxidant response and its crosstalk with metabolic pathways is emerging. We hypothesized that the Nrf2 pathway is induced in embryos during calorie restriction in pregnant mothers. METHODS From gestational day 10 up to day 16, 50% of the necessary mouse diet was provided to Nrf2 heterozygous pregnant females with fathers being of the same genotype. Embryos were harvested at the end of gestational day 16 and fetal liver was used for qRT-PCR and assessment of oxidative stress (OS). RESULTS Intrauterine calorie restriction led to upregulation of mRNA expression of antioxidant genes (Nqo1, Gsta1, Gsta4) and of genes related to integrated stress response (Chac1, Ddit3) in WT embryos. The expression of a key gluconeogenic (G6pase) and two lipogenic genes (Acacb, Fasn) was repressed in calorie-restricted embryos. In Nrf2 knockout embryos, the induction of Nqo1 and Gsta1 genes was abrogated while that of Gsta4 was preserved, indicating an at least partially Nrf2-dependent induction of antioxidant genes after in utero calorie restriction. Measures of OS showed no difference (superoxide radical and malondialdehyde) or a small decrease (thiobarbituric reactive substances) in calorie-restricted WT embryos. CONCLUSIONS Calorie restriction during pregnancy elicits the transcriptional induction of cytoprotective/antioxidant genes in the fetal liver, which is at least partially Nrf2-dependent, with a physiological significance that warrants further investigation.
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Affiliation(s)
- George I. Habeos
- Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of Patras, 26504 Patras, Greece
| | - Fotini Filippopoulou
- Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of Patras, 26504 Patras, Greece
| | - Evagelia E. Habeos
- Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of Patras, 26504 Patras, Greece
| | - Electra Kalaitzopoulou
- Section of Genetics, Cell Biology and Development, Department of Biology, University of Patras, 26504 Patras, Greece
| | - Marianna Skipitari
- Section of Genetics, Cell Biology and Development, Department of Biology, University of Patras, 26504 Patras, Greece
| | - Polyxeni Papadea
- Section of Genetics, Cell Biology and Development, Department of Biology, University of Patras, 26504 Patras, Greece
| | - George Lagoumintzis
- Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of Patras, 26504 Patras, Greece
- Department of Pharmacy, University of Patras, 26504 Patras, Greece
| | - Athanasios Niarchos
- Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of Patras, 26504 Patras, Greece
| | - Christos D. Georgiou
- Section of Genetics, Cell Biology and Development, Department of Biology, University of Patras, 26504 Patras, Greece
| | - Dionysios V. Chartoumpekis
- Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of Patras, 26504 Patras, Greece
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Sigma-1 receptor agonist PRE-084 confers protection against TAR DNA-binding protein-43 toxicity through NRF2 signalling. Redox Biol 2022; 58:102542. [PMID: 36442393 PMCID: PMC9706169 DOI: 10.1016/j.redox.2022.102542] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 11/08/2022] [Accepted: 11/14/2022] [Indexed: 11/18/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons. As a consequence, ALS patients display a locomotor disorder related to muscle weakness and progressive paralysis. Pathological mechanisms that participate in ALS involve deficient unfolded protein response, mitochondrial dysfunction and oxidative stress, among others. Finding a therapeutic target to break the vicious circle is particularly challenging. Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) chaperone that may be one of those targets. We here address and decipher the efficiency of S1R activation on a key ALS gene, TDP43, in zebrafish vertebrate model. While expression of mutant TDP43 (TDP43G348C) led to locomotor defects, treatment with the reference S1R agonist PRE-084 rescued motor performances in a zebrafish model. Treatment with the agonist ameliorated maximal mitochondrial respiration in the TDP43 context. We observed that TDP43G348C exacerbated ER stress induced by tunicamycin, resulting in increased levels of ER stress chaperone BiP and pro-apoptotic factor CHOP. Importantly, PRE-084 treatment in the same condition further heightened BiP levels but also EIF2α/ATF4 and NRF2 signalling cascades, both known to promote antioxidant protection during ER stress. Moreover, we showed that increasing NRF2 levels directly or by sulforaphane treatment rescued locomotor defects of TDP43G348C zebrafish. For the first time, we here provide the proof of concept that PRE-084 prevents mutant TDP43 toxicity by boosting ER stress response and antioxidant cascade through NRF2 signalling.
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27
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Nwosu GO, Powell JA, Pitson SM. Targeting the integrated stress response in hematologic malignancies. Exp Hematol Oncol 2022; 11:94. [DOI: 10.1186/s40164-022-00348-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 10/22/2022] [Indexed: 11/09/2022] Open
Abstract
AbstractWhile numerous targeted therapies have been recently adopted to improve the treatment of hematologic malignancies, acquired or intrinsic resistance poses a significant obstacle to their efficacy. Thus, there is increasing need to identify novel, targetable pathways to further improve therapy for these diseases. The integrated stress response is a signaling pathway activated in cancer cells in response to both dysregulated growth and metabolism, and also following exposure to many therapies that appears one such targetable pathway for improved treatment of these diseases. In this review, we discuss the role of the integrated stress response in the biology of hematologic malignancies, its critical involvement in the mechanism of action of targeted therapies, and as a target for pharmacologic modulation as a novel strategy for the treatment of hematologic malignancies.
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28
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Ji Y, Zheng K, Li S, Ren C, Shen Y, Tian L, Zhu H, Zhou Z, Jiang Y. Insight into the potential role of ferroptosis in neurodegenerative diseases. Front Cell Neurosci 2022; 16:1005182. [PMID: 36385946 PMCID: PMC9647641 DOI: 10.3389/fncel.2022.1005182] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/14/2022] [Indexed: 11/30/2022] Open
Abstract
Ferroptosis is a newly discovered way of programmed cell death, mainly caused by the accumulation of iron-dependent lipid peroxides in cells, which is morphologically, biochemically and genetically different from the previously reported apoptosis, necrosis and autophagy. Studies have found that ferroptosis plays a key role in the occurrence and development of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and vascular dementia, which suggest that ferroptosis may be involved in regulating the progression of neurodegenerative diseases. At present, on the underlying mechanism of ferroptosis in neurodegenerative diseases is still unclear, and relevant research is urgently needed to clarify the regulatory mechanism and provide the possibility for the development of agents targeting ferroptosis. This review focused on the regulatory mechanism of ferroptosis and its various effects in neurodegenerative diseases, in order to provide reference for the research on ferroptosis in neurodegenerative diseases.
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Affiliation(s)
- Yingying Ji
- The Affiliated Wuxi Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, China
| | - Kai Zheng
- The Affiliated Wuxi Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, China
| | - Shiming Li
- The Affiliated Wuxi Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, China
| | - Caili Ren
- The Affiliated Wuxi Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, China
| | - Ying Shen
- Rehabilitation Medicine Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lin Tian
- The Affiliated Wuxi Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, China
| | - Haohao Zhu
- The Affiliated Wuxi Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, China
- *Correspondence: Haohao Zhu
| | - Zhenhe Zhou
- The Affiliated Wuxi Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, China
- Zhenhe Zhou
| | - Ying Jiang
- The Affiliated Wuxi Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, China
- Ying Jiang
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Mishra PK, Kumari R, Bhargava A, Bunkar N, Chauhan P, Tiwari R, Shandilya R, Srivastava RK, Singh RD. Prenatal exposure to environmental pro-oxidants induces mitochondria-mediated epigenetic changes: a cross-sectional pilot study. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:74133-74149. [PMID: 35633452 DOI: 10.1007/s11356-022-21059-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 05/20/2022] [Indexed: 05/24/2023]
Abstract
Mitochondria play a central role in maintaining cellular and metabolic homeostasis during vital development cycles of foetal growth. Optimal mitochondrial functions are important not only to sustain adequate energy production but also for regulated epigenetic programming. However, these organelles are subtle targets of environmental exposures, and any perturbance in the defined mitochondrial machinery during the developmental stage can lead to the re-programming of the foetal epigenetic landscape. As these modifications can be transferred to subsequent generations, we herein performed a cross-sectional study to have an in-depth understanding of this intricate phenomenon. The study was conducted with two arms: whereas the first group consisted of in utero pro-oxidant exposed individuals and the second group included controls. Our results showed higher levels of oxidative mtDNA damage and associated integrated stress response among the exposed individuals. These disturbances were found to be closely related to the observed discrepancies in mitochondrial biogenesis. The exposed group showed mtDNA hypermethylation and changes in allied mitochondrial functioning. Altered expression of mitomiRs and their respective target genes in the exposed group indicated the possibilities of a disturbed mitochondrial-nuclear cross talk. This was further confirmed by the modified activity of the mitochondrial stress regulators and pro-inflammatory mediators among the exposed group. Importantly, the disturbed DNMT functioning, hypermethylation of nuclear DNA, and higher degree of post-translational histone modifications established the existence of aberrant epigenetic modifications in the exposed individuals. Overall, our results demonstrate the first molecular insights of in utero pro-oxidant exposure associated changes in the mitochondrial-epigenetic axis. Although, our study might not cement an exposure-response relationship for any particular environmental pro-oxidant, but suffice to establish a dogma of mito-epigenetic reprogramming at intrauterine milieu with chronic illness, a hitherto unreported interaction.
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Affiliation(s)
- Pradyumna Kumar Mishra
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bypass Road, Bhauri, Bhopal, 462030, India.
| | - Roshani Kumari
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bypass Road, Bhauri, Bhopal, 462030, India
| | - Arpit Bhargava
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bypass Road, Bhauri, Bhopal, 462030, India
| | - Neha Bunkar
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bypass Road, Bhauri, Bhopal, 462030, India
| | - Prachi Chauhan
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bypass Road, Bhauri, Bhopal, 462030, India
| | - Rajnarayan Tiwari
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bypass Road, Bhauri, Bhopal, 462030, India
| | - Ruchita Shandilya
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bypass Road, Bhauri, Bhopal, 462030, India
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | | | - Radha Dutt Singh
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bypass Road, Bhauri, Bhopal, 462030, India
- Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada
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NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson's Disease. Cells 2022; 11:cells11152416. [PMID: 35954260 PMCID: PMC9367803 DOI: 10.3390/cells11152416] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/01/2022] [Accepted: 08/01/2022] [Indexed: 02/01/2023] Open
Abstract
Dysfunctional mitochondrial quality control (MQC) is implicated in the pathogenesis of Parkinson's disease (PD). The improper selection of mitochondria for mitophagy increases reactive oxygen species (ROS) levels and lowers ATP levels. The downstream effects include oxidative damage, failure to maintain proteostasis and ion gradients, and decreased NAD+ and NADPH levels, resulting in insufficient energy metabolism and neurotransmitter synthesis. A ketosis-based metabolic therapy that increases the levels of (R)-3-hydroxybutyrate (BHB) may reverse the dysfunctional MQC by partially replacing glucose as an energy source, by stimulating mitophagy, and by decreasing inflammation. Fasting can potentially raise cytoplasmic NADPH levels by increasing the mitochondrial export and cytoplasmic metabolism of ketone body-derived citrate that increases flux through isocitrate dehydrogenase 1 (IDH1). NADPH is an essential cofactor for nitric oxide synthase, and the nitric oxide synthesized can diffuse into the mitochondrial matrix and react with electron transport chain-synthesized superoxide to form peroxynitrite. Excessive superoxide and peroxynitrite production can cause the opening of the mitochondrial permeability transition pore (mPTP) to depolarize the mitochondria and activate PINK1-dependent mitophagy. Both fasting and exercise increase ketogenesis and increase the cellular NAD+/NADH ratio, both of which are beneficial for neuronal metabolism. In addition, both fasting and exercise engage the adaptive cellular stress response signaling pathways that protect neurons against the oxidative and proteotoxic stress implicated in PD. Here, we discuss how intermittent fasting from the evening meal through to the next-day lunch together with morning exercise, when circadian NAD+/NADH is most oxidized, circadian NADP+/NADPH is most reduced, and circadian mitophagy gene expression is high, may slow the progression of PD.
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31
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Falletta P, Goding CR, Vivas-García Y. Connecting Metabolic Rewiring With Phenotype Switching in Melanoma. Front Cell Dev Biol 2022; 10:930250. [PMID: 35912100 PMCID: PMC9334657 DOI: 10.3389/fcell.2022.930250] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/24/2022] [Indexed: 11/13/2022] Open
Abstract
Melanoma is a complex and aggressive cancer type that contains different cell subpopulations displaying distinct phenotypes within the same tumor. Metabolic reprogramming, a hallmark of cell transformation, is essential for melanoma cells to adopt different phenotypic states necessary for adaptation to changes arising from a dynamic milieu and oncogenic mutations. Increasing evidence demonstrates how melanoma cells can exhibit distinct metabolic profiles depending on their specific phenotype, allowing adaptation to hostile microenvironmental conditions, such as hypoxia or nutrient depletion. For instance, increased glucose consumption and lipid anabolism are associated with proliferation, while a dependency on exogenous fatty acids and an oxidative state are linked to invasion and metastatic dissemination. How these different metabolic dependencies are integrated with specific cell phenotypes is poorly understood and little is known about metabolic changes underpinning melanoma metastasis. Recent evidence suggests that metabolic rewiring engaging transitions to invasion and metastatic progression may be dependent on several factors, such as specific oncogenic programs or lineage-restricted mechanisms controlling cell metabolism, intra-tumor microenvironmental cues and anatomical location of metastasis. In this review we highlight how the main molecular events supporting melanoma metabolic rewiring and phenotype-switching are parallel and interconnected events that dictate tumor progression and metastatic dissemination through interplay with the tumor microenvironment.
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Affiliation(s)
- Paola Falletta
- Vita-Salute San Raffaele University, Milan, Italy
- Experimental Imaging Center, IRCCS Ospedale San Raffaele, Milan, Italy
- *Correspondence: Paola Falletta, ; Colin R. Goding, ; Yurena Vivas-García, ,
| | - Colin R. Goding
- Nuffield Department of Clinical Medicine, Ludwig Cancer Research, University of Oxford, Oxford, United Kingdom
- *Correspondence: Paola Falletta, ; Colin R. Goding, ; Yurena Vivas-García, ,
| | - Yurena Vivas-García
- Nuffield Department of Clinical Medicine, Ludwig Cancer Research, University of Oxford, Oxford, United Kingdom
- *Correspondence: Paola Falletta, ; Colin R. Goding, ; Yurena Vivas-García, ,
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Carraro V, Combaret L, Coudy-Gandilhon C, Parry L, Averous J, Maurin AC, Jousse C, Voyard G, Fafournoux P, Papet I, Bruhat A. Activation of the eIF2α-ATF4 Pathway by Chronic Paracetamol Treatment Is Prevented by Dietary Supplementation with Cysteine. Int J Mol Sci 2022; 23:ijms23137196. [PMID: 35806203 PMCID: PMC9266523 DOI: 10.3390/ijms23137196] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/23/2022] [Accepted: 06/24/2022] [Indexed: 02/01/2023] Open
Abstract
Chronic treatment with acetaminophen (APAP) induces cysteine (Cys) and glutathione (GSH) deficiency which leads to adverse metabolic effects including muscle atrophy. Mammalian cells respond to essential amino acid deprivation through the phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α). Phosphorylated eIF2α leads to the recruitment of activating transcription factor 4 (ATF4) to specific CCAAT/enhancer-binding protein-ATF response element (CARE) located in the promoters of target genes. Our purpose was to study the activation of the eIF2α-ATF4 pathway in response to APAP-induced Cys deficiency, as well as the potential contribution of the eIF2α kinase GCN2 and the effect of dietary supplementation with Cys. Our results showed that chronic treatment with APAP activated both GCN2 and PERK eIF2α kinases and downstream target genes in the liver. Activation of the eIF2α-ATF4 pathway in skeletal muscle was accompanied by muscle atrophy even in the absence of GCN2. The dietary supplementation with cysteine reversed APAP-induced decreases in plasma-free Cys, liver GSH, muscle mass, and muscle GSH. Our new findings demonstrate that dietary Cys supplementation also reversed the APAP-induced activation of GCN2 and PERK and downstream ATF4-target genes in the liver.
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Affiliation(s)
- Valérie Carraro
- Université Clermont Auvergne, INRAE, UNH Unité de Nutrition Humaine, UMR1019, F-63000 Clermont-Ferrand, France; (V.C.); (L.C.); (C.C.-G.); (L.P.); (J.A.); (A.-C.M.); (C.J.); (P.F.)
| | - Lydie Combaret
- Université Clermont Auvergne, INRAE, UNH Unité de Nutrition Humaine, UMR1019, F-63000 Clermont-Ferrand, France; (V.C.); (L.C.); (C.C.-G.); (L.P.); (J.A.); (A.-C.M.); (C.J.); (P.F.)
| | - Cécile Coudy-Gandilhon
- Université Clermont Auvergne, INRAE, UNH Unité de Nutrition Humaine, UMR1019, F-63000 Clermont-Ferrand, France; (V.C.); (L.C.); (C.C.-G.); (L.P.); (J.A.); (A.-C.M.); (C.J.); (P.F.)
| | - Laurent Parry
- Université Clermont Auvergne, INRAE, UNH Unité de Nutrition Humaine, UMR1019, F-63000 Clermont-Ferrand, France; (V.C.); (L.C.); (C.C.-G.); (L.P.); (J.A.); (A.-C.M.); (C.J.); (P.F.)
| | - Julien Averous
- Université Clermont Auvergne, INRAE, UNH Unité de Nutrition Humaine, UMR1019, F-63000 Clermont-Ferrand, France; (V.C.); (L.C.); (C.C.-G.); (L.P.); (J.A.); (A.-C.M.); (C.J.); (P.F.)
| | - Anne-Catherine Maurin
- Université Clermont Auvergne, INRAE, UNH Unité de Nutrition Humaine, UMR1019, F-63000 Clermont-Ferrand, France; (V.C.); (L.C.); (C.C.-G.); (L.P.); (J.A.); (A.-C.M.); (C.J.); (P.F.)
| | - Céline Jousse
- Université Clermont Auvergne, INRAE, UNH Unité de Nutrition Humaine, UMR1019, F-63000 Clermont-Ferrand, France; (V.C.); (L.C.); (C.C.-G.); (L.P.); (J.A.); (A.-C.M.); (C.J.); (P.F.)
| | - Guillaume Voyard
- Université Clermont Auvergne, CNRS, Institut de Chimie de Clermont-Ferrand, F-63000 Clermont-Ferrand, France;
| | - Pierre Fafournoux
- Université Clermont Auvergne, INRAE, UNH Unité de Nutrition Humaine, UMR1019, F-63000 Clermont-Ferrand, France; (V.C.); (L.C.); (C.C.-G.); (L.P.); (J.A.); (A.-C.M.); (C.J.); (P.F.)
| | - Isabelle Papet
- Université Clermont Auvergne, INRAE, UNH Unité de Nutrition Humaine, UMR1019, F-63000 Clermont-Ferrand, France; (V.C.); (L.C.); (C.C.-G.); (L.P.); (J.A.); (A.-C.M.); (C.J.); (P.F.)
- Correspondence: (I.P.); (A.B.)
| | - Alain Bruhat
- Université Clermont Auvergne, INRAE, UNH Unité de Nutrition Humaine, UMR1019, F-63000 Clermont-Ferrand, France; (V.C.); (L.C.); (C.C.-G.); (L.P.); (J.A.); (A.-C.M.); (C.J.); (P.F.)
- Correspondence: (I.P.); (A.B.)
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Suárez-Rivero JM, Pastor-Maldonado CJ, Povea-Cabello S, Álvarez-Córdoba M, Villalón-García I, Talaverón-Rey M, Suárez-Carrillo A, Munuera-Cabeza M, Reche-López D, Cilleros-Holgado P, Piñero-Perez R, Sánchez-Alcázar JA. UPR mt activation improves pathological alterations in cellular models of mitochondrial diseases. Orphanet J Rare Dis 2022; 17:204. [PMID: 35581596 PMCID: PMC9115953 DOI: 10.1186/s13023-022-02331-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 04/26/2022] [Indexed: 12/23/2022] Open
Abstract
Background Mitochondrial diseases represent one of the most common groups of genetic diseases. With a prevalence greater than 1 in 5000 adults, such diseases still lack effective treatment. Current therapies are purely palliative and, in most cases, insufficient. Novel approaches to compensate and, if possible, revert mitochondrial dysfunction must be developed. Results In this study, we tackled the issue using as a model fibroblasts from a patient bearing a mutation in the GFM1 gene, which is involved in mitochondrial protein synthesis. Mutant GFM1 fibroblasts could not survive in galactose restrictive medium for more than 3 days, making them the perfect screening platform to test several compounds. Tetracycline enabled mutant GFM1 fibroblasts survival under nutritional stress. Here we demonstrate that tetracycline upregulates the mitochondrial Unfolded Protein Response (UPRmt), a compensatory pathway regulating mitochondrial proteostasis. We additionally report that activation of UPRmt improves mutant GFM1 cellular bioenergetics and partially restores mitochondrial protein expression. Conclusions Overall, we provide compelling evidence to propose the activation of intrinsic cellular compensatory mechanisms as promising therapeutic strategy for mitochondrial diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02331-8.
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Affiliation(s)
- Juan M Suárez-Rivero
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Carmen J Pastor-Maldonado
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Suleva Povea-Cabello
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Mónica Álvarez-Córdoba
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Irene Villalón-García
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Marta Talaverón-Rey
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Alejandra Suárez-Carrillo
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Manuel Munuera-Cabeza
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Diana Reche-López
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Paula Cilleros-Holgado
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Rocío Piñero-Perez
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - José A Sánchez-Alcázar
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain. .,Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, 41013, Seville, Spain.
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Taouktsi E, Kyriakou E, Smyrniotis S, Borbolis F, Bondi L, Avgeris S, Trigazis E, Rigas S, Voutsinas GE, Syntichaki P. Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease. Cells 2022; 11:cells11081363. [PMID: 35456042 PMCID: PMC9025075 DOI: 10.3390/cells11081363] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/09/2022] [Accepted: 04/14/2022] [Indexed: 02/01/2023] Open
Abstract
Cells engage complex surveillance mechanisms to maintain mitochondrial function and protein homeostasis. LonP1 protease is a key component of mitochondrial quality control and has been implicated in human malignancies and other pathological disorders. Here, we employed two experimental systems, the worm Caenorhabditis elegans and human cancer cells, to investigate and compare the effects of LONP-1/LonP1 deficiency at the molecular, cellular, and organismal levels. Deletion of the lonp-1 gene in worms disturbed mitochondrial function, provoked reactive oxygen species accumulation, and impaired normal processes, such as growth, behavior, and lifespan. The viability of lonp-1 mutants was dependent on the activity of the ATFS-1 transcription factor, and loss of LONP-1 evoked retrograde signaling that involved both the mitochondrial and cytoplasmic unfolded protein response (UPRmt and UPRcyt) pathways and ensuing diverse organismal stress responses. Exposure of worms to triterpenoid CDDO-Me, an inhibitor of human LonP1, stimulated only UPRcyt responses. In cancer cells, CDDO-Me induced key components of the integrated stress response (ISR), the UPRmt and UPRcyt pathways, and the redox machinery. However, genetic knockdown of LonP1 revealed a genotype-specific cellular response and induced apoptosis similar to CDDO-Me treatment. Overall, the mitochondrial dysfunction ensued by disruption of LonP1 elicits adaptive cytoprotective mechanisms that can inhibit cancer cell survival but diversely modulate organismal stress response and aging.
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Affiliation(s)
- Eirini Taouktsi
- Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece; (E.T.); (E.K.); (F.B.); (L.B.); (E.T.)
- Department of Biotechnology, Agricultural University of Athens, 11855 Athens, Greece;
| | - Eleni Kyriakou
- Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece; (E.T.); (E.K.); (F.B.); (L.B.); (E.T.)
| | - Stefanos Smyrniotis
- Laboratory of Molecular Carcinogenesis and Rare Disease Genetics, Institute of Biosciences and Applications, National Center for Scientific Research “Demokritos”, 15341 Athens, Greece; (S.S.); (S.A.)
| | - Fivos Borbolis
- Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece; (E.T.); (E.K.); (F.B.); (L.B.); (E.T.)
| | - Labrina Bondi
- Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece; (E.T.); (E.K.); (F.B.); (L.B.); (E.T.)
- Laboratory of Molecular Carcinogenesis and Rare Disease Genetics, Institute of Biosciences and Applications, National Center for Scientific Research “Demokritos”, 15341 Athens, Greece; (S.S.); (S.A.)
| | - Socratis Avgeris
- Laboratory of Molecular Carcinogenesis and Rare Disease Genetics, Institute of Biosciences and Applications, National Center for Scientific Research “Demokritos”, 15341 Athens, Greece; (S.S.); (S.A.)
| | - Efstathios Trigazis
- Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece; (E.T.); (E.K.); (F.B.); (L.B.); (E.T.)
| | - Stamatis Rigas
- Department of Biotechnology, Agricultural University of Athens, 11855 Athens, Greece;
| | - Gerassimos E. Voutsinas
- Laboratory of Molecular Carcinogenesis and Rare Disease Genetics, Institute of Biosciences and Applications, National Center for Scientific Research “Demokritos”, 15341 Athens, Greece; (S.S.); (S.A.)
- Correspondence: (G.E.V.); (P.S.); Tel.: +30-21-0650-3579 (G.E.V.); +30-21-0659-7474 (P.S.)
| | - Popi Syntichaki
- Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece; (E.T.); (E.K.); (F.B.); (L.B.); (E.T.)
- Correspondence: (G.E.V.); (P.S.); Tel.: +30-21-0650-3579 (G.E.V.); +30-21-0659-7474 (P.S.)
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Binder P, Nguyen B, Collins L, Zi M, Liu W, Christou F, Luo X, Hille SS, Frey N, Cartwright EJ, Chernoff J, Müller OJ, Guan K, Wang X. Pak2 Regulation of Nrf2 Serves as a Novel Signaling Nexus Linking ER Stress Response and Oxidative Stress in the Heart. Front Cardiovasc Med 2022; 9:851419. [PMID: 35350536 PMCID: PMC8957820 DOI: 10.3389/fcvm.2022.851419] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 02/11/2022] [Indexed: 12/20/2022] Open
Abstract
Endoplasmic Reticulum (ER) stress and oxidative stress have been highly implicated in the pathogenesis of cardiac hypertrophy and heart failure (HF). However, the mechanisms involved in the interplay between these processes in the heart are not fully understood. The present study sought to determine a causative link between Pak2-dependent UPR activation and oxidative stress via Nrf2 regulation under pathological ER stress. We report that sustained ER stress and Pak2 deletion in cardiomyocytes enhance Nrf2 expression. Conversely, AAV9 mediated Pak2 delivery in the heart leads to a significant decrease in Nrf2 levels. Pak2 overexpression enhances the XBP1-Hrd1 UPR axis and ameliorates tunicamycin induced cardiac apoptosis and dysfunction in mice. We found that Pak2 deletion and altered proteostasis render Nrf2 detrimental by switching from its antioxidant role to renin-angiotensin aldosterone system (RAAS) gene regulator. Mechanistically, Pak2 mediated Hrd1 expression targets Nrf2 for ubiquitination and degradation thus preventing its aberrant activation. Moreover, we find a significant increase in Nrf2 with a decrease in Pak2 in human myocardium of dilated heart disease. Using human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we find that Pak2 is able to ameliorate Nrf2 induced RAAS activation under ER stress. These findings demonstrate that Pak2 is a novel Nrf2 regulator in the stressed heart. Activation of XBP1-Hrd1 is attributed to prevent ER stress-induced Nrf2 RAAS component upregulation. This mechanism explains the functional dichotomy of Nrf2 in the stressed heart. Thus, Pak2 regulation of Nrf2 homeostasis may present as a potential therapeutic route to alleviate detrimental ER stress and heart failure.
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Affiliation(s)
- Pablo Binder
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Binh Nguyen
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Lucy Collins
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Min Zi
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Wei Liu
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Foteini Christou
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Xiaojing Luo
- Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany
| | - Susanne S. Hille
- Department of Internal Medicine III, University of Kiel, Kiel, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
| | - Norbert Frey
- Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany
| | - Elizabeth J. Cartwright
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Jonathan Chernoff
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Oliver J. Müller
- Department of Internal Medicine III, University of Kiel, Kiel, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
| | - Kaomei Guan
- Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany
| | - Xin Wang
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
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36
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Ryan DG, Knatko EV, Casey AM, Hukelmann JL, Dayalan Naidu S, Brenes AJ, Ekkunagul T, Baker C, Higgins M, Tronci L, Nikitopolou E, Honda T, Hartley RC, O’Neill LA, Frezza C, Lamond AI, Abramov AY, Arthur JSC, Cantrell DA, Murphy MP, Dinkova-Kostova AT. Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response. iScience 2022; 25:103827. [PMID: 35198887 PMCID: PMC8844662 DOI: 10.1016/j.isci.2022.103827] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 01/17/2022] [Accepted: 01/22/2022] [Indexed: 12/14/2022] Open
Abstract
To overcome oxidative, inflammatory, and metabolic stress, cells have evolved cytoprotective protein networks controlled by nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) and its negative regulator, Kelch-like ECH associated protein 1 (Keap1). Here, using high-resolution mass spectrometry we characterize the proteomes of macrophages with altered Nrf2 status revealing significant differences among the genotypes in metabolism and redox homeostasis, which were validated with respirometry and metabolomics. Nrf2 affected the proteome following lipopolysaccharide (LPS) stimulation, with alterations in redox, carbohydrate and lipid metabolism, and innate immunity. Notably, Nrf2 activation promoted mitochondrial fusion. The Keap1 inhibitor, 4-octyl itaconate remodeled the inflammatory macrophage proteome, increasing redox and suppressing type I interferon (IFN) response. Similarly, pharmacologic or genetic Nrf2 activation inhibited the transcription of IFN-β and its downstream effector IFIT2 during LPS stimulation. These data suggest that Nrf2 activation facilitates metabolic reprogramming and mitochondrial adaptation, and finetunes the innate immune response in macrophages.
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Affiliation(s)
- Dylan G. Ryan
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK
| | - Elena V. Knatko
- Division of Cellular Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arrott Drive, Dundee, Scotland, UK
| | - Alva M. Casey
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
| | - Jens L. Hukelmann
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK
- Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, Scotland, UK
| | - Sharadha Dayalan Naidu
- Division of Cellular Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arrott Drive, Dundee, Scotland, UK
| | - Alejandro J. Brenes
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK
- Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, Scotland, UK
| | - Thanapon Ekkunagul
- Division of Cellular Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arrott Drive, Dundee, Scotland, UK
| | - Christa Baker
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK
| | - Maureen Higgins
- Division of Cellular Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arrott Drive, Dundee, Scotland, UK
| | - Laura Tronci
- Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK
| | - Efterpi Nikitopolou
- Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK
| | - Tadashi Honda
- Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY, USA
| | | | - Luke A.J. O’Neill
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Christian Frezza
- Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK
| | - Angus I. Lamond
- Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, Scotland, UK
| | - Andrey Y. Abramov
- Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UK
| | - J. Simon C. Arthur
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK
| | - Doreen A. Cantrell
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK
| | - Michael P. Murphy
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
| | - Albena T. Dinkova-Kostova
- Division of Cellular Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arrott Drive, Dundee, Scotland, UK
- Department of Pharmacology and Molecular Sciences and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Sun Y, Lin X, Liu B, Zhang Y, Li W, Zhang S, He F, Tian H, Zhu X, Liu X, Wu J, Cai J, Li M. Loss of ATF4 leads to functional aging-like attrition of adult hematopoietic stem cells. SCIENCE ADVANCES 2021; 7:eabj6877. [PMID: 34936448 PMCID: PMC8694622 DOI: 10.1126/sciadv.abj6877] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
Aging of hematopoietic stem cells (HSCs) directly contributes to dysfunction of hematopoietic and immune systems due to aging-associated alterations in HSC features. How the function of adult HSCs is regulated during aging so that relevant pathologic abnormalities may occur, however, remains incompletely understood. Here, we report that ATF4 deficiency provokes severe HSC defects with multifaceted aging-like phenotype via cell-autonomous mechanisms. ATF4 deletion caused expansion of phenotypical HSCs with functional attrition, characterized by defective repopulating and self-renewal capacities and myeloid bias. Moreover, the ATF4−/− HSC defects were associated with elevated mitochondrial ROS production by targeting HIF1α. In addition, loss of ATF4 significantly delayed leukemogenesis in the MLL-AF9–induced leukemia model. Mechanistically, ATF4 deficiency impaired HSC function with aging-like phenotype and alleviated leukemogenesis by regulating HIF1α and p16Ink4a. Together, our findings suggest a possibility of developing new strategies for the prevention and management of HSC aging and related pathological conditions.
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Affiliation(s)
- Yan Sun
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
- Corresponding author. (M.L.); (Y.S.); (J.C.)
| | - Xiaolin Lin
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Bangdong Liu
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Yaxuan Zhang
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Wei Li
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Sheng Zhang
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Falian He
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Han Tian
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Xun Zhu
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Ximeng Liu
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Jueheng Wu
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Junchao Cai
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
- Corresponding author. (M.L.); (Y.S.); (J.C.)
| | - Mengfeng Li
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
- Corresponding author. (M.L.); (Y.S.); (J.C.)
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Kitakata H, Endo J, Matsushima H, Yamamoto S, Ikura H, Hirai A, Koh S, Ichihara G, Hiraide T, Moriyama H, Shirakawa K, Goto S, Katsumata Y, Anzai A, Kataoka M, Tokuyama T, Ishido S, Yanagi S, Fukuda K, Sano M. MITOL/MARCH5 determines the susceptibility of cardiomyocytes to doxorubicin-induced ferroptosis by regulating GSH homeostasis. J Mol Cell Cardiol 2021; 161:116-129. [PMID: 34390730 DOI: 10.1016/j.yjmcc.2021.08.006] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 08/02/2021] [Accepted: 08/08/2021] [Indexed: 12/27/2022]
Abstract
MITOL/MARCH5 is an E3 ubiquitin ligase that plays a crucial role in the control of mitochondrial quality and function. However, the significance of MITOL in cardiomyocytes under physiological and pathological conditions remains unclear. First, to determine the significance of MITOL in unstressed hearts, we assessed the cellular changes with the reduction of MITOL expression by siRNA in neonatal rat primary ventricular cardiomyocytes (NRVMs). MITOL knockdown in NRVMs induced cell death via ferroptosis, a newly defined non-apoptotic programmed cell death, even under no stress conditions. This phenomenon was observed only in NRVMs, not in other cell types. MITOL knockdown markedly reduced mitochondria-localized GPX4, a key enzyme associated with ferroptosis, promoting accumulation of lipid peroxides in mitochondria. In contrast, the activation of GPX4 in MITOL knockdown cells suppressed lipid peroxidation and cell death. MITOL knockdown reduced the glutathione/oxidized glutathione (GSH/GSSG) ratio that regulated GPX4 expression. Indeed, the administration of GSH or N-acetylcysteine improved the expression of GPX4 and viability in MITOL-knockdown NRVMs. MITOL-knockdown increased the expression of the glutathione-degrading enzyme, ChaC glutathione-specific γ-glutamylcyclotransferase 1 (Chac1). The knockdown of Chac1 restored the GSH/GSSG ratio, GPX4 expression, and viability in MITOL-knockdown NRVMs. Further, in cultured cardiomyocytes stressed with DOX, both MITOL and GPX4 were reduced, whereas forced-expression of MITOL suppressed DOX-induced ferroptosis by maintaining GPX4 content. Additionally, MITOL knockdown worsened vulnerability to DOX, which was almost completely rescued by treatment with ferrostatin-1, a ferroptosis inhibitor. In vivo, cardiac-specific depletion of MITOL did not produce obvious abnormality, but enhanced susceptibility to DOX toxicity. Finally, administration of ferrostatin-1 suppressed exacerbation of DOX-induced myocardial damage in MITOL-knockout hearts. The present study demonstrates that MITOL determines the cell fate of cardiomyocytes via the ferroptosis process and plays a key role in regulating vulnerability to DOX treatment. (288/300).
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Affiliation(s)
- Hiroki Kitakata
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Jin Endo
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
| | | | - Shoichi Yamamoto
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Hidehiko Ikura
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Akeo Hirai
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Seien Koh
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Genki Ichihara
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Takahiro Hiraide
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Hidenori Moriyama
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Kohsuke Shirakawa
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Shinichi Goto
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | | | - Atsushi Anzai
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Masaharu Kataoka
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Takeshi Tokuyama
- Laboratory of Molecular Biochemistry, School of Life Science. Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Satoshi Ishido
- Department of Microbiology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Shigeru Yanagi
- Laboratory of Molecular Biochemistry, School of Life Science. Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Keiichi Fukuda
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Motoaki Sano
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
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39
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Mitochondrial Management of Reactive Oxygen Species. Antioxidants (Basel) 2021; 10:antiox10111824. [PMID: 34829696 PMCID: PMC8614740 DOI: 10.3390/antiox10111824] [Citation(s) in RCA: 109] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 01/10/2023] Open
Abstract
Mitochondria in aerobic eukaryotic cells are both the site of energy production and the formation of harmful species, such as radicals and other reactive oxygen species, known as ROS. They contain an efficient antioxidant system, including low-molecular-mass molecules and enzymes that specialize in removing various types of ROS or repairing the oxidative damage of biological molecules. Under normal conditions, ROS production is low, and mitochondria, which are their primary target, are slightly damaged in a similar way to other cellular compartments, since the ROS released by the mitochondria into the cytosol are negligible. As the mitochondrial generation of ROS increases, they can deactivate components of the respiratory chain and enzymes of the Krebs cycle, and mitochondria release a high amount of ROS that damage cellular structures. More recently, the feature of the mitochondrial antioxidant system, which does not specifically deal with intramitochondrial ROS, was discovered. Indeed, the mitochondrial antioxidant system detoxifies exogenous ROS species at the expense of reducing the equivalents generated in mitochondria. Thus, mitochondria are also a sink of ROS. These observations highlight the importance of the mitochondrial antioxidant system, which should be considered in our understanding of ROS-regulated processes. These processes include cell signaling and the progression of metabolic and neurodegenerative disease.
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40
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Tian X, Zhang S, Zhou L, Seyhan AA, Hernandez Borrero L, Zhang Y, El-Deiry WS. Targeting the Integrated Stress Response in Cancer Therapy. Front Pharmacol 2021; 12:747837. [PMID: 34630117 PMCID: PMC8498116 DOI: 10.3389/fphar.2021.747837] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/10/2021] [Indexed: 12/11/2022] Open
Abstract
The integrated stress response (ISR) is an evolutionarily conserved intra-cellular signaling network which is activated in response to intrinsic and extrinsic stresses. Various stresses are sensed by four specialized kinases, PKR-like ER kinase (PERK), general control non-derepressible 2 (GCN2), double-stranded RNA-dependent protein kinase (PKR) and heme-regulated eIF2α kinase (HRI) that converge on phosphorylation of serine 51 of eIF2α. eIF2α phosphorylation causes a global reduction of protein synthesis and triggers the translation of specific mRNAs, including activating transcription factor 4 (ATF4). Although the ISR promotes cell survival and homeostasis, when stress is severe or prolonged the ISR signaling will shift to regulate cellular apoptosis. We review the ISR signaling pathway, regulation and importance in cancer therapy.
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Affiliation(s)
- Xiaobing Tian
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States.,Cancer Center at Brown University, Providence, RI, United States
| | - Shengliang Zhang
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States.,Cancer Center at Brown University, Providence, RI, United States
| | - Lanlan Zhou
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States.,Cancer Center at Brown University, Providence, RI, United States
| | - Attila A Seyhan
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States.,Cancer Center at Brown University, Providence, RI, United States
| | - Liz Hernandez Borrero
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
| | - Yiqun Zhang
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
| | - Wafik S El-Deiry
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States.,Cancer Center at Brown University, Providence, RI, United States.,Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, RI, United States
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41
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Song J, Yang X, Zhang M, Wang C, Chen L. Glutamate Metabolism in Mitochondria is Closely Related to Alzheimer's Disease. J Alzheimers Dis 2021; 84:557-578. [PMID: 34602474 DOI: 10.3233/jad-210595] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Glutamate is the main excitatory neurotransmitter in the brain, and its excitatory neurotoxicity is closely related to the occurrence and development of Alzheimer's disease. However, increasing evidence shows that in the process of Alzheimer's disease, glutamate is not only limited to its excitotoxicity as a neurotransmitter but also related to the disorder of its metabolic balance. The balance of glutamate metabolism in the brain is an important determinant of central nervous system health, and the maintenance of this balance is closely related to glutamate uptake, glutamate circulation, intracellular mitochondrial transport, and mitochondrial metabolism. In this paper, we intend to elaborate the key role of mitochondrial glutamate metabolism in the pathogenesis of Alzheimer's disease and review glutamate metabolism in mitochondria as a potential target in the treatment of Alzheimer's disease.
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Affiliation(s)
- Jiayi Song
- Department of Pharmacology, Basic College of Medicine, Jilin University, Changchun, People's Republic of China.,Cadre's Ward, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Xuehan Yang
- Department of Pharmacology, Basic College of Medicine, Jilin University, Changchun, People's Republic of China
| | - Ming Zhang
- Department of Pharmacology, Basic College of Medicine, Jilin University, Changchun, People's Republic of China
| | - Chunyan Wang
- Cadre's Ward, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Li Chen
- Department of Pharmacology, Basic College of Medicine, Jilin University, Changchun, People's Republic of China
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42
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Yang M, Luo S, Wang X, Li C, Yang J, Zhu X, Xiao L, Sun L. ER-Phagy: A New Regulator of ER Homeostasis. Front Cell Dev Biol 2021; 9:684526. [PMID: 34307364 PMCID: PMC8299523 DOI: 10.3389/fcell.2021.684526] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/04/2021] [Indexed: 12/17/2022] Open
Abstract
The endoplasmic reticulum (ER) is one of the most important cellular organelles and is essential for cell homeostasis. Upon external stimulation, ER stress induces the unfolded protein response (UPR) and ER-associated degradation (ERAD) to maintain ER homeostasis. However, persistent ER stress can lead to cell damage. ER-phagy is a selective form of autophagy that ensures the timely removal of damaged ER, thereby protecting cells from damage caused by excessive ER stress. As ER-phagy is a newly identified form of autophagy, many receptor-mediated ER-phagy pathways have been discovered in recent years. In this review, we summarize our understanding of the maintenance of ER homeostasis and describe the receptors identified to date. Finally, the relationships between ER-phagy and diseases are also discussed.
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Affiliation(s)
- Ming Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Shilu Luo
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Xi Wang
- Department of Nutrition, Xiangya Hospital, Central South University, Changsha, China
| | - Chenrui Li
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jinfei Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xuejing Zhu
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Li Xiao
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
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43
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D'Errico M, Parlanti E, Pascucci B, Filomeni G, Mastroberardino PG, Dogliotti E. The interplay between mitochondrial functionality and genome integrity in the prevention of human neurologic diseases. Arch Biochem Biophys 2021; 710:108977. [PMID: 34174223 DOI: 10.1016/j.abb.2021.108977] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 06/18/2021] [Accepted: 06/19/2021] [Indexed: 12/23/2022]
Abstract
As mitochondria are vulnerable to oxidative damage and represent the main source of reactive oxygen species (ROS), they are considered key tuners of ROS metabolism and buffering, whose dysfunction can progressively impact neuronal networks and disease. Defects in DNA repair and DNA damage response (DDR) may also affect neuronal health and lead to neuropathology. A number of congenital DNA repair and DDR defective syndromes, indeed, show neurological phenotypes, and a growing body of evidence indicate that defects in the mechanisms that control genome stability in neurons acts as aging-related modifiers of common neurodegenerative diseases such as Alzheimer, Parkinson's, Huntington diseases and Amyotrophic Lateral Sclerosis. In this review we elaborate on the established principles and recent concepts supporting the hypothesis that deficiencies in either DNA repair or DDR might contribute to neurodegeneration via mechanisms involving mitochondrial dysfunction/deranged metabolism.
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Affiliation(s)
| | - Eleonora Parlanti
- Department of Environment and Health, Istituto Superiore di Sanità, Rome, Italy
| | - Barbara Pascucci
- Institute of Crystallography, Consiglio Nazionale Delle Ricerche, Rome, Italy
| | - Giuseppe Filomeni
- Redox Biology, Danish Cancer Society Research Center, Copenhagen, Denmark; Center for Healthy Aging, Copenhagen University, Copenhagen, Denmark; Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Pier Giorgio Mastroberardino
- Department of Molecular Genetics, Erasmus MC, Rotterdam, the Netherlands; IFOM- FIRC Institute of Molecular Oncology, Milan, Italy; Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Eugenia Dogliotti
- Department of Environment and Health, Istituto Superiore di Sanità, Rome, Italy.
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44
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Vig S, Lambooij JM, Zaldumbide A, Guigas B. Endoplasmic Reticulum-Mitochondria Crosstalk and Beta-Cell Destruction in Type 1 Diabetes. Front Immunol 2021; 12:669492. [PMID: 33936111 PMCID: PMC8085402 DOI: 10.3389/fimmu.2021.669492] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 03/29/2021] [Indexed: 12/11/2022] Open
Abstract
Beta-cell destruction in type 1 diabetes (T1D) results from the combined effect of inflammation and recurrent autoimmunity. In response to inflammatory signals, beta-cells engage adaptive mechanisms where the endoplasmic reticulum (ER) and mitochondria act in concert to restore cellular homeostasis. In the recent years it has become clear that this adaptive phase may trigger the development of autoimmunity by the generation of autoantigens recognized by autoreactive CD8 T cells. The participation of the ER stress and the unfolded protein response to the increased visibility of beta-cells to the immune system has been largely described. However, the role of the other cellular organelles, and in particular the mitochondria that are central mediator for beta-cell survival and function, remains poorly investigated. In this review we will dissect the crosstalk between the ER and mitochondria in the context of T1D, highlighting the key role played by this interaction in beta-cell dysfunctions and immune activation, especially through regulation of calcium homeostasis, oxidative stress and generation of mitochondrial-derived factors.
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Affiliation(s)
- Saurabh Vig
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
| | - Joost M. Lambooij
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | - Arnaud Zaldumbide
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
| | - Bruno Guigas
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
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45
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Kong Q, Deng H, Li C, Wang X, Shimoda Y, Tao S, Kato K, Zhang J, Yamanaka K, An Y. Sustained high expression of NRF2 and its target genes induces dysregulation of cellular proliferation and apoptosis is associated with arsenite-induced malignant transformation of human bronchial epithelial cells. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 756:143840. [PMID: 33261869 DOI: 10.1016/j.scitotenv.2020.143840] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 10/14/2020] [Accepted: 11/06/2020] [Indexed: 06/12/2023]
Abstract
In arsenic toxicity, activation of the erythroid 2-related factor 2 (NRF2) pathway is regarded as a driver of cancer development and progression; however, the mechanisms by which NRF2 gene expression regulates cell cycle progression and mediates pathways of cellular proliferation and apoptosis in arsenic-induced lung carcinogenesis are poorly understood. In this study, we explored the regulatory functions of NRF2 expression and its target genes in immortalized human bronchial epithelial (HBE) cells continuously exposed to 1.0 μM sodium arsenite over approximately 43 passages (22 weeks). The experimental treatment induced malignant transformation in HBE cells, characterized by increased cellular proliferation and soft agar clone formation, as well as cell migration, and accelerated cell cycle progression from G0/G1 to S phase with increased levels of cyclin E-CDK2 complex,decreased cellular apoptosis rate. Moreover, we observed a sustained increase in NRF2 protein levels and those of its target gene products (NQO1, BCL-2) with concurrently decreased expression of apoptosis-related proteins (BAX, Cleaved-caspase-3/Caspase-3 and CHOP) and increased expression of the anti-apoptotic protein MCL-1. Silencing NRF2 expression with small interfering RNA (siRNA) in arsenite-transformed (T-HBE) cells was shown to reverse the malignant phenotype. Further, siRNA silencing of NQO1 significantly decreased levels of the cyclin E-CDK2 complex, inhibiting G0/G1 to S phase cell cycle progression and transformation to the T-HBE phenotypes. This study demonstrated a novel role for the NRF2/NQO1 signaling pathway in mediating arsenite-induced cell transformation by increasing the expression of cyclin E-CDK2, and accelerating the cell cycle and cell proliferation. Arsenite promotes activation of the NRF2/BCL-2 signaling pathway inhibited CHOP increasing cellular resistance to apoptosis and further promoting malignant transformation.
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Affiliation(s)
- Qi Kong
- Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou 215123, Jiangsu, China
| | - Hanyi Deng
- Shanghai Municipal Center for Disease Control and Prevention, Shanghai 200336, China
| | - Chunchun Li
- Changzhou Wujin District Center for Disease Control and Prevention, Changzhou 213164, Jiangsu, China
| | - Xiaojuan Wang
- Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou 215123, Jiangsu, China
| | - Yasuyo Shimoda
- Laboratory of Environmental Toxicology and Carcinogenesis, School of Pharmacy, Nihon University, Chiba 274-8555, Japan
| | - Shasha Tao
- Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou 215123, Jiangsu, China
| | - Koichi Kato
- Laboratory of Environmental Toxicology and Carcinogenesis, School of Pharmacy, Nihon University, Chiba 274-8555, Japan
| | - Jie Zhang
- Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou 215123, Jiangsu, China.
| | - Kenzo Yamanaka
- Laboratory of Environmental Toxicology and Carcinogenesis, School of Pharmacy, Nihon University, Chiba 274-8555, Japan.
| | - Yan An
- Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou 215123, Jiangsu, China.
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Pan S, Fan M, Liu Z, Li X, Wang H. Serine, glycine and one‑carbon metabolism in cancer (Review). Int J Oncol 2021; 58:158-170. [PMID: 33491748 PMCID: PMC7864012 DOI: 10.3892/ijo.2020.5158] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 11/19/2020] [Indexed: 12/11/2022] Open
Abstract
Serine/glycine biosynthesis and one‑carbon metabolism are crucial in sustaining cancer cell survival and rapid proliferation, and of high clinical relevance. Excessive activation of serine/glycine biosynthesis drives tumorigenesis and provides a single carbon unit for one‑carbon metabolism. One‑carbon metabolism, which is a complex cyclic metabolic network based on the chemical reaction of folate compounds, provides the necessary proteins, nucleic acids, lipids and other biological macromolecules to support tumor growth. Moreover, one‑carbon metabolism also maintains the redox homeostasis of the tumor microenvironment and provides substrates for the methylation reaction. The present study reviews the role of key enzymes with tumor‑promoting functions and important intermediates that are physiologically relevant to tumorigenesis in serine/glycine/one‑carbon metabolism pathways. The related regulatory mechanisms of action of the key enzymes and important intermediates in tumors are also discussed. It is hoped that investigations into these pathways will provide new translational opportunities for human cancer drug development, dietary interventions, and biomarker identification.
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Affiliation(s)
- Sijing Pan
- Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Kaifeng, Henan 475004, P.R. China
| | - Ming Fan
- Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Kaifeng, Henan 475004, P.R. China
| | - Zhangnan Liu
- Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Kaifeng, Henan 475004, P.R. China
| | - Xia Li
- Correspondence to: Dr Huijuan Wang or Dr Xia Li, Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Jinming Road, Kaifeng, Henan 475004, P.R. China, E-mail: , E-mail:
| | - Huijuan Wang
- Correspondence to: Dr Huijuan Wang or Dr Xia Li, Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Jinming Road, Kaifeng, Henan 475004, P.R. China, E-mail: , E-mail:
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P A, Bulbule SR, N H, G A, R.L B, K.S D. Elevation of gene expression of Btg2, Gadd 153, and antioxidant markers in RONS-induced PC12 cells. BENI-SUEF UNIVERSITY JOURNAL OF BASIC AND APPLIED SCIENCES 2020. [DOI: 10.1186/s43088-020-00080-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Free radicals generated in the biological system bring about modifications in biological molecules causing damage to their structure and function. Identifying the damage caused by ROS and RNS is important to predict the pathway of apoptosis due to stress in PC12 cells. The first defense mechanisms against them are antioxidants which act in various pathways through important cellular organelles like the mitochondria and endoplasmic reticulum. Specific biomarkers like Gadd153 which is a marker for endoplasmic reticulum stress, Nrf2 which responds to the redox changes and translocates the antioxidant response elements, and Btg2 which is an antioxidant regulator have not been addressed in different stress conditions previously in PC12 cells. Therefore, the study was conducted to analyze the gene expression pattern (SOD, Catalase, Btg2, Gadd153, and Nrf2) and the protein expression pattern (iNOS and MnSOD) of the antioxidant stress markers in differential stress-induced PC12 cells. Peroxynitrite (1 μM), rotenone (1 μM), H2O2(100 mM), and high glucose (33 mM) were used to induce oxidative and nitrosative stress in PC12 cells.
Results
The results obtained suggested that rotenone-induced PC12 cells showed a significant increase in the expression of catalase, Btg2, and Gadd153 compared to the control. Peroxynitrite-induced PC12 cells showed higher expression of Btg2 compared to the control. H2O2 and high glucose showed lesser expression compared to the control in all stress marker genes. In contrast, the Nrf2 gene expression is downregulated in all the stress-induced PC12 cells compared to the control. Further, MnSOD and iNOS protein expression studies suggest that PC12 cells exhibit a selective downregulation. Lower protein expression of MnSOD and iNOS may be resulted due to the mitochondrial dysfunction in peroxynitrite-, high glucose-, and H2O2-treated cells, whereas rotenone-induced cells showed lower expression, which could be the result of a dysfunction of the endoplasmic reticulum.
Conclusion
Different stress inducers like rotenone, peroxynitrite, H2O2, and high glucose increase the NO and ROS. Btg2 and Gadd153 genes were upregulated in the stress-induced cells, whereas the Nrf2 was significantly downregulated in differential stress-induced PC12 cells. Further, antioxidant marker genes were differentially expressed with different stress inducers.
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48
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ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress. Proc Natl Acad Sci U S A 2020; 117:31198-31207. [PMID: 33229544 PMCID: PMC7733819 DOI: 10.1073/pnas.1922342117] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mutations in ATP13A2 cause a spectrum of related neurodegenerative disorders. ATP13A2 is a lysosomal exporter of polyamines that contributes to lysosomal health and controls cellular polyamine content. Conversely, loss of ATP13A2 leads to lysosomal dysfunction, a hallmark of neurodegeneration. Here, we show that polyamines transported by ATP13A2 provide cellular protection by lowering reactive oxygen species (ROS), which may relate to the antioxidant properties of polyamines. Consequently, dysfunctional ATP13A2 sensitizes cells to oxidative stress, which impairs mitochondria, and induces toxicity and cell death. ATP13A2-mediated polyamine transport represents a conserved pathway that protects against mitochondrial oxidative stress. The combined protective impact of ATP13A2 on lysosomal health and mitochondrial oxidative stress may explain why ATP13A2 exerts potent neuroprotective effects. Recessive loss-of-function mutations in ATP13A2 (PARK9) are associated with a spectrum of neurodegenerative disorders, including Parkinson’s disease (PD). We recently revealed that the late endo-lysosomal transporter ATP13A2 pumps polyamines like spermine into the cytosol, whereas ATP13A2 dysfunction causes lysosomal polyamine accumulation and rupture. Here, we investigate how ATP13A2 provides protection against mitochondrial toxins such as rotenone, an environmental PD risk factor. Rotenone promoted mitochondrial-generated superoxide (MitoROS), which was exacerbated by ATP13A2 deficiency in SH-SY5Y cells and patient-derived fibroblasts, disturbing mitochondrial functionality and inducing toxicity and cell death. Moreover, ATP13A2 knockdown induced an ATF4-CHOP-dependent stress response following rotenone exposure. MitoROS and ATF4-CHOP were blocked by MitoTEMPO, a mitochondrial antioxidant, suggesting that the impact of ATP13A2 on MitoROS may relate to the antioxidant properties of spermine. Pharmacological inhibition of intracellular polyamine synthesis with α-difluoromethylornithine (DFMO) also increased MitoROS and ATF4 when ATP13A2 was deficient. The polyamine transport activity of ATP13A2 was required for lowering rotenone/DFMO-induced MitoROS, whereas exogenous spermine quenched rotenone-induced MitoROS via ATP13A2. Interestingly, fluorescently labeled spermine uptake in the mitochondria dropped as a consequence of ATP13A2 transport deficiency. Our cellular observations were recapitulated in vivo, in a Caenorhabditis elegans strain deficient in the ATP13A2 ortholog catp-6. These animals exhibited a basal elevated MitoROS level, mitochondrial dysfunction, and enhanced stress response regulated by atfs-1, the C. elegans ortholog of ATF4, causing hypersensitivity to rotenone, which was reversible with MitoTEMPO. Together, our study reveals a conserved cell protective pathway that counters mitochondrial oxidative stress via ATP13A2-mediated lysosomal spermine export.
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Goyal S, Chaturvedi RK. Mitochondrial Protein Import Dysfunction in Pathogenesis of Neurodegenerative Diseases. Mol Neurobiol 2020; 58:1418-1437. [PMID: 33180216 DOI: 10.1007/s12035-020-02200-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 11/03/2020] [Indexed: 02/06/2023]
Abstract
Mitochondria play an essential role in maintaining energy homeostasis and cellular survival. In the brain, higher ATP production is required by mature neurons for communication. Most of the mitochondrial proteins transcribe in the nucleus and import in mitochondria through different pathways of the mitochondrial protein import machinery. This machinery plays a crucial role in determining mitochondrial morphology and functions through mitochondrial biogenesis. Failure of this machinery and any alterations during mitochondrial biogenesis underlies neurodegeneration resulting in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD) etc. Current knowledge has revealed the different pathways of mitochondrial protein import machinery such as translocase of the outer mitochondrial membrane complex, the presequence pathway, carrier pathway, β-barrel pathway, and mitochondrial import and assembly machinery etc. In this review, we have discussed the recent studies regarding protein import machinery, beyond the well-known effects of increased oxidative stress and bioenergetics dysfunctions. We have elucidated in detail how these types of machinery help to import and locate the precursor proteins to their specific location inside the mitochondria and play a major role in mitochondrial biogenesis. We further discuss their involvement in mitochondrial dysfunctioning and the induction of toxic aggregates in neurodegenerative diseases like AD and PD. The review supports the importance of import machinery in neuronal functions and its association with toxic aggregated proteins in mitochondrial impairment, suggesting a critical role in fostering and maintaining neurodegeneration and therapeutic response.
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Affiliation(s)
- Shweta Goyal
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Rajnish Kumar Chaturvedi
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India. .,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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Autophagy and Redox Homeostasis in Parkinson's: A Crucial Balancing Act. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:8865611. [PMID: 33224433 PMCID: PMC7671810 DOI: 10.1155/2020/8865611] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/23/2020] [Accepted: 10/14/2020] [Indexed: 12/13/2022]
Abstract
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated primarily from endogenous biochemical reactions in mitochondria, endoplasmic reticulum (ER), and peroxisomes. Typically, ROS/RNS correlate with oxidative damage and cell death; however, free radicals are also crucial for normal cellular functions, including supporting neuronal homeostasis. ROS/RNS levels influence and are influenced by antioxidant systems, including the catabolic autophagy pathways. Autophagy is an intracellular lysosomal degradation process by which invasive, damaged, or redundant cytoplasmic components, including microorganisms and defunct organelles, are removed to maintain cellular homeostasis. This process is particularly important in neurons that are required to cope with prolonged and sustained operational stress. Consequently, autophagy is a primary line of protection against neurodegenerative diseases. Parkinson's is caused by the loss of midbrain dopaminergic neurons (mDANs), resulting in progressive disruption of the nigrostriatal pathway, leading to motor, behavioural, and cognitive impairments. Mitochondrial dysfunction, with associated increases in oxidative stress, and declining proteostasis control, are key contributors during mDAN demise in Parkinson's. In this review, we analyse the crosstalk between autophagy and redoxtasis, including the molecular mechanisms involved and the detrimental effect of an imbalance in the pathogenesis of Parkinson's.
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