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Delaney FT, Chung R, Blake MA, Sweeney AT. Imaging of Adrenal Masses. Endocr Pract 2025:S1530-891X(25)00894-8. [PMID: 40419086 DOI: 10.1016/j.eprac.2025.05.743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2025] [Revised: 05/16/2025] [Accepted: 05/20/2025] [Indexed: 05/28/2025]
Abstract
Adrenal lesions are common and require appropriate management when clinically relevant. The approach to the evaluation of an adrenal lesion is to exclude malignancy and hormone excess as these are associated with significant morbidity and mortality. Imaging of adrenal lesions primarily aims to identify features indicating benignity. Non-contrast CT is recommended as first-line imaging for adrenal lesions. Indeterminate lesions that require further characterization may proceed to adrenal protocol CT (with contrast) or MRI, with a trend in recent years towards increasing use of MRI. PET-CT may also be used to assess adrenal lesions in certain clinical scenarios. Clinical guidelines recommend that all adrenal incidentalomas require further dedicated imaging unless they are clearly benign on imaging. The imaging strategy of adrenal lesions depends upon a number of factors including patient history, nature of detection, imaging characteristics (size, heterogeneity, presence of intracellular lipid), and the presence or absence of hormone excess. Special considerations are given to pregnant patients, young patients < 40 years, and those with a history of an extra-adrenal malignancy. This review outlines the role of imaging for adrenal lesions, describes the various imaging options and investigation strategies, and highlights relevant imaging findings.
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Affiliation(s)
- Francis T Delaney
- Department of Radiology, Massachusetts General Hospital, Boston, MA.
| | - Ryan Chung
- Department of Radiology, Massachusetts General Hospital, Boston, MA; Instructor, Harvard Medical School, Boston, MA
| | - Michael A Blake
- Department of Radiology, Massachusetts General Hospital, Boston, MA; Associate Professor of Radiology, Harvard Medical School, Boston, MA
| | - Ann T Sweeney
- Department of Medicine, Division of Endocrinology, St Elizabeth's Medical Center, Brighton, MA; Associate Professor of Medicine, Tufts University School of Medicine, Boston, MA
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2
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Shiota Y, Kosaka T. Insight on flavinylation and functioning factor in Type B succinate dehydrogenase from Gram-positive bacteria. Biosci Biotechnol Biochem 2025; 89:832-840. [PMID: 40053489 DOI: 10.1093/bbb/zbaf026] [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: 12/12/2024] [Accepted: 03/01/2025] [Indexed: 03/09/2025]
Abstract
Succinate dehydrogenase (SDH), a multisubunit complex enzyme, catalyzes the oxidation of succinate to fumarate, coupled with quinone reduction. Maturation of each subunit and assembly of the complex is essential. However, little is known about the maturation mechanisms of SDH in Gram-positive bacteria. To elucidate the maturation of Type B SDH in Gram-positive bacteria, we heterologously expressed 3 SDH from Bacillus subtilis, Corynebacterium glutamicum, and Pelotomaculum thermopropionicum in Escherichia coli. The covalent binding of flavin adenine dinucleotide (FAD) at these SDH flavoprotein subunits was observed in heterologous expression as a complex. Their flavinylation was enhanced by the presence of the iron-sulfur subunit and fumarate. In contrast, the iron-sulfur subunit of heterologously expressed SDH without SDH activity showed no iron-sulfur clusters. These results suggest that during maturation of SDH, flavinylation is achieved by the complex and that other factors are required for the iron-sulfur cluster maturation.
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Affiliation(s)
- Yusuke Shiota
- Life Science, Graduate School of Science and Technology for Innovation, Yamaguchi University, Yamaguchi 753-8515, Japan
| | - Tomoyuki Kosaka
- Life Science, Graduate School of Science and Technology for Innovation, Yamaguchi University, Yamaguchi 753-8515, Japan
- Research Center for Thermotolerant Microbial Resources, Yamaguchi University, Yamaguchi 753-8515, Japan
- Department of Biological Chemistry, Faculty of Agriculture, Yamaguchi University, Yamaguchi 753-8515, Japan
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3
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Brewczyński A, Kolasińska-Ćwikła A, Jabłońska B, Wyrwicz L. Pheochromocytomas and Paragangliomas-Current Management. Cancers (Basel) 2025; 17:1029. [PMID: 40149362 PMCID: PMC11941679 DOI: 10.3390/cancers17061029] [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: 02/11/2025] [Revised: 03/14/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025] Open
Abstract
Pheochromocytomas and paragangliomas (PPGLs) are infrequent neuroendocrine hypervascular neoplasms arising within different sites of the paraganglion system. They are divided into sympathetic (including pheochromocytomas and extraadrenal paragangliomas) and parasympathetic extraadrenal tumors. These tumors are usually not malignant and grow slowly; about 90% of them are found in the adrenal paraganglia (pheochromocytomas). Extraadrenal tumors are most frequently located in the abdominal cavity (85%), followed by the thoracic cavity (12%), and head and neck (3%). About 25% of PPGLs are related to germline mutations, which are risk factors for multifocal and metastatic disease. In PPGL diagnostics, laboratory, biochemical, and imaging (anatomical and functional) examinations are used. Surgery is the standard management choice for locoregional disease. For patients who are not candidates for surgery and who have stable, not-growing, or slow-growing tumors, active observation or other less invasive techniques (i.e., stereotactic surgery, hypofractionated stereotactic radiotherapy) are considered. In metastatic disease, systemic therapies (tyrosine kinase inhibitors [TKIs], mTORC1 inhibitor everolimus, immunotherapy, cold somatostatin analogs [biotherapy], and radioligand therapy) are used. The prognosis for PPGLs is quite good, and the 5-year survival rate is >90%. The goal of this paper is to review knowledge on the etiopathogenesis, current diagnostics, and therapy for PPGL patients. Our paper is particularly focused on the current management of PPGLs.
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Affiliation(s)
- Adam Brewczyński
- Oncology and Radiotherapy Department, Maria Skłodowska-Curie National Research Institute of Oncology, 02-034 Warsaw, Poland; (A.K.-Ć.); (L.W.)
| | - Agnieszka Kolasińska-Ćwikła
- Oncology and Radiotherapy Department, Maria Skłodowska-Curie National Research Institute of Oncology, 02-034 Warsaw, Poland; (A.K.-Ć.); (L.W.)
| | - Beata Jabłońska
- Department of Digestive Tract Surgery, Medical University of Silesia, 40-752 Katowice, Poland
| | - Lucjan Wyrwicz
- Oncology and Radiotherapy Department, Maria Skłodowska-Curie National Research Institute of Oncology, 02-034 Warsaw, Poland; (A.K.-Ć.); (L.W.)
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Lanzetti L. Oncometabolites at the crossroads of genetic, epigenetic and ecological alterations in cancer. Cell Death Differ 2024; 31:1582-1594. [PMID: 39438765 PMCID: PMC11618380 DOI: 10.1038/s41418-024-01402-6] [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: 08/29/2024] [Revised: 10/16/2024] [Accepted: 10/18/2024] [Indexed: 10/25/2024] Open
Abstract
By the time a tumor reaches clinical detectability, it contains around 108-109 cells. However, during tumor formation, significant cell loss occurs due to cell death. In some estimates, it could take up to a thousand cell generations, over a ~ 20-year life-span of a tumor, to reach clinical detectability, which would correspond to a "theoretical" generation of ~1030 cells. These rough calculations indicate that cancers are under negative selection. The fact that they thrive implies that they "evolve", and that their evolutionary trajectories are shaped by the pressure of the environment. Evolvability of a cancer is a function of its heterogeneity, which could be at the genetic, epigenetic, and ecological/microenvironmental levels [1]. These principles were summarized in a proposed classification in which Evo (evolutionary) and Eco (ecological) indexes are used to label cancers [1]. The Evo index addresses cancer cell-autonomous heterogeneity (genetic/epigenetic). The Eco index describes the ecological landscape (non-cell-autonomous) in terms of hazards to cancer survival and resources available. The reciprocal influence of Evo and Eco components is critical, as it can trigger self-sustaining loops that shape cancer evolvability [2]. Among the various hallmarks of cancer [3], metabolic alterations appear unique in that they intersect with both Evo and Eco components. This is partly because altered metabolism leads to the accumulation of oncometabolites. These oncometabolites have traditionally been viewed as mediators of non-cell-autonomous alterations in the cancer microenvironment. However, they are now increasingly recognized as inducers of genetic and epigenetic modifications. Thus, oncometabolites are uniquely positioned at the crossroads of genetic, epigenetic and ecological alterations in cancer. In this review, the mechanisms of action of oncometabolites will be summarized, together with their roles in the Evo and Eco phenotypic components of cancer evolvability. An evolutionary perspective of the impact of oncometabolites on the natural history of cancer will be presented.
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Affiliation(s)
- Letizia Lanzetti
- Department of Oncology, University of Turin Medical School, Turin, Italy.
- Candiolo Cancer Institute, FPO-IRCCS, Str. Provinciale 142 km 3.95, 10060, Candiolo, Turin, Italy.
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Chen CL, Ishihara T, Pal S, Huang WL, Ogasawara E, Chang CR, Ishihara N. SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies. Mitochondrion 2024; 79:101952. [PMID: 39237068 DOI: 10.1016/j.mito.2024.101952] [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: 05/10/2024] [Revised: 08/18/2024] [Accepted: 08/27/2024] [Indexed: 09/07/2024]
Abstract
Succinate dehydrogenase (SDH) plays pivotal roles in maintaining cellular metabolism, modulating regulatory control over both the tricarboxylic acid cycle and oxidative phosphorylation to facilitate energy production within mitochondria. Given that SDH malfunction may serve as a hallmark triggering pseudo-hypoxia signaling and promoting tumorigenesis, elucidating the impact of SDH assembly defects on mitochondrial functions and cellular responses is of paramount importance. In this study, we aim to clarify the role of SDHAF2, one assembly factor of SDH, in mitochondrial respiratory activities. To achieve this, we utilize the CRISPR/Cas9 system to generate SDHAF2 knockout in HeLa cells and examine mitochondrial respiratory functions. Our findings demonstrate a substantial reduction in oxygen consumption rate in SDHAF2 knockout cells, akin to cells with inhibited SDH activity. In addition, in our in-gel activity assays reveal a significant decrease not only in SDH activity but also in cytochrome c oxidase (COX) activity in SDHAF2 knockout cells. The reduced COX activity is attributed to the assembly defect and remains independent of SDH inactivation or SDH complex disassembly. Together, our results indicate a critical role of SDHAF2 in regulating respiration by facilitating the assembly of COX.
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Affiliation(s)
- Chang-Lin Chen
- Institute of Biotechnology, National Tsing Hua University, Hsinchu 300044, Taiwan; Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
| | - Takaya Ishihara
- Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan; Department of Life Science, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan
| | - Soumyadip Pal
- Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
| | - Wei-Ling Huang
- Institute of Biotechnology, National Tsing Hua University, Hsinchu 300044, Taiwan
| | - Emi Ogasawara
- Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
| | - Chuang-Rung Chang
- Institute of Biotechnology, National Tsing Hua University, Hsinchu 300044, Taiwan; Department of Medical Science, National Tsing Hua University, Hsinchu 300044, Taiwan; School of Medicine, National Tsing Hua University, Hsinchu 300044, Taiwan.
| | - Naotada Ishihara
- Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan.
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Hossen MS, Akter A, Azmal M, Rayhan M, Islam KS, Islam MM, Ahmed S, Abdullah-Al-Shoeb M. Unveiling the molecular basis of paracetamol-induced hepatotoxicity: Interaction of N-acetyl- p-benzoquinone imine with mitochondrial succinate dehydrogenase. Biochem Biophys Rep 2024; 38:101727. [PMID: 38766381 PMCID: PMC11098724 DOI: 10.1016/j.bbrep.2024.101727] [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: 12/20/2023] [Revised: 03/13/2024] [Accepted: 04/30/2024] [Indexed: 05/22/2024] Open
Abstract
Background and aim N-acetyl-p-benzoquinoneimine (NAPQI), a toxic byproduct of paracetamol (Acetaminophen, APAP), can accumulate and cause liver damage by depleting glutathione and forming protein adducts in the mitochondria. These adducts disrupt the respiratory chain, increasing superoxide production and reducing ATP. The goal of this study was to provide computational proof that succinate dehydrogenase (SDH), a subunit of complex II in the mitochondrial respiratory chain, is a favorable binding partner for NAPQI in this regard. Method Molecular docking, molecular dynamics simulation, protein-protein interaction networks (PPI), and KEGG metabolic pathway analysis were employed to identify binding characteristics, interaction partners, and their associations with metabolic pathways. A lipid membrane was added to the experimental apparatus to mimic the natural cellular environment of SDH. This modification made it possible to develop a context for investigating the role and interactions of SDH within a cellular ecosystem that was more realistic and biologically relevant. Result The molecular binding affinity score for APAP and NAPQI with SDH was predicted -6.5 and -6.7 kcal/mol, respectively. Furthermore, RMSD, RMSF, and Rog from the molecular dynamics simulations study revealed that NAPQI has slightly higher stability and compactness compared to APAP at 100 ns timeframe with mitochondrial SDH. Conclusion This study serves to predict the mechanistic process of paracetamol toxicity by using different computational approaches. In addition, this study will provide information about the drug target against APAP hepatotoxicity.
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Affiliation(s)
- Md Sahadot Hossen
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Adiba Akter
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Mahir Azmal
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Mostakim Rayhan
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Kazi Saiful Islam
- Department of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka, Bangladesh
| | - Md Mahmodul Islam
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali 3814, Bangladesh
| | - Shamim Ahmed
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Mohammad Abdullah-Al-Shoeb
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
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7
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Zhu LH, Yang J, Zhang YF, Yan L, Lin WR, Liu WQ. Identification and validation of a pyroptosis-related prognostic model for colorectal cancer based on bulk and single-cell RNA sequencing data. World J Clin Oncol 2024; 15:329-355. [PMID: 38455135 PMCID: PMC10915942 DOI: 10.5306/wjco.v15.i2.329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 12/24/2023] [Accepted: 01/15/2024] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND Pyroptosis impacts the development of malignant tumors, yet its role in colorectal cancer (CRC) prognosis remains uncertain. AIM To assess the prognostic significance of pyroptosis-related genes and their association with CRC immune infiltration. METHODS Gene expression data were obtained from The Cancer Genome Atlas (TCGA) and single-cell RNA sequencing dataset GSE178341 from the Gene Expression Omnibus (GEO). Pyroptosis-related gene expression in cell clusters was analyzed, and enrichment analysis was conducted. A pyroptosis-related risk model was developed using the LASSO regression algorithm, with prediction accuracy assessed through K-M and receiver operating characteristic analyses. A nomogram predicting survival was created, and the correlation between the risk model and immune infiltration was analyzed using CIBERSORTx calculations. Finally, the differential expression of the 8 prognostic genes between CRC and normal samples was verified by analyzing TCGA-COADREAD data from the UCSC database. RESULTS An effective pyroptosis-related risk model was constructed using 8 genes-CHMP2B, SDHB, BST2, UBE2D2, GJA1, AIM2, PDCD6IP, and SEZ6L2 (P < 0.05). Seven of these genes exhibited differential expression between CRC and normal samples based on TCGA database analysis (P < 0.05). Patients with higher risk scores demonstrated increased death risk and reduced overall survival (P < 0.05). Significant differences in immune infiltration were observed between low- and high-risk groups, correlating with pyroptosis-related gene expression. CONCLUSION We developed a pyroptosis-related prognostic model for CRC, affirming its correlation with immune infiltration. This model may prove useful for CRC prognostic evaluation.
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Affiliation(s)
- Li-Hua Zhu
- Department of Surgical Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jun Yang
- Department of Surgical Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Yun-Fei Zhang
- Department of Surgical Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Li Yan
- Department of Internal Medicine-Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Wan-Rong Lin
- Department of Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Wei-Qing Liu
- Department of Internal Medicine-Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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8
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Sharma P, Maklashina E, Voehler M, Balintova S, Dvorakova S, Kraus M, Hadrava Vanova K, Nahacka Z, Zobalova R, Boukalova S, Cunatova K, Mracek T, Ghayee HK, Pacak K, Rohlena J, Neuzil J, Cecchini G, Iverson TM. Disordered-to-ordered transitions in assembly factors allow the complex II catalytic subunit to switch binding partners. Nat Commun 2024; 15:473. [PMID: 38212624 PMCID: PMC10784507 DOI: 10.1038/s41467-023-44563-7] [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: 11/29/2022] [Accepted: 12/19/2023] [Indexed: 01/13/2024] Open
Abstract
Complex II (CII) activity controls phenomena that require crosstalk between metabolism and signaling, including neurodegeneration, cancer metabolism, immune activation, and ischemia-reperfusion injury. CII activity can be regulated at the level of assembly, a process that leverages metastable assembly intermediates. The nature of these intermediates and how CII subunits transfer between metastable complexes remains unclear. In this work, we identify metastable species containing the SDHA subunit and its assembly factors, and we assign a preferred temporal sequence of appearance of these species during CII assembly. Structures of two species show that the assembly factors undergo disordered-to-ordered transitions without the appearance of significant secondary structure. The findings identify that intrinsically disordered regions are critical in regulating CII assembly, an observation that has implications for the control of assembly in other biomolecular complexes.
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Affiliation(s)
- Pankaj Sharma
- Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA
| | - Elena Maklashina
- Molecular Biology Division, San Francisco VA Health Care System, San Francisco, CA, 94121, USA
- Department of Biochemistry & Biophysics, University of California, San Francisco, CA, 94158, USA
| | - Markus Voehler
- Department of Chemistry Vanderbilt University, Nashville, TN, 37232, USA
- Center for Structural Biology Vanderbilt University, Nashville, TN, 37232, USA
| | - Sona Balintova
- Institute of Biotechnology, Czech Academy of Sciences, 252 50, Prague-West, Czech Republic
- Faculty of Science, Charles University, 128 00, Prague 2, Czech Republic
| | - Sarka Dvorakova
- Institute of Biotechnology, Czech Academy of Sciences, 252 50, Prague-West, Czech Republic
| | - Michal Kraus
- Institute of Biotechnology, Czech Academy of Sciences, 252 50, Prague-West, Czech Republic
| | - Katerina Hadrava Vanova
- Institute of Biotechnology, Czech Academy of Sciences, 252 50, Prague-West, Czech Republic
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20814, USA
| | - Zuzana Nahacka
- Institute of Biotechnology, Czech Academy of Sciences, 252 50, Prague-West, Czech Republic
| | - Renata Zobalova
- Institute of Biotechnology, Czech Academy of Sciences, 252 50, Prague-West, Czech Republic
| | - Stepana Boukalova
- Institute of Biotechnology, Czech Academy of Sciences, 252 50, Prague-West, Czech Republic
| | - Kristyna Cunatova
- Institute of Physiology, Czech Academy of Sciences, Prague 4, 142 20, Prague, Czech Republic
| | - Tomas Mracek
- Institute of Physiology, Czech Academy of Sciences, Prague 4, 142 20, Prague, Czech Republic
| | - Hans K Ghayee
- Department of Medicine, Division of Endocrinology & Metabolism, University of Florida College of Medicine and Malcom Randall, VA Medical Center, Gainesville, FL, 32608, USA
| | - Karel Pacak
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20814, USA
| | - Jakub Rohlena
- Institute of Biotechnology, Czech Academy of Sciences, 252 50, Prague-West, Czech Republic
| | - Jiri Neuzil
- Institute of Biotechnology, Czech Academy of Sciences, 252 50, Prague-West, Czech Republic.
- Faculty of Science, Charles University, 128 00, Prague 2, Czech Republic.
- School of Pharmacy and Medical Science, Griffith University, Southport, QLD, 4222, Australia.
- 1st Faculty of Medicine, Charles University, 128 00, Prague 2, Czech Republic.
| | - Gary Cecchini
- Molecular Biology Division, San Francisco VA Health Care System, San Francisco, CA, 94121, USA.
- Department of Biochemistry & Biophysics, University of California, San Francisco, CA, 94158, USA.
| | - T M Iverson
- Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA.
- Center for Structural Biology Vanderbilt University, Nashville, TN, 37232, USA.
- Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
- Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN, 37232, USA.
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9
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Marumo T, Maduka CV, Ural E, Apu EH, Chung SJ, Tanabe K, van den Berg NS, Zhou Q, Martin BA, Miura T, Rosenthal EL, Shibahara T, Contag CH. Flavinated SDHA underlies the change in intrinsic optical properties of oral cancers. Commun Biol 2023; 6:1134. [PMID: 37945749 PMCID: PMC10636189 DOI: 10.1038/s42003-023-05510-w] [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: 11/25/2021] [Accepted: 10/26/2023] [Indexed: 11/12/2023] Open
Abstract
The molecular basis of reduced autofluorescence in oral squamous cell carcinoma (OSCC) cells relative to normal cells has been speculated to be due to lower levels of free flavin adenine dinucleotide (FAD). This speculation, along with differences in the intrinsic optical properties of extracellular collagen, lies at the foundation of the design of currently-used clinical optical detection devices. Here, we report that free FAD levels may not account for differences in autofluorescence of OSCC cells, but that the differences relate to FAD as a co-factor for flavination. Autofluorescence from a 70 kDa flavoprotein, succinate dehydrogenase A (SDHA), was found to be responsible for changes in optical properties within the FAD spectral region, with lower levels of flavinated SDHA in OSCC cells. Since flavinated SDHA is required for functional complexation with succinate dehydrogenase B (SDHB), decreased SDHB levels were observed in human OSCC tissue relative to normal tissues. Accordingly, the metabolism of OSCC cells was found to be significantly altered relative to normal cells, revealing vulnerabilities for both diagnosis and targeted therapy. Optimizing non-invasive tools based on optical and metabolic signatures of cancers will enable more precise and early diagnosis leading to improved outcomes in patients.
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Affiliation(s)
- Tomoko Marumo
- Department of Oral and Maxillofacial Surgery, Tokyo Dental College, 2-9-18 Kanda-Misakicho, Chiyoda-ku, Tokyo, 101-0061, Japan
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI, 48824, USA
- Institute for Quantitative Health Science & Engineering, Michigan State University, East Lansing, MI, 48824, USA
| | - Chima V Maduka
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI, 48824, USA
- Institute for Quantitative Health Science & Engineering, Michigan State University, East Lansing, MI, 48824, USA
- Comparative Medicine & Integrative Biology, Michigan State University, East Lansing, MI, 48824, USA
- BioFrontiers Institute, University of Colorado, Boulder, CO, 80303, USA
| | - Evran Ural
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI, 48824, USA
- Institute for Quantitative Health Science & Engineering, Michigan State University, East Lansing, MI, 48824, USA
| | - Ehsanul Hoque Apu
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI, 48824, USA
- Institute for Quantitative Health Science & Engineering, Michigan State University, East Lansing, MI, 48824, USA
- Division of Hematology and Oncology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Seock-Jin Chung
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI, 48824, USA
- Institute for Quantitative Health Science & Engineering, Michigan State University, East Lansing, MI, 48824, USA
| | - Koji Tanabe
- Department of Biomedical Engineering, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
| | - Nynke S van den Berg
- Department of Otolaryngology - Division of Head and Neck Surgery, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA
| | - Quan Zhou
- Department of Otolaryngology - Division of Head and Neck Surgery, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA
| | - Brock A Martin
- Department of Pathology, Stanford University School of Medicine, 3100 Pasteur Drive, Stanford, CA, 94305, USA
| | - Tadashi Miura
- Oral Health Science Center, Tokyo Dental College, 2-1-14 Kanda-Misakicho, Chiyoda-ku, Tokyo, 101-0061, Japan
| | - Eben L Rosenthal
- Department of Otolaryngology - Division of Head and Neck Surgery, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA
- Department of Otolaryngology - Head and Neck Surgery, Vanderbilt University Medical Center, 1211 Medical Center Dr, Nashville, TN, 37232, USA
| | - Takahiko Shibahara
- Department of Oral and Maxillofacial Surgery, Tokyo Dental College, 2-9-18 Kanda-Misakicho, Chiyoda-ku, Tokyo, 101-0061, Japan
| | - Christopher H Contag
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI, 48824, USA.
- Institute for Quantitative Health Science & Engineering, Michigan State University, East Lansing, MI, 48824, USA.
- Department of Microbiology & Molecular Genetics, Michigan State University, East Lansing, MI, 48824, USA.
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10
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Lin HH, Chang CY, Huang YR, Shen CH, Wu YC, Chang KL, Lee YC, Lin YC, Ting WC, Chien HJ, Zheng YF, Lai CC, Hsiao KY. Exon Junction Complex Mediates the Cap-Independent Translation of Circular RNA. Mol Cancer Res 2023; 21:1220-1233. [PMID: 37527157 DOI: 10.1158/1541-7786.mcr-22-0877] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 06/22/2023] [Accepted: 07/25/2023] [Indexed: 08/03/2023]
Abstract
Evidence that circular RNAs (circRNA) serve as protein template is accumulating. However, how the cap-independent translation is controlled remains largely uncharacterized. Here, we show that the presence of intron and thus splicing promote cap-independent translation. By acquiring the exon junction complex (EJC) after splicing, the interaction between circRNA and ribosomes was promoted, thereby facilitating translation. Prevention of splicing by treatment with spliceosome inhibitor or mutating splicing signal hindered cap-independent translation of circRNA. Moreover, EJC-tethering using Cas13 technology reconstituted EJC-dependent circRNA translation. Finally, the level of a coding circRNA from succinate dehydrogenase assembly factor 2 (circSDHAF2) was found to be elevated in the tumorous tissues from patients with colorectal cancer, and shown to be critical in tumorigenesis of colorectal cancer in both cell and murine models. These findings reveal that EJC-dependent control of circSDHAF2 translation is involved in the regulation of oncogenic pathways. IMPLICATIONS EJC-mediated cap-independent translation of circRNA is implicated in the tumorigenesis of colorectal cancer.
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Affiliation(s)
- Hui-Hsuan Lin
- Doctoral Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung, Taiwan
- Institute of Biochemistry, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Chiu-Yuan Chang
- Institute of Biochemistry, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Yi-Ren Huang
- Institute of Biochemistry, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Che-Hung Shen
- Doctoral Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Yu-Chen Wu
- Institute of Biochemistry, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Kai-Li Chang
- Department of Physiology, National Cheng Kung University, Tainan, Taiwan
| | - Yueh-Chun Lee
- Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Ya-Chi Lin
- Department of Plant Pathology, College of Agriculture and Natural Resources, National Chung Hsing University, Taichung, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan
| | - Wen-Chien Ting
- Division of Colorectal Surgery, Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Han-Ju Chien
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan
| | - Yi-Feng Zheng
- Institute of Molecular Biology, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Chien-Chen Lai
- Institute of Molecular Biology, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Kuei-Yang Hsiao
- Doctoral Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung, Taiwan
- Institute of Biochemistry, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan
- Doctoral Program in Translational Medicine, College of Life Sciences, National Chung Hsing University, Taichung
- Rong Hsing Research Center for Translational Medicine, College of Life Sciences, National Chung Hsing University, Taichung
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11
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Kamradt ML, Makarewich CA. Mitochondrial microproteins: critical regulators of protein import, energy production, stress response pathways, and programmed cell death. Am J Physiol Cell Physiol 2023; 325:C807-C816. [PMID: 37642234 PMCID: PMC11540166 DOI: 10.1152/ajpcell.00189.2023] [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: 05/05/2023] [Revised: 08/15/2023] [Accepted: 08/16/2023] [Indexed: 08/31/2023]
Abstract
Mitochondria rely upon the coordination of protein import, protein translation, and proper functioning of oxidative phosphorylation (OXPHOS) complexes I-V to sustain the activities of life for an organism. Each process is dependent upon the function of profoundly large protein complexes found in the mitochondria [translocase of the outer mitochondrial membrane (TOMM) complex, translocase of the inner mitochondrial membrane (TIMM) complex, OXPHOS complexes, mitoribosomes]. These massive protein complexes, in some instances more than one megadalton, are built up from numerous protein subunits of varying sizes, including many proteins that are ≤100-150 amino acids. However, these small proteins, termed microproteins, not only act as cogs in large molecular machines but also have important steps in inhibiting or promoting the intrinsic pathway of apoptosis, coordinate responses to cellular stress, and even act as hormones. This review focuses on microproteins that occupy the mitochondria and are critical for its function. Although the microprotein field is relatively new, researchers have long recognized the existence of these mitochondrial proteins as critical components of virtually all aspects of mitochondrial biology. Thus, recent studies estimating that hundreds of new microproteins of unknown function exist and are missing from current genome annotations suggests that the mitochondrial "microproteome" is a rich area for future biological investigation.
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Affiliation(s)
- Michael L Kamradt
- Division of Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
| | - Catherine A Makarewich
- Division of Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
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12
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Duarte Hospital C, Tête A, Debizet K, Imler J, Tomkiewicz-Raulet C, Blanc EB, Barouki R, Coumoul X, Bortoli S. SDHi fungicides: An example of mitotoxic pesticides targeting the succinate dehydrogenase complex. ENVIRONMENT INTERNATIONAL 2023; 180:108219. [PMID: 37778286 DOI: 10.1016/j.envint.2023.108219] [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: 03/11/2023] [Revised: 06/15/2023] [Accepted: 09/18/2023] [Indexed: 10/03/2023]
Abstract
Succinate dehydrogenase inhibitors (SDHi) are fungicides used to control the proliferation of pathogenic fungi in crops. Their mode of action is based on blocking the activity of succinate dehydrogenase (SDH), a universal enzyme expressed by all species harboring mitochondria. The SDH is involved in two interconnected metabolic processes for energy production: the transfer of electrons in the mitochondrial respiratory chain and the oxidation of succinate to fumarate in the Krebs cycle. In humans, inherited SDH deficiencies may cause major pathologies including encephalopathies and cancers. The cellular and molecular mechanisms related to such genetic inactivation have been well described in neuroendocrine tumors, in which it induces an oxidative stress, a pseudohypoxic phenotype, a metabolic, epigenetic and transcriptomic remodeling, and alterations in the migration and invasion capacities of cancer cells, in connection with the accumulation of succinate, an oncometabolite, substrate of the SDH. We will discuss recent studies reporting toxic effects of SDHi in non-target organisms and their implications for risk assessment of pesticides. Recent data show that the SDH structure is highly conserved during evolution and that SDHi can inhibit SDH activity in mitochondria of non-target species, including humans. These observations suggest that SDHi are not specific inhibitors of fungal SDH. We hypothesize that SDHi could have toxic effects in other species, including humans. Moreover, the analysis of regulatory assessment reports shows that most SDHi induce tumors in animals without evidence of genotoxicity. Thus, these substances could have a non-genotoxic mechanism of carcinogenicity that still needs to be fully characterized and that could be related to SDH inhibition. The use of pesticides targeting mitochondrial enzymes encoded by tumor suppressor genes raises questions on the risk assessment framework of mitotoxic pesticides. The issue of SDHi fungicides is therefore a textbook case that highlights the urgent need for changes in regulatory assessment.
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Affiliation(s)
| | - Arnaud Tête
- Université Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 Paris
| | - Kloé Debizet
- Université Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 Paris
| | - Jules Imler
- Université Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 Paris
| | | | - Etienne B Blanc
- Université Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 Paris
| | - Robert Barouki
- Université Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 Paris
| | - Xavier Coumoul
- Université Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 Paris.
| | - Sylvie Bortoli
- Université Paris Cité, INSERM UMR-S 1124, T3S, 45 rue des Saints-Pères, 75006 Paris.
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13
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Cao K, Xu J, Cao W, Wang X, Lv W, Zeng M, Zou X, Liu J, Feng Z. Assembly of mitochondrial succinate dehydrogenase in human health and disease. Free Radic Biol Med 2023; 207:247-259. [PMID: 37490987 DOI: 10.1016/j.freeradbiomed.2023.07.023] [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] [Received: 05/03/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 07/27/2023]
Abstract
Mitochondrial succinate dehydrogenase (SDH), also known as electron transport chain (ETC) Complex II, is the only enzyme complex engaged in both oxidative phosphorylation and the tricarboxylic acid (TCA) cycle. SDH has received increasing attention due to its crucial role in regulating mitochondrial metabolism and human health. Despite having the fewest subunits among the four ETC complexes, functional SDH is formed via a sequential and well-coordinated assembly of subunits. Along with the discovery of subunit-specific assembly factors, the dynamic involvement of the SDH assembly process in a broad range of diseases has been revealed. Recently, we reported that perturbation of SDH assembly in different tissues leads to interesting and distinct pathophysiological changes in mice, indicating a need to understand the intricate SDH assembly process in human health and diseases. Thus, in this review, we summarize recent findings on SDH pathogenesis with respect to disease and a focus on SDH assembly.
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Affiliation(s)
- Ke Cao
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, Shaanxi, China; Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Jie Xu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, Shaanxi, China
| | - Wenli Cao
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, Shaanxi, China
| | - Xueqiang Wang
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266071, China
| | - Weiqiang Lv
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, Shaanxi, China
| | - Mengqi Zeng
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266071, China
| | - Xuan Zou
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China
| | - Jiankang Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, Shaanxi, China; School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266071, China.
| | - Zhihui Feng
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China; School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266071, China.
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14
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Rosenthal GE, McClain DA, High KP, Easterling D, Sharkey A, Wagenknecht LE, O’Byrne C, Woodside R, Houston TK. The Academic Learning Health System: A Framework for Integrating the Multiple Missions of Academic Medical Centers. ACADEMIC MEDICINE : JOURNAL OF THE ASSOCIATION OF AMERICAN MEDICAL COLLEGES 2023; 98:1002-1007. [PMID: 37099650 PMCID: PMC10453356 DOI: 10.1097/acm.0000000000005259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
The learning health system (LHS) has emerged over the past 15 years as a concept for improving health care delivery. Core aspects of the LHS concept include: promoting improved patient care through organizational learning, innovation, and continuous quality improvement; identifying, critically assessing, and translating knowledge and evidence into improved practices; building new knowledge and evidence around how to improve health care and health outcomes; analyzing clinical data to support learning, knowledge generation, and improved patient care; and engaging clinicians, patients, and other stakeholders in processes of learning, knowledge generation, and translation. However, the literature has paid less attention to how these LHS aspects may integrate with the multiple missions of academic medical centers (AMCs). The authors define an academic learning health system (aLHS) as an LHS built around a robust academic community and central academic mission, and they propose 6 features that emphasize how an aLHS differs from an LHS. An aLHS capitalizes on embedded academic expertise in health system sciences; engages the full spectrum of translational investigation from mechanistic basic sciences to population health; builds pipelines of experts in LHS sciences and clinicians with fluency in practicing in an LHS; applies core LHS principles to the development of curricula and clinical rotations for medical students, housestaff, and other learners; disseminates knowledge more broadly to advance the evidence for clinical practice and health systems science methods; and addresses social determinants of health, creating community partnerships to mitigate disparities and improve health equity. As AMCs evolve, the authors expect that additional differentiating features and ways to operationalize the aLHS will be identified and hope this article stimulates further discussion around the intersection of the LHS concept and AMCs.
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Affiliation(s)
- Gary E. Rosenthal
- G.E. Rosenthal is professor and chair, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Donald A. McClain
- D.A. McClain is professor, Department of Internal Medicine, Section on Endocrinology and Metabolism, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Kevin P. High
- K.P. High is professor, Department of Internal Medicine, and president, Atrium Health Wake Forest Baptist, Winston-Salem, North Carolina
| | - Douglas Easterling
- D. Easterling is professor, Department of Social Sciences and Health Policy, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Angela Sharkey
- A. Sharkey is professor, Department of Pediatrics, and senior associate dean for undergraduate medical education, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Lynne E. Wagenknecht
- L.E. Wagenknecht is professor and chair, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Christopher O’Byrne
- C. O’Byrne is vice president and associate dean, Research Administration and Operations, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Rachel Woodside
- R. Woodside is director, Research Strategy and Operations, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Thomas K. Houston
- T.K. Houston is professor and vice chair for learning health systems, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
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15
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Shi C, Liu JZ, Zeng ZP, Miao Q, Fang LG, Chen S, Ping F, Sun H, Lu L, Chen LB, Fu Y, Zhao DC, Yu CH, JiaJue RZ, Wang X, Liu XR, Ma GT, Zhang CJ, Pan H, Yang HB, Wang YN, Li M, Li F, Shen ZJ, Liang ZY, Xing XP, Zhu WL. Diagnosis, Genetics, and Management of 24 Patients With Cardiac Paragangliomas: Experience From a Single Center. J Endocr Soc 2023; 7:bvad093. [PMID: 37873498 PMCID: PMC10590637 DOI: 10.1210/jendso/bvad093] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Indexed: 10/25/2023] Open
Abstract
Context Paragangliomas located within the pericardium represent a rare yet challenging clinical situation. Objective The current analysis aimed to describe the clinical characteristics of cardiac paragangliomas, with emphasis on the diagnostic approach, genetic background, and multidisciplinary management. Methods Twenty-four patients diagnosed with cardiac paraganglioma (PGL) in Peking Union Medical College Hospital, Beijing, China, between 2003 and 2021 were identified. Clinical data was collected from medical record. Genetic screening and succinate dehydrogenase subunit B immunohistochemistry were performed in 22 patients. Results The median age at diagnosis was 38 years (range 11-51 years), 8 patients (33%) were females, and 4 (17%) had familial history. Hypertension and/or symptoms related to catecholamine secretion were present in 22 (92%) patients. Excess levels of catecholamines and/or metanephrines were detected in 22 (96%) of the 23 patients who have completed biochemical testing. Cardiac PGLs were localized with 131I-metaiodobenzylguanidine scintigraphy in 11/22 (50%), and 99mTc-hydrazinonicotinyl-tyr3-octreotide scintigraphy in 24/24 (100%) patients. Genetic testing identified germline SDHx mutations in 13/22 (59%) patients, while immunohistochemistry revealed succinate dehydrogenase (SDH) deficiency in tumors from 17/22 (77%) patients. All patients were managed by a multidisciplinary team through medical preparation, surgery, and follow-up. Twenty-three patients received surgical treatment and perioperative death occurred in 2 cases. Overall, 21 patients were alive at follow-up (median 7.0 years, range 0.6-18 years). Local recurrence or metastasis developed in 3 patients, all of whom had SDH-deficient tumors. Conclusion Cardiac PGLs can be diagnosed based on clinical manifestations, biochemical tests, and appropriate imaging studies. Genetic screening, multidisciplinary approach, and long-term follow-up are crucial in the management of this disease.
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Affiliation(s)
- Chuan Shi
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Jian-Zhou Liu
- Department of Cardiac Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Zheng-Pei Zeng
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Qi Miao
- Department of Cardiac Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Li-Gang Fang
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Shi Chen
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Fan Ping
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Hao Sun
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Lin Lu
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Li-Bo Chen
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Yong Fu
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Da-Chun Zhao
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Chun-Hua Yu
- Department of Anesthesiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Rui-Zhi JiaJue
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xi Wang
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xing-Rong Liu
- Department of Cardiac Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Guo-Tao Ma
- Department of Cardiac Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Chao-Ji Zhang
- Department of Cardiac Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Hui Pan
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Hong-Bo Yang
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yi-Ning Wang
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Ming Li
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Fang Li
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Zhu-Jun Shen
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Zhi-Yong Liang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Xiao-Ping Xing
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Wen-Ling Zhu
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
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Iverson TM, Singh PK, Cecchini G. An evolving view of complex II-noncanonical complexes, megacomplexes, respiration, signaling, and beyond. J Biol Chem 2023; 299:104761. [PMID: 37119852 PMCID: PMC10238741 DOI: 10.1016/j.jbc.2023.104761] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/20/2023] [Accepted: 04/22/2023] [Indexed: 05/01/2023] Open
Abstract
Mitochondrial complex II is traditionally studied for its participation in two key respiratory processes: the electron transport chain and the Krebs cycle. There is now a rich body of literature explaining how complex II contributes to respiration. However, more recent research shows that not all of the pathologies associated with altered complex II activity clearly correlate with this respiratory role. Complex II activity has now been shown to be necessary for a range of biological processes peripherally related to respiration, including metabolic control, inflammation, and cell fate. Integration of findings from multiple types of studies suggests that complex II both participates in respiration and controls multiple succinate-dependent signal transduction pathways. Thus, the emerging view is that the true biological function of complex II is well beyond respiration. This review uses a semichronological approach to highlight major paradigm shifts that occurred over time. Special emphasis is given to the more recently identified functions of complex II and its subunits because these findings have infused new directions into an established field.
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Affiliation(s)
- T M Iverson
- Departments of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA; Departments of Biochemistry, Vanderbilt University, Nashville, Tennessee, USA; Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee, USA.
| | - Prashant K Singh
- Departments of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA; Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA
| | - Gary Cecchini
- Molecular Biology Division, San Francisco VA Health Care System, San Francisco, California, USA; Department of Biochemistry & Biophysics, University of California, San Francisco, California, USA.
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17
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Mahmood S, Borkar AN, Khan FA, Naab T. Aggressive Malignant Paraganglioma Involving the Pancreas and Vertebral Column. Cureus 2023; 15:e40985. [PMID: 37503488 PMCID: PMC10370504 DOI: 10.7759/cureus.40985] [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] [Accepted: 06/24/2023] [Indexed: 07/29/2023] Open
Abstract
Paraganglioma (PGL) is a rare neuroendocrine tumor arising from chromaffin cells outside the adrenal medulla. The most common sites are the abdomen and head and neck. Seventy percent (70%) of PGLs are sporadic, and 30% are hereditary; the latter are more often aggressive and malignant and occur in young adults. We report a case of a 36-year-old woman with a history of hypertension and abdominal pheochromocytoma resected at the age of 10 years who presented with back pain. Magnetic resonance imaging of the spine showed vertebral metastasis at L2-L5. Computed tomography of the abdomen showed a mass in the body of the pancreas and a laparoscopic biopsy was performed. The tumor cells had granular eosinophilic/basophilic cytoplasm and showed a nested pattern (Zellballen) with a prominent vascular network and infiltration of dense fibrous connective tissue. Strong and diffuse expression of synaptophysin in tumor cells, S100 expression in sustentacular cells at the periphery of nests, and lack of pancytokeratin expression supported the diagnosis of PGL. Due to limited tissue, it was difficult to determine metastatic vs primary neoplasm of the pancreas. The earlier age of onset and history of abdominal pheochromocytoma suggested the possibility of hereditary PGL associated with succinate dehydrogenase (SDH) deficiency. The tumor cells lacked SDHB expression. Germline mutation testing for SDH was recommended. The patient underwent palliative radiotherapy and systemic chemotherapy. Most PGLs are benign and asymptomatic, but there is an increased risk of cardiovascular mortality secondary to catecholamine secretion, and surgical excision is curative. Malignant PGLs are rare (10-40%), have poor prognosis, and are incurable. Increased size of the tumor, deep tissue infiltration, and high proliferative index increase the risk of malignancy, but metastasis is required for the diagnosis of malignant PGL. The advanced disease is treated with surgical removal of the tumor and combined radiotherapy and chemotherapy.
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Affiliation(s)
- Salahudin Mahmood
- Internal Medicine, Nishtar Medical University and Hospital, Multan, PAK
| | - Abhilasha N Borkar
- Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, USA
| | - Farhan A Khan
- Pathology and Laboratory Medicine, Pathology Specialists of Memphis, Memphis, USA
- Pathology and Laboratory Medicine, Methodist Le Bonheur Healthcare, Memphis, USA
| | - Tammey Naab
- Pathology and Medical Microbiology, Athari Bio + Sciences, Washington DC, USA
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18
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Mamedova EO, Lisina DV, Belaya ZE. [Rare forms of hereditary endocrine neoplasia: co-existence of pituitary adenoma and pheochromocytoma/paraganglioma]. PROBLEMY ENDOKRINOLOGII 2023; 69:24-30. [PMID: 37448268 DOI: 10.14341/probl13196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 11/24/2022] [Accepted: 11/25/2022] [Indexed: 07/15/2023]
Abstract
Functioning pituitary adenomas and pheochromocytomas/paragangliomas are rare in the general population. Pituitary adenomas occur in the familial setting in approximately 5% of cases, whereas pheochromocytomas/paragangliomas can be hereditary in 30-40% of cases. Hereditary syndromes associated with pituitary adenomas include multiple endocrine neoplasia types 1 and 4, familial isolated pituitary adenomas, and Carney complex. Hereditary syndromes associated with pheochromocytomas/paragangliomas and genes, mutations in which predispose to their development, are more numerous. The first clinical descriptions of the co-occurrence of pituitary adenoma and pheochromocytoma/paraganglioma in one patient date back to the mid 20th century, however delineating such a co-occurrence into a particular syndrome («3PAs» (pituitary adenoma, pheochromocytoma, paraganglioma)) was suggested only in 2015. To date, approximately 100 cases of such a co-occurrence have been described in the literature. Mutations in genes encoding subunits of succinate dehydrogenase complex II (SDHx) are revealed in the majority of cases, much less common are mutations in MAX, MEN1 and some other genes. This review summarizes the current information on the «3PAs» syndrome.
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19
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Di W, Jin Z, Lei W, Liu Q, Yang W, Zhang S, Lu C, Xu X, Yang Y, Zhao H. Protection of melatonin treatment and combination with traditional antibiotics against septic myocardial injury. Cell Mol Biol Lett 2023; 28:35. [PMID: 37101253 PMCID: PMC10134561 DOI: 10.1186/s11658-022-00415-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 12/23/2022] [Indexed: 04/28/2023] Open
Abstract
BACKGROUND Heart failure is a common complication of sepsis with a high mortality rate. It has been reported that melatonin can attenuate septic injury due to various properties. On the basis of previous reports, this study will further explore the effects and mechanisms of melatonin pretreatment, posttreatment, and combination with antibiotics in the treatment of sepsis and septic myocardial injury. METHODS AND RESULTS Our results showed that melatonin pretreatment showed an obvious protective effect on sepsis and septic myocardial injury, which was related to the attenuation of inflammation and oxidative stress, the improvement of mitochondrial function, the regulation of endoplasmic reticulum stress (ERS), and the activation of the AMPK signaling pathway. In particular, AMPK serves as a key effector for melatonin-initiated myocardial benefits. In addition, melatonin posttreatment also had a certain degree of protection, while its effect was not as remarkable as that of pretreatment. The combination of melatonin and classical antibiotics had a slight but limited effect. RNA-seq detection clarified the cardioprotective mechanism of melatonin. CONCLUSION Altogether, this study provides a theoretical basis for the application strategy and combination of melatonin in septic myocardial injury.
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Affiliation(s)
- Wencheng Di
- Department of Cardiovascular Medicine, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, 29 Bulan Road, Shenzhen, Guangdong Province, China
| | - Zhenxiao Jin
- Department of Cardiovascular Surgery, Xijing Hospital, The Airforce Military Medical University, 127 Changle West Road, Xi'an, China
| | - Wangrui Lei
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, 229 Taibai North Road, Xi'an, China
- Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Qiong Liu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, 229 Taibai North Road, Xi'an, China
- Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Wenwen Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, 229 Taibai North Road, Xi'an, China
- Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Shaofei Zhang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, 229 Taibai North Road, Xi'an, China
- Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Chenxi Lu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, 229 Taibai North Road, Xi'an, China
- Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Xiaoling Xu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, 229 Taibai North Road, Xi'an, China
- Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, 229 Taibai North Road, Xi'an, China.
- Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, China.
| | - Huadong Zhao
- Department of General Surgery, Tangdu Hospital, The Airforce Military Medical University, 1 Xinsi Road, Xi'an, China.
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20
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Sawant Dessai A, Kalhotra P, Novickis AT, Dasgupta S. Regulation of tumor metabolism by post translational modifications on metabolic enzymes. Cancer Gene Ther 2023; 30:548-558. [PMID: 35999357 PMCID: PMC9947196 DOI: 10.1038/s41417-022-00521-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 07/05/2022] [Accepted: 08/04/2022] [Indexed: 11/09/2022]
Abstract
Metabolic reprogramming is a hallmark of cancer development, progression, and metastasis. Several metabolic pathways such as glycolysis, tricarboxylic acid (TCA) cycle, lipid metabolism, and glutamine catabolism are frequently altered to support cancer growth. Importantly, the activity of the rate-limiting metabolic enzymes in these pathways are specifically modulated in cancer cells. This is achieved by transcriptional, translational, and post translational regulations that enhance the expression, activity, stability, and substrate sensitivity of the rate-limiting enzymes. These mechanisms allow the enzymes to retain increased activity supporting the metabolic needs of rapidly growing tumors, sustain their survival in the hostile tumor microenvironments and in the metastatic lesions. In this review, we primarily focused on the post translational modifications of the rate-limiting enzymes in the glucose and glutamine metabolism, TCA cycle, and fatty acid metabolism promoting tumor progression and metastasis.
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Affiliation(s)
- Abhisha Sawant Dessai
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Poonam Kalhotra
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Aaron T Novickis
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Subhamoy Dasgupta
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
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21
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Hart ML, Quon E, Vigil ALBG, Engstrom IA, Newsom OJ, Davidsen K, Hoellerbauer P, Carlisle SM, Sullivan LB. Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells. eLife 2023; 12:78654. [PMID: 36883551 PMCID: PMC10027318 DOI: 10.7554/elife.78654] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 03/06/2023] [Indexed: 03/09/2023] Open
Abstract
The oxidative tricarboxylic acid (TCA) cycle is a central mitochondrial pathway integrating catabolic conversions of NAD +to NADH and anabolic production of aspartate, a key amino acid for cell proliferation. Several TCA cycle components are implicated in tumorigenesis, including loss-of-function mutations in subunits of succinate dehydrogenase (SDH), also known as complex II of the electron transport chain (ETC), but mechanistic understanding of how proliferating cells tolerate the metabolic defects of SDH loss is still lacking. Here, we identify that SDH supports human cell proliferation through aspartate synthesis but, unlike other ETC impairments, the effects of SDH inhibition are not ameliorated by electron acceptor supplementation. Interestingly, we find aspartate production and cell proliferation are restored to SDH-impaired cells by concomitant inhibition of ETC complex I (CI). We determine that the benefits of CI inhibition in this context depend on decreasing mitochondrial NAD+/NADH, which drives SDH-independent aspartate production through pyruvate carboxylation and reductive carboxylation of glutamine. We also find that genetic loss or restoration of SDH selects for cells with concordant CI activity, establishing distinct modalities of mitochondrial metabolism for maintaining aspartate synthesis. These data therefore identify a metabolically beneficial mechanism for CI loss in proliferating cells and reveal how compartmentalized redox changes can impact cellular fitness.
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Affiliation(s)
- Madeleine L Hart
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States
- Molecular Medicine & Mechanisms of Disease Program, University of Washington, Seattle, United States
| | - Evan Quon
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States
| | - Anna-Lena B G Vigil
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States
| | - Ian A Engstrom
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States
| | - Oliver J Newsom
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States
| | - Kristian Davidsen
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States
| | - Pia Hoellerbauer
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States
| | - Samantha M Carlisle
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, United States
| | - Lucas B Sullivan
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States
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22
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Brischigliaro M, Fernandez-Vizarra E, Viscomi C. Mitochondrial Neurodegeneration: Lessons from Drosophila melanogaster Models. Biomolecules 2023; 13:378. [PMID: 36830747 PMCID: PMC9953451 DOI: 10.3390/biom13020378] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 02/09/2023] [Accepted: 02/13/2023] [Indexed: 02/19/2023] Open
Abstract
The fruit fly-i.e., Drosophila melanogaster-has proven to be a very useful model for the understanding of basic physiological processes, such as development or ageing. The availability of straightforward genetic tools that can be used to produce engineered individuals makes this model extremely interesting for the understanding of the mechanisms underlying genetic diseases in physiological models. Mitochondrial diseases are a group of yet-incurable genetic disorders characterized by the malfunction of the oxidative phosphorylation system (OXPHOS), which is the highly conserved energy transformation system present in mitochondria. The generation of D. melanogaster models of mitochondrial disease started relatively recently but has already provided relevant information about the molecular mechanisms and pathological consequences of mitochondrial dysfunction. Here, we provide an overview of such models and highlight the relevance of D. melanogaster as a model to study mitochondrial disorders.
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Affiliation(s)
- Michele Brischigliaro
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
- Veneto Institute of Molecular Medicine, 35129 Padova, Italy
| | - Erika Fernandez-Vizarra
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
- Veneto Institute of Molecular Medicine, 35129 Padova, Italy
| | - Carlo Viscomi
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
- Veneto Institute of Molecular Medicine, 35129 Padova, Italy
- Centre for the Study of Neurodegeneration (CESNE), University of Padova, 35131 Padova, Italy
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23
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FitzHugh ZT, Schiller MR. Systematic Assessment of Protein C-Termini Mutated in Human Disorders. Biomolecules 2023; 13:biom13020355. [PMID: 36830724 PMCID: PMC9953674 DOI: 10.3390/biom13020355] [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: 11/30/2022] [Revised: 01/23/2023] [Accepted: 02/02/2023] [Indexed: 02/16/2023] Open
Abstract
All proteins have a carboxyl terminus, and we previously summarized eight mutations in binding and trafficking sequence determinants in the C-terminus that, when disrupted, cause human diseases. These sequence elements for binding and trafficking sites, as well as post-translational modifications (PTMs), are called minimotifs or short linear motifs. We wanted to determine how frequently mutations in minimotifs in the C-terminus cause disease. We searched specifically for PTMs because mutation of a modified amino acid almost always changes the chemistry of the side chain and can be interpreted as loss-of-function. We analyzed data from ClinVar for disease variants, Minimotif Miner and the C-terminome for PTMs, and RefSeq for protein sequences, yielding 20 such potential disease-causing variants. After additional screening, they include six with a previously reported PTM disruption mechanism and nine with new hypotheses for mutated minimotifs in C-termini that may cause disease. These mutations were generally for different genes, with four different PTM types and several different diseases. Our study helps to identify new molecular mechanisms for nine separate variants that cause disease, and this type of analysis could be extended as databases grow and to binding and trafficking motifs. We conclude that mutated motifs in C-termini are an infrequent cause of disease.
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Affiliation(s)
- Zachary T. FitzHugh
- Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, 4505 S. Maryland Pkwy, Las Vegas, NV 89154, USA
- School of Life Sciences, University of Nevada, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA
| | - Martin R. Schiller
- Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, 4505 S. Maryland Pkwy, Las Vegas, NV 89154, USA
- School of Life Sciences, University of Nevada, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA
- Heligenics Inc., 833 Las Vegas Blvd. North, Suite B, Las Vegas, NV 89101, USA
- Correspondence: ; Tel.: +1-702-895-5546; Fax: +1-702-895-5728
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24
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Arnold PK, Finley LWS. Regulation and function of the mammalian tricarboxylic acid cycle. J Biol Chem 2023; 299:102838. [PMID: 36581208 PMCID: PMC9871338 DOI: 10.1016/j.jbc.2022.102838] [Citation(s) in RCA: 189] [Impact Index Per Article: 94.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 12/15/2022] [Accepted: 12/20/2022] [Indexed: 12/27/2022] Open
Abstract
The tricarboxylic acid (TCA) cycle, otherwise known as the Krebs cycle, is a central metabolic pathway that performs the essential function of oxidizing nutrients to support cellular bioenergetics. More recently, it has become evident that TCA cycle behavior is dynamic, and products of the TCA cycle can be co-opted in cancer and other pathologic states. In this review, we revisit the TCA cycle, including its potential origins and the history of its discovery. We provide a detailed accounting of the requirements for sustained TCA cycle function and the critical regulatory nodes that can stimulate or constrain TCA cycle activity. We also discuss recent advances in our understanding of the flexibility of TCA cycle wiring and the increasingly appreciated heterogeneity in TCA cycle activity exhibited by mammalian cells. Deeper insight into how the TCA cycle can be differentially regulated and, consequently, configured in different contexts will shed light on how this pathway is primed to meet the requirements of distinct mammalian cell states.
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Affiliation(s)
- Paige K Arnold
- Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Lydia W S Finley
- Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
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25
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Atalay EB, Senturk S, Kayali HA. Wild-type IDH1 Knockout Leads to G0/G1 Arrest, Impairs Cancer Cell Proliferation, Altering Glycolysis, and the TCA Cycle in Colon Cancer. Biochem Genet 2023:10.1007/s10528-022-10325-1. [PMID: 36633771 DOI: 10.1007/s10528-022-10325-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 12/28/2022] [Indexed: 01/13/2023]
Abstract
The isocitrate dehydrogenase (IDH), which participates in the TCA cycle, is an important key enzyme in regulating cell metabolism. The effect of the metabolic IDH enzyme on cancer pathogenesis has recently been shown in different types of cancer. However, the role of wild-type (wt) IDH1 in the development of colon cancer is still unknown. Our study investigated the role of the IDH1 enzyme in key hallmarks of colon cancer using various methods such as wound healing, cell cycle, colony formation ability, invasion, and apoptosis analysis. Furthermore, cell metabolism was investigated by pyruvate analysis, dinitrosalicylic acid, and HPLC methods. In addition, CRISPR/Cas9 tool was utilized to knockout the IDH1 gene in colon adenocarcinoma cells (SW620). Further studies were performed in two isogenic IDH1 KO clones. Our findings in both clones suggest that IDH1 KO results in G0/G1 arrest, and reduces proliferation by approximately twofold compared to IDH1 WT cells. In addition, the invasion, migration, and colony formation abilities of IDH1 KO clones were significantly decreased accompanied by significant morphological changes. In the context of metabolism, intracellular glucose, pyruvate, αKG, and malate levels were decreased, while the intracellular citrate level was increased in IDH1 KO clones as compared to IDH1 WT cells. Our results reveal that wt IDH1 knockout leads to a decrease in the aggressive features of colon cancer cells. In conclusion, we reported that wt IDH1 has an effective role in colon cancer progression and could be a potential therapeutic target.
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Affiliation(s)
- Esra Bulut Atalay
- Izmir Biomedicine and Genome Center, Izmir, 35340, Turkey
- Izmir International Biomedicine and Genome Institute (IBG), Dokuz Eylül University, Mithatpasa St. No: 58/5, Balcova, 35340, Izmir, Turkey
| | - Serif Senturk
- Izmir Biomedicine and Genome Center, Izmir, 35340, Turkey
- Izmir International Biomedicine and Genome Institute (IBG), Dokuz Eylül University, Mithatpasa St. No: 58/5, Balcova, 35340, Izmir, Turkey
| | - Hulya Ayar Kayali
- Izmir Biomedicine and Genome Center, Izmir, 35340, Turkey.
- Izmir International Biomedicine and Genome Institute (IBG), Dokuz Eylül University, Mithatpasa St. No: 58/5, Balcova, 35340, Izmir, Turkey.
- Department of Chemistry, Division of Biochemistry, Faculty of Science, Dokuz Eylul University, 35160, İzmir, Turkey.
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26
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Akbari V, Hanlon VC, O’Neill K, Lefebvre L, Schrader KA, Lansdorp PM, Jones SJ. Parent-of-origin detection and chromosome-scale haplotyping using long-read DNA methylation sequencing and Strand-seq. CELL GENOMICS 2023; 3:100233. [PMID: 36777186 PMCID: PMC9903809 DOI: 10.1016/j.xgen.2022.100233] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 09/08/2022] [Accepted: 11/29/2022] [Indexed: 12/24/2022]
Abstract
Hundreds of loci in human genomes have alleles that are methylated differentially according to their parent of origin. These imprinted loci generally show little variation across tissues, individuals, and populations. We show that such loci can be used to distinguish the maternal and paternal homologs for all human autosomes without the need for the parental DNA. We integrate methylation-detecting nanopore sequencing with the long-range phase information in Strand-seq data to determine the parent of origin of chromosome-length haplotypes for both DNA sequence and DNA methylation in five trios with diverse genetic backgrounds. The parent of origin was correctly inferred for all autosomes with an average mismatch error rate of 0.31% for SNVs and 1.89% for insertions or deletions (indels). Because our method can determine whether an inherited disease allele originated from the mother or the father, we predict that it will improve the diagnosis and management of many genetic diseases.
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Affiliation(s)
- Vahid Akbari
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
- Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | | | - Kieran O’Neill
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | - Louis Lefebvre
- Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Kasmintan A. Schrader
- Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
- Department of Molecular Oncology, BC Cancer, Vancouver, BC, Canada
| | - Peter M. Lansdorp
- Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
- Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada
| | - Steven J.M. Jones
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
- Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
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27
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Martinelli S, Amore F, Canu L, Maggi M, Rapizzi E. Tumour microenvironment in pheochromocytoma and paraganglioma. Front Endocrinol (Lausanne) 2023; 14:1137456. [PMID: 37033265 PMCID: PMC10073672 DOI: 10.3389/fendo.2023.1137456] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 03/07/2023] [Indexed: 04/11/2023] Open
Abstract
Pheochromocytomas and Paragangliomas (Pheo/PGL) are rare catecholamine-producing tumours derived from adrenal medulla or from the extra-adrenal paraganglia respectively. Around 10-15% of Pheo/PGL develop metastatic forms and have a poor prognosis with a 37% of mortality rate at 5 years. These tumours have a strong genetic determinism, and the presence of succinate dehydrogenase B (SDHB) mutations are highly associated with metastatic forms. To date, no effective treatment is present for metastatic forms. In addition to cancer cells, the tumour microenvironment (TME) is also composed of non-neoplastic cells and non-cellular components, which are essential for tumour initiation and progression in multiple cancers, including Pheo/PGL. This review, for the first time, provides an overview of the roles of TME cells such as cancer-associated fibroblasts (CAFs) and tumour-associated macrophages (TAMs) on Pheo/PGL growth and progression. Moreover, the functions of the non-cellular components of the TME, among which the most representatives are growth factors, extracellular vesicles and extracellular matrix (ECM) are explored. The importance of succinate as an oncometabolite is emerging and since Pheo/PGL SDH mutated accumulate high levels of succinate, the role of succinate and of its receptor (SUCNR1) in the modulation of the carcinogenesis process is also analysed. Further understanding of the mechanism behind the complicated effects of TME on Pheo/PGL growth and spread could suggest novel therapeutic targets for further clinical treatments.
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Affiliation(s)
- Serena Martinelli
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
- Centro di Ricerca e Innovazione sulle Patologie Surrenaliche, Azienda Ospedaliera Universitaria (AOU) Careggi, Florence, Italy
- European Network for the Study of Adrenal Tumours (ENS@T) Center of Excellence, Florence, Italy
| | - Francesca Amore
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Letizia Canu
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
- Centro di Ricerca e Innovazione sulle Patologie Surrenaliche, Azienda Ospedaliera Universitaria (AOU) Careggi, Florence, Italy
- European Network for the Study of Adrenal Tumours (ENS@T) Center of Excellence, Florence, Italy
| | - Mario Maggi
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
- Centro di Ricerca e Innovazione sulle Patologie Surrenaliche, Azienda Ospedaliera Universitaria (AOU) Careggi, Florence, Italy
- European Network for the Study of Adrenal Tumours (ENS@T) Center of Excellence, Florence, Italy
| | - Elena Rapizzi
- Centro di Ricerca e Innovazione sulle Patologie Surrenaliche, Azienda Ospedaliera Universitaria (AOU) Careggi, Florence, Italy
- European Network for the Study of Adrenal Tumours (ENS@T) Center of Excellence, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
- *Correspondence: Elena Rapizzi,
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Torres J, Touati E. Mitochondrial Function in Health and Disease: Responses to Helicobacter pylori Metabolism and Impact in Gastric Cancer Development. Curr Top Microbiol Immunol 2023; 444:53-81. [PMID: 38231215 DOI: 10.1007/978-3-031-47331-9_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
Mitochondria are major cellular organelles that play an essential role in metabolism, stress response, immunity, and cell fate. Mitochondria are organized in a network with other cellular compartments, functioning as a signaling hub to maintain cells' health. Mitochondrial dysfunctions and genome alterations are associated with diseases including cancer. Mitochondria are a preferential target for pathogens, which have developed various mechanisms to hijack cellular functions for their benefit. Helicobacter pylori is recognized as the major risk factor for gastric cancer development. H. pylori induces oxidative stress and chronic gastric inflammation associated with mitochondrial dysfunction. Its pro-apoptotic cytotoxin VacA interacts with the mitochondrial inner membrane, leading to increased permeability and decreased ATP production. Furthermore, H. pylori induces mitochondrial DNA damage and mutation, concomitant with the development of gastric intraepithelial neoplasia as observed in infected mice. In this chapter, we present diverse aspects of the role of mitochondria as energy supplier and signaling hubs and their adaptation to stress conditions. The metabolic activity of mitochondria is directly linked to biosynthetic pathways. While H. pylori virulence factors and derived metabolites are essential for gastric colonization and niche adaptation, they may also impact mitochondrial function and metabolism, and may have consequences in gastric pathogenesis. Importantly, during its long way to reach the gastric epithelium, H. pylori faces various cellular types along the gastric mucosa. We discuss how the mitochondrial response of these different cells is affected by H. pylori and impacts the colonization and bacterium niche adaptation and point to areas that remain to be investigated.
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Affiliation(s)
- Javier Torres
- Unidad de Investigacion en Enfermedades Infecciosas, UMAE Pediatriıa, Instituto Mexicano del Seguro Social, Ciudad de Mexico, Mexico
| | - Eliette Touati
- Equipe DMic01-Infection, Génotoxicité et Cancer, Département de Microbiologie, UMR CNRS 6047, Institut Pasteur, Université Paris Cité, F-75015, Paris, France.
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29
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Nan H, Guo P, Fan J, Zeng W, Hu C, Zheng C, Pan B, Cao Y, Ge Y, Xue X, Li W, Lin K. Comprehensive analysis of the prognosis, tumor microenvironment, and immunotherapy response of SDHs in colon adenocarcinoma. Front Immunol 2023; 14:1093974. [PMID: 36949947 PMCID: PMC10025334 DOI: 10.3389/fimmu.2023.1093974] [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: 11/09/2022] [Accepted: 02/13/2023] [Indexed: 03/08/2023] Open
Abstract
Background Succinate dehydrogenase (SDH), one of the key enzymes in the tricarboxylic acid cycle, is mainly found in the mitochondria. SDH consists of four subunits encoding SDHA, SDHB, SDHC, and SDHD. The biological function of SDH is significantly related to cancer progression. Colorectal cancer (CRC) is one of the most common malignant tumors globally, whose most common histological subtype is colon adenocarcinoma (COAD). However, the correlation between SDH factors and COAD remains unclear. Methods The data on pan-cancer was obtained from The Cancer Genome Atlas (TCGA) database. Kaplan-Meier survival analysis showed the prognostic ability of SDHs. The cBioPortal database reflected genetic variations of SDHs. The correlation analysis was conducted between SDHs and mitochondrial energy metabolism genes (MMGs) and the protein-protein interaction (PPI) network was built. Consequently, Univariate and Multivariate Cox Regression Analysis on SDHs and other clinical characteristics were conducted. A nomogram was established. The ssGSEA analysis visualized the association between SDHs and immune infiltration. Immunophenoscore (IPS) explored the correlation between SDHs and immunotherapy, and the correlation between SDHs and targeted therapy was investigated through Genomics of Drug Sensitivity in Cancer. Finally, qPCR and immunohistochemistry detected SDHs' expression. Results After assessing SDHs differential expression in pan-cancer, we found that SDHB, SDHC, and SDHD benefit COAD patients. The cBioPortal database demonstrated that SDHA was the top gene in mutation frequency rank. Correlation analysis mirrored a strong link between SDHs and MMGs. We formulated a nomogram and found that SDHB, SDHC, SDHD, and clinical characteristics correlated with COAD patients' survival. For T helper cells, Th2 cells, and Tem, SDHA, SDHB, SDHC, and SDHD were significantly enriched in the high expression group. Moreover, COAD patients with high SDHA expression were more suitable for immunotherapy. And COAD patients with different SDHs' expression have different sensitivity to targeted drugs. Further verifying the gene and protein expression levels of SDHs, we found that the tissues were consistent with the bioinformatics analysis. Conclusions Our study analyzed the expression and prognostic value of SDHs in COAD, explored the pathway mechanisms involved, and the immune cell correlations, indicating that SDHs might be biomarkers for COAD patients.
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Affiliation(s)
- Han Nan
- School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Pengkun Guo
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jianing Fan
- School of Second Clinical Medical, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wen Zeng
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Chonghan Hu
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Can Zheng
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
| | - Bujian Pan
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, China
| | - Yu Cao
- School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yiwen Ge
- School of Second Clinical Medical, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiangyang Xue
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Experiemtial Center of Basic Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
- Department of General Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
- *Correspondence: Xiangyang Xue, ; Wenshu Li, ; Kezhi Lin,
| | - Wenshu Li
- Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- *Correspondence: Xiangyang Xue, ; Wenshu Li, ; Kezhi Lin,
| | - Kezhi Lin
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Experiemtial Center of Basic Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
- *Correspondence: Xiangyang Xue, ; Wenshu Li, ; Kezhi Lin,
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Wu H, Zhang D, Xia H, Li Y, Mao F, Liao Y. SDH5 down-regulation mitigates the damage of osteoporosis via inhibiting the MyD88/NF-κB signaling pathway. Immunopharmacol Immunotoxicol 2022; 45:317-327. [DOI: 10.1080/08923973.2022.2143372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Hongzi Wu
- Department of Orthopaedic Surgery, The Center Hospital of Karamay, Karamay City
| | - Dehua Zhang
- Department of Orthopaedic Surgery, The Center Hospital of Karamay, Karamay City
| | - Haijun Xia
- Department of Orthopaedic Surgery, The Center Hospital of Karamay, Karamay City
| | - Yongqi Li
- Department of Orthopaedic Surgery, The Center Hospital of Karamay, Karamay City
| | - Feng Mao
- Department of Orthopaedic Surgery, The Center Hospital of Karamay, Karamay City
| | - Yi Liao
- Department of Orthopaedic Surgery, The Center Hospital of Karamay, Karamay City
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Jaitovich A. Impaired regenerative capacity contributes to skeletal muscle dysfunction in chronic obstructive pulmonary disease. Am J Physiol Cell Physiol 2022; 323:C974-C989. [PMID: 35993519 PMCID: PMC9484993 DOI: 10.1152/ajpcell.00292.2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/16/2022] [Accepted: 08/16/2022] [Indexed: 01/18/2023]
Abstract
Locomotor skeletal muscle dysfunction is a relevant comorbidity of chronic obstructive pulmonary disease (COPD) and is strongly associated with worse clinical outcomes including higher mortality. Over the last decades, a large body of literature helped characterize the process, defining the disruptive muscle phenotype caused by COPD that involves reduction in muscle mass, force-generation capacity, fatigue-tolerance, and regenerative potential following injury. A major limitation in the field has been the scarcity of well-calibrated animal models to conduct mechanistic research based on loss- and gain-of-function studies. This article provides an overall description of the process, the tools available to mechanistically investigate it, and the potential role of mitochondrially driven metabolic signals on the regulation muscle regeneration after injury in COPD. Finally, a description of future avenues to further expand on the area is proposed based on very recent evidence involving mitochondrial metabolic cues affecting myogenesis.
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Affiliation(s)
- Ariel Jaitovich
- Division of Pulmonary and Critical Care Medicine, Department of Molecular and Cellular Physiology, Albany Medical College, Albany, New York
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32
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WANG M, ZHANG W, WANG N. Covalent flavoproteins: types, occurrence, biogenesis and catalytic mechanisms. Chin J Nat Med 2022; 20:749-760. [DOI: 10.1016/s1875-5364(22)60194-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Indexed: 11/03/2022]
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How an assembly factor enhances covalent FAD attachment to the flavoprotein subunit of complex II. J Biol Chem 2022; 298:102472. [PMID: 36089066 PMCID: PMC9557727 DOI: 10.1016/j.jbc.2022.102472] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/31/2022] [Accepted: 09/02/2022] [Indexed: 01/25/2023] Open
Abstract
The membrane-bound complex II family of proteins is composed of enzymes that catalyze succinate and fumarate interconversion coupled with reduction or oxidation of quinones within the membrane domain. The majority of complex II enzymes are protein heterotetramers with the different subunits harboring a variety of redox centers. These redox centers are used to transfer electrons between the site of succinate-fumarate oxidation/reduction and the membrane domain harboring the quinone. A covalently bound FAD cofactor is present in the flavoprotein subunit, and the covalent flavin linkage is absolutely required to enable the enzyme to oxidize succinate. Assembly of the covalent flavin linkage in eukaryotic cells and many bacteria requires additional protein assembly factors. Here, we provide mechanistic details for how the assembly factors work to enhance covalent flavinylation. Both prokaryotic SdhE and mammalian SDHAF2 enhance FAD binding to their respective apoprotein of complex II. These assembly factors also increase the affinity for dicarboxylates to the apoprotein-noncovalent FAD complex and stabilize the preassembly complex. These findings are corroborated by previous investigations of the roles of SdhE in enhancing covalent flavinylation in both bacterial succinate dehydrogenase and fumarate reductase flavoprotein subunits and of SDHAF2 in performing the same function for the human mitochondrial succinate dehydrogenase flavoprotein. In conclusion, we provide further insight into assembly factor involvement in building complex II flavoprotein subunit active site required for succinate oxidation.
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Maklashina E. Structural Insight into Evolution of the Quinone Binding Site in Complex II. BIOCHEMISTRY. BIOKHIMIIA 2022; 87:752-761. [PMID: 36171656 DOI: 10.1134/s0006297922080077] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/09/2022] [Accepted: 06/10/2022] [Indexed: 06/16/2023]
Abstract
The Complex II family encompasses membrane bound succinate:quinones reductases and quinol:fumarate reductases that catalyze interconversion of succinate and fumarate coupled with reduction and oxidation of quinone. These enzymes are found in all biological genres and share a modular structure where a highly conserved soluble domain is bound to a membrane-spanning domain that is represented by distinct variations. The current classification of the complex II family members is based on the number of subunits and co-factors in the membrane anchor (types A-F). This classification also provides insights into possible evolutionary paths and suggests that some of the complex II enzymes (types A-C) co-evolved as the whole assembly. Origin of complex II types D and F may have arisen from independent events of de novo association of the conserved soluble domain with a new anchor. Here we analyze a recent structure of Mycobacterium smegmatis Sdh2, a complex II enzyme with two transmembrane subunits and two heme b molecules. This analysis supports an earlier hypothesis suggesting that mitochondrial complex II (type C) with a single heme b may have evolved as an assembled unit from an ancestor similar to M. smegmatis Sdh2.
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Affiliation(s)
- Elena Maklashina
- Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA.
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Tian Q, Wang G, Ma X, Shen Q, Ding M, Yang X, Luo X, Li R, Wang Z, Wang X, Fu Z, Yang Q, Tang J, Wang G. Riboflavin integrates cellular energetics and cell cycle to regulate maize seed development. PLANT BIOTECHNOLOGY JOURNAL 2022; 20:1487-1501. [PMID: 35426230 PMCID: PMC9342611 DOI: 10.1111/pbi.13826] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 04/10/2022] [Indexed: 05/23/2023]
Abstract
Riboflavin is the precursor of essential cofactors for diverse metabolic processes. Unlike animals, plants can de novo produce riboflavin through an ancestrally conserved pathway, like bacteria and fungi. However, the mechanism by which riboflavin regulates seed development is poorly understood. Here, we report a novel maize (Zea mays L.) opaque mutant o18, which displays an increase in lysine accumulation, but impaired endosperm filling and embryo development. O18 encodes a rate-limiting bifunctional enzyme ZmRIBA1, targeted to plastid where to initiate riboflavin biosynthesis. Loss of function of O18 specifically disrupts respiratory complexes I and II, but also decreases SDH1 flavinylation, and in turn shifts the mitochondrial tricarboxylic acid (TCA) cycle to glycolysis. The deprivation of cellular energy leads to cell-cycle arrest at G1 and S phases in both mitosis and endoreduplication during endosperm development. The unexpected up-regulation of cell-cycle genes in o18 correlates with the increase of H3K4me3 levels, revealing a possible H3K4me-mediated epigenetic back-up mechanism for cell-cycle progression under unfavourable circumstances. Overexpression of O18 increases riboflavin production and confers osmotic tolerance. Altogether, our results substantiate a key role of riboflavin in coordinating cellular energy and cell cycle to modulate maize endosperm development.
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Affiliation(s)
- Qiuzhen Tian
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Gang Wang
- School of Agriculture and BiologyShanghai Jiao Tong UniversityShanghaiChina
| | - Xuexia Ma
- Shanghai Key Laboratory of Bio‐Energy CropsSchool of Life SciencesShanghai UniversityShanghaiChina
| | - Qingwen Shen
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Mengli Ding
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Xueyi Yang
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Xiaoli Luo
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Rongrong Li
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Zhenghui Wang
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Xiangyang Wang
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Zhiyuan Fu
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Qinghua Yang
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Jihua Tang
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
- The Shennong LaboratoryZhengzhouChina
| | - Guifeng Wang
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
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Chen C, Wang Z, Qin Y. Connections between metabolism and epigenetics: mechanisms and novel anti-cancer strategy. Front Pharmacol 2022; 13:935536. [PMID: 35935878 PMCID: PMC9354823 DOI: 10.3389/fphar.2022.935536] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 06/29/2022] [Indexed: 12/26/2022] Open
Abstract
Cancer cells undergo metabolic adaptations to sustain their growth and proliferation under several stress conditions thereby displaying metabolic plasticity. Epigenetic modification is known to occur at the DNA, histone, and RNA level, which can alter chromatin state. For almost a century, our focus in cancer biology is dominated by oncogenic mutations. Until recently, the connection between metabolism and epigenetics in a reciprocal manner was spotlighted. Explicitly, several metabolites serve as substrates and co-factors of epigenetic enzymes to carry out post-translational modifications of DNA and histone. Genetic mutations in metabolic enzymes facilitate the production of oncometabolites that ultimately impact epigenetics. Numerous evidences also indicate epigenome is sensitive to cancer metabolism. Conversely, epigenetic dysfunction is certified to alter metabolic enzymes leading to tumorigenesis. Further, the bidirectional relationship between epigenetics and metabolism can impact directly and indirectly on immune microenvironment, which might create a new avenue for drug discovery. Here we summarize the effects of metabolism reprogramming on epigenetic modification, and vice versa; and the latest advances in targeting metabolism-epigenetic crosstalk. We also discuss the principles linking cancer metabolism, epigenetics and immunity, and seek optimal immunotherapy-based combinations.
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Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy. Nat Commun 2022; 13:3947. [PMID: 35803927 PMCID: PMC9270418 DOI: 10.1038/s41467-022-31548-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 06/15/2022] [Indexed: 12/30/2022] Open
Abstract
Succinate dehydrogenase, which is known as mitochondrial complex II, has proven to be a fascinating machinery, attracting renewed and increased interest in its involvement in human diseases. Herein, we find that succinate dehydrogenase assembly factor 4 (SDHAF4) is downregulated in cardiac muscle in response to pathological stresses and in diseased hearts from human patients. Cardiac loss of Sdhaf4 suppresses complex II assembly and results in subunit degradation and complex II deficiency in fetal mice. These defects are exacerbated in young adults with globally impaired metabolic capacity and activation of dynamin-related protein 1, which induces excess mitochondrial fission and mitophagy, thereby causing progressive dilated cardiomyopathy and lethal heart failure in animals. Targeting mitochondria via supplementation with fumarate or inhibiting mitochondrial fission improves mitochondrial dynamics, partially restores cardiac function and prolongs the lifespan of mutant mice. Moreover, the addition of fumarate is found to dramatically improve cardiac function in myocardial infarction mice. These findings reveal a vital role for complex II assembly in the development of dilated cardiomyopathy and provide additional insights into therapeutic interventions for heart diseases. Functional succinate dehydrogenase (SDH) complex is vital to mitochondrial homeostasis. Here the authors show that disruption of SDH assembly in the heart causes dilated cardiomyopathy via impairing the mitochondrial integrity and metabolism and that mitochondrial interventions can be an effective approach to ameliorate the disease progression.
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Lyle DA, Lopez A, Osofsky R, Wiemann B, Boyd N, Olson G, Rana MA. Outcomes of Carotid Body Tumor Management with Active Surveillance. Ann Otol Rhinol Laryngol 2022; 132:551-557. [PMID: 35723203 DOI: 10.1177/00034894221105833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVES To assess outcomes of carotid body tumors (CBTs) managed with active surveillance. METHODS Retrospective chart review of CBTs managed with active surveillance from 2001 to 2019. RESULTS A total of 115 cases were identified during chart review. Sixty-five of these patients were managed with active surveillance, and 11 patients had bilateral tumors for a total of 76 tumors. Follow-up records with symptomatic outcomes were available for 51 patients, and 47 tumors had follow-up imaging. Thirty-one (66%) actively surveilled CBTs remained stable or decreased in size while 16 (34%) increased in size. Patients undergoing active surveillance developed symptoms in 12 cases, 6 of these patients underwent surgical intervention. Nine CBTs managed with active surveillance (18%) were ultimately resected. The majority of patients who did not undergo surgical intervention never developed symptoms (36/42, 86%). CONCLUSIONS Active surveillance may be a reasonable approach for a subset of CBTs.
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Affiliation(s)
- Daniel A Lyle
- School of Medicine, University of New Mexico School of Medicine MSC08 4720, Albuquerque, NM, USA
| | - Alexis Lopez
- Division of Otolaryngology-Head and Neck Surgery, University of New Mexico School of Medicine MSC10 5610, Albuquerque, NM, USA
| | - Robin Osofsky
- Department of Surgery, University of New Mexico School of Medicine MSC08 4720, Albuquerque, NM, USA
| | - Brianne Wiemann
- Department of Surgery, University of New Mexico School of Medicine MSC08 4720, Albuquerque, NM, USA
| | - Nathan Boyd
- Division of Otolaryngology-Head and Neck Surgery, University of New Mexico School of Medicine MSC10 5610, Albuquerque, NM, USA
| | - Garth Olson
- Division of Otolaryngology-Head and Neck Surgery, University of New Mexico School of Medicine MSC10 5610, Albuquerque, NM, USA
| | - Muhammad Ali Rana
- Department of Surgery, University of New Mexico School of Medicine MSC08 4720, Albuquerque, NM, USA.,Division of Vascular Surgery, University of New Mexico School of Medicine MSC10 5610, Albuquerque, NM, USA
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Bayley JP, Devilee P. Hypothesis: Why Different Types of SDH Gene Variants Cause Divergent Tumor Phenotypes. Genes (Basel) 2022; 13:genes13061025. [PMID: 35741787 PMCID: PMC9222429 DOI: 10.3390/genes13061025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 06/01/2022] [Accepted: 06/02/2022] [Indexed: 11/16/2022] Open
Abstract
Despite two decades of paraganglioma-pheochromocytoma research, the fundamental question of how the different succinate dehydrogenase (SDH)-related tumor phenotypes are initiated has remained unanswered. Here, we discuss two possible scenarios by which missense (hypomorphic alleles) or truncating (null alleles) SDH gene variants determine clinical phenotype. Dysfunctional SDH is a major source of reactive oxygen species (ROS) but ROS are inhibited by rising succinate levels. In scenario 1, we propose that SDH missense variants disrupt electron flow, causing elevated ROS levels that are toxic in sympathetic PPGL precursor cells but well controlled in oxygen-sensing parasympathetic paraganglion cells. We also suggest that SDHAF2 variants, solely associated with HNPGL, may cause the reversal of succinate dehydrogenase to fumarate reductase, producing very high ROS levels. In scenario 2, we propose a modified succinate threshold model of tumor initiation. Truncating SDH variants cause high succinate accumulation and likely initiate tumorigenesis via disruption of 2-oxoglutarate-dependent enzymes in both PPGL and HNPGL precursor tissues. We propose that missense variants (including SDHAF2) cause lower succinate accumulation and thus initiate tumorigenesis only in very metabolically active tissues such as parasympathetic paraganglia, which naturally show very high levels of succinate.
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Affiliation(s)
- Jean-Pierre Bayley
- Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
- Correspondence:
| | - Peter Devilee
- Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
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Lacombe V, Lenaers G, Urbanski G. Diagnostic and Therapeutic Perspectives Associated to Cobalamin-Dependent Metabolism and Transcobalamins' Synthesis in Solid Cancers. Nutrients 2022; 14:2058. [PMID: 35631199 PMCID: PMC9145230 DOI: 10.3390/nu14102058] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 05/11/2022] [Indexed: 02/01/2023] Open
Abstract
Cobalamin or vitamin B12 (B12) is a cofactor for methionine synthase and methylmalonyl-CoA mutase, two enzymes implicated in key pathways for cell proliferation: methylation, purine synthesis, succinylation and ATP production. Ensuring these functions in cancer cells therefore requires important cobalamin needs and its uptake through the transcobalamin II receptor (TCII-R). Thus, both the TCII-R and the cobalamin-dependent metabolic pathways constitute promising therapeutic targets to inhibit cancer development. However, the link between cobalamin and solid cancers is not limited to cellular metabolism, as it also involves the circulating transcobalamins I and II (TCI or haptocorrin and TCII) carrier proteins, encoded by TCN1 and TCN2, respectively. In this respect, elevations of B12, TCI and TCII concentrations in plasma are associated with cancer onset and relapse, and with the presence of metastases and worse prognosis. In addition, TCN1 and TCN2 overexpressions are associated with chemoresistance and a proliferative phenotype, respectively. Here we review the involvement of cobalamin and transcobalamins in cancer diagnosis and prognosis, and as potential therapeutic targets. We further detail the relationship between cobalamin-dependent metabolic pathways in cancer cells and the transcobalamins' abundancies in plasma and tumors, to ultimately hypothesize screening and therapeutic strategies linking these aspects.
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Affiliation(s)
- Valentin Lacombe
- MitoLab Team, MitoVasc Institut, CNRS UMR6015, INSERM U1083, Angers University, 49000 Angers, France; (G.L.); (G.U.)
- Department of Internal Medicine and Clinical Immunology, Angers University Hospital, 49000 Angers, France
| | - Guy Lenaers
- MitoLab Team, MitoVasc Institut, CNRS UMR6015, INSERM U1083, Angers University, 49000 Angers, France; (G.L.); (G.U.)
- Department of Neurology, Angers University Hospital, 49000 Angers, France
| | - Geoffrey Urbanski
- MitoLab Team, MitoVasc Institut, CNRS UMR6015, INSERM U1083, Angers University, 49000 Angers, France; (G.L.); (G.U.)
- Department of Internal Medicine and Clinical Immunology, Angers University Hospital, 49000 Angers, France
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Beimers W, Braun M, Schwinefus K, Pearson K, Wilbanks B, Maher LJ. A suppressor of dioxygenase inhibition in a yeast model of SDH deficiency. Endocr Relat Cancer 2022; 29:345-358. [PMID: 35315791 PMCID: PMC9175558 DOI: 10.1530/erc-21-0349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 03/21/2022] [Indexed: 12/04/2022]
Abstract
A fascinating class of familial paraganglioma (PGL) neuroendocrine tumors is driven by the loss of the tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) resulting in succinate accumulation as an oncometabolite and other metabolic derangements. Here, we exploit a Saccharomyces cerevisiae yeast model of SDH loss where accumulating succinate, and possibly reactive oxygen species, poison a dioxygenase enzyme required for sulfur scavenging. Using this model, we performed a chemical suppression screen for compounds that relieve dioxygenase inhibition. After testing 1280 pharmaceutically active compounds, we identified meclofenoxate HCl and its hydrolysis product, dimethylaminoethanol (DMAE), as suppressors of dioxygenase intoxication in SDH-loss yeast cells. We show that DMAE acts to alter metabolism so as to normalize the succinate:2-ketoglutarate ratio, improving dioxygenase function. This study raises the possibility that oncometabolite effects might be therapeutically suppressed by drugs that rewire metabolism to reduce the flux of carbon into pathological metabolic pathways.
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Affiliation(s)
- William Beimers
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Megan Braun
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Kaleb Schwinefus
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Keenan Pearson
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Brandon Wilbanks
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Louis James Maher
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
- Correspondence should be addressed to L J Maher:
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Martinelli S, Riverso M, Mello T, Amore F, Parri M, Simeone I, Mannelli M, Maggi M, Rapizzi E. SDHB and SDHD silenced pheochromocytoma spheroids respond differently to tumour microenvironment and their aggressiveness is inhibited by impairing stroma metabolism. Mol Cell Endocrinol 2022; 547:111594. [PMID: 35149119 DOI: 10.1016/j.mce.2022.111594] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 01/11/2022] [Accepted: 02/04/2022] [Indexed: 12/18/2022]
Abstract
Germline mutations in more than 20 genes, including those encoding for the succinate dehydrogenase (SDH), predispose to rare tumours, such as pheochromocytoma/paraganglioma (PPGL). Despite encoding for the same enzymatic complex, SDHC and SDHD mutated PHEO/PGLs are generally benign, while up to 80% of SDHB mutated ones are malignant. In this study, we evaluated the different effects of tumour microenvironment on tumour cell migration/invasion, by co-culturing SDHB or SDHD silenced tumour spheroids with primary cancer-associated fibroblasts (CAFs). We observed that SDHD silenced spheroids had an intermediate migration pattern, compared to the highest migration capability of SDHB and the lowest one of the wild type (Wt) spheroids. Interestingly, we noticed that co-culturing Wt, SDHB and SDHD silenced spheroids with CAFs in low glucose (1 g/l) medium, caused a decreased migration of all the spheroids, but only for SDHB silenced ones this reduction was significant. Moreover, the collective migration, observed in high glucose (4.5 g/l) and characteristic of the SDHB silenced cells, was completely lost in low glucose. Importantly, migration could not be recovered even adding glucose (3.5 g/l) to low glucose conditioned medium. When we investigated cell metabolism, we found that low glucose concentration led to a reduction of oxygen consumption rate (OCR), basal and maximal oxidative metabolism, and ATP production only in CAFs, but not in tumour cells. These results suggest that CAFs metabolism impairment was responsible for the decreased invasion process of tumour cells, most likely preventing the release of the pro-migratory factors produced by CAFs. In conclusion, the interplay between CAFs and tumour cells is distinctive depending on the gene involved, and highlights the possibility to inhibit CAF-induced migration by impairing CAFs metabolism, indicating new potential therapeutic scenarios for medical therapy.
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Affiliation(s)
- Serena Martinelli
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Maria Riverso
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Tommaso Mello
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Francesca Amore
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Matteo Parri
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Irene Simeone
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Massimo Mannelli
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Mario Maggi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Elena Rapizzi
- Department of Experimental and Clinical Medicine, University of Florence, Italy.
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43
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Mighton C, Lerner‐Ellis J. Principles of molecular testing for hereditary cancer. Genes Chromosomes Cancer 2022; 61:356-381. [DOI: 10.1002/gcc.23048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 04/03/2022] [Accepted: 04/06/2022] [Indexed: 11/10/2022] Open
Affiliation(s)
- Chloe Mighton
- Laboratory Medicine and Pathology, Mount Sinai Hospital, Sinai Health Toronto ON Canada
- Lunenfeld Tanenbaum Research Institute, Sinai Health Toronto ON Canada
- Genomics Health Services Research Program Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto Toronto ON Canada
- Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health University of Toronto Toronto ON Canada
| | - Jordan Lerner‐Ellis
- Laboratory Medicine and Pathology, Mount Sinai Hospital, Sinai Health Toronto ON Canada
- Lunenfeld Tanenbaum Research Institute, Sinai Health Toronto ON Canada
- Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada
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44
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Li Y, Belt K, Alqahtani SF, Saha S, Fenske R, Van Aken O, Whelan J, Millar AH, Murcha MW, Huang S. The mitochondrial LYR protein SDHAF1 is required for succinate dehydrogenase activity in Arabidopsis. THE PLANT JOURNAL : FOR CELL AND MOLECULAR BIOLOGY 2022; 110:499-512. [PMID: 35080330 PMCID: PMC9306560 DOI: 10.1111/tpj.15684] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/21/2021] [Accepted: 01/18/2022] [Indexed: 06/02/2023]
Abstract
Succinate dehydrogenase (SDH, complex II), which plays an essential role in mitochondrial respiration and tricarboxylic acid metabolism, requires the assembly of eight nuclear-encoded subunits and the insertion of various cofactors. Here, we report on the characterization of an Arabidopsis thaliana leucine-tyrosine-arginine (LYR) protein family member SDHAF1, (At2g39725) is a factor required for SDH activity. SDHAF1 is located in mitochondria and can fully complement the yeast SDHAF1 deletion strain. Knockdown of SDHAF1 using RNA interference resulted in a decrease in seedling hypocotyl elongation and reduced SDH activity. Proteomic analyses revealed a decreased abundance of various SDH subunits and assembly factors. Protein interaction assays revealed that SDHAF1 can interact exclusively with the Fe-S cluster-containing subunit SDH2 and HSCB, a cochaperone involved in Fe-S cluster complex recruitment. Therefore, we propose that in Arabidopsis, SDHAF1 plays a role in the biogenesis of SDH2 to form the functional complex II, which is essential for mitochondrial respiration and metabolism.
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Affiliation(s)
- Ying Li
- ARC Centre of Excellence in Plant Energy BiologySchool of Molecular SciencesThe University of Western Australia35 Stirling HighwayCrawleyWestern Australia6009Australia
| | - Katharina Belt
- ARC Centre of Excellence in Plant Energy BiologySchool of Molecular SciencesThe University of Western Australia35 Stirling HighwayCrawleyWestern Australia6009Australia
| | - Saad F. Alqahtani
- ARC Centre of Excellence in Plant Energy BiologySchool of Molecular SciencesThe University of Western Australia35 Stirling HighwayCrawleyWestern Australia6009Australia
- Biochemistry Department, College of ScienceKing Saud UniversityRiyadhSaudi Arabia
| | - Saurabh Saha
- ARC Centre of Excellence in Plant Energy BiologySchool of Molecular SciencesThe University of Western Australia35 Stirling HighwayCrawleyWestern Australia6009Australia
| | - Ricarda Fenske
- ARC Centre of Excellence in Plant Energy BiologySchool of Molecular SciencesThe University of Western Australia35 Stirling HighwayCrawleyWestern Australia6009Australia
| | - Olivier Van Aken
- ARC Centre of Excellence in Plant Energy BiologySchool of Molecular SciencesThe University of Western Australia35 Stirling HighwayCrawleyWestern Australia6009Australia
- Department of Biology, Faculty of ScienceLund UniversitySE‐223 62LundSweden
| | - James Whelan
- ARC Centre of Excellence in Plant Energy Biology, Department of Animal, Plant and Soil Science, School of Life ScienceLa Trobe UniversityVictoriaAustralia
| | - A. Harvey Millar
- ARC Centre of Excellence in Plant Energy BiologySchool of Molecular SciencesThe University of Western Australia35 Stirling HighwayCrawleyWestern Australia6009Australia
| | - Monika W. Murcha
- ARC Centre of Excellence in Plant Energy BiologySchool of Molecular SciencesThe University of Western Australia35 Stirling HighwayCrawleyWestern Australia6009Australia
| | - Shaobai Huang
- ARC Centre of Excellence in Plant Energy BiologySchool of Molecular SciencesThe University of Western Australia35 Stirling HighwayCrawleyWestern Australia6009Australia
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45
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Chen F, Ni C, Wang X, Cheng R, Pan C, Wang Y, Liang J, Zhang J, Cheng J, Chin YE, Zhou Y, Wang Z, Guo Y, Chen S, Htun S, Mathes EF, de Alba Campomanes AG, Slavotinek AM, Zhang S, Li M, Yao Z. S1P defects cause a new entity of cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome. EMBO Mol Med 2022; 14:e14904. [PMID: 35362222 PMCID: PMC9081911 DOI: 10.15252/emmm.202114904] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 02/28/2022] [Accepted: 03/08/2022] [Indexed: 11/17/2022] Open
Abstract
In this report, we discovered a new entity named cataract, alopecia, oral mucosal disorder, and psoriasis‐like (CAOP) syndrome in two unrelated and ethnically diverse patients. Furthermore, patient 1 failed to respond to regular treatment. We found that CAOP syndrome was caused by an autosomal recessive defect in the mitochondrial membrane‐bound transcription factor peptidase/site‐1 protease (MBTPS1, S1P). Mitochondrial abnormalities were observed in patient 1 with CAOP syndrome. Furthermore, we found that S1P is a novel mitochondrial protein that forms a trimeric complex with ETFA/ETFB. S1P enhances ETFA/ETFB flavination and maintains its stability. Patient S1P variants destabilize ETFA/ETFB, impair mitochondrial respiration, decrease fatty acid β‐oxidation activity, and shift mitochondrial oxidative phosphorylation (OXPHOS) to glycolysis. Mitochondrial dysfunction and inflammatory lesions in patient 1 were significantly ameliorated by riboflavin supplementation, which restored the stability of ETFA/ETFB. Our study discovered that mutations in MBTPS1 resulted in a new entity of CAOP syndrome and elucidated the mechanism of the mutations in the new disease.
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Affiliation(s)
- Fuying Chen
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Cheng Ni
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiaoxiao Wang
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ruhong Cheng
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Chaolan Pan
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yumeng Wang
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jianying Liang
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jia Zhang
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jinke Cheng
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Y Eugene Chin
- Instituteof Health Sciences, Chinese Academy of Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yi Zhou
- Department of gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhen Wang
- Department of Dermatology, Children's Hospital of Shanghai Jiaotong University, Shanghai, China
| | - Yiran Guo
- Center for Data Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, PA, USA
| | - She Chen
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Stephanie Htun
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA
| | - Erin F Mathes
- Departments of Dermatology and Pediatrics, University California, San Francisco, CA, USA
| | | | - Anne M Slavotinek
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA
| | - Si Zhang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ming Li
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhirong Yao
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
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46
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Záhonová K, Treitli SC, Le T, Škodová-Sveráková I, Hanousková P, Čepička I, Tachezy J, Hampl V. Anaerobic derivates of mitochondria and peroxisomes in the free-living amoeba Pelomyxa schiedti revealed by single-cell genomics. BMC Biol 2022; 20:56. [PMID: 35227266 PMCID: PMC8887013 DOI: 10.1186/s12915-022-01247-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 02/03/2022] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Mitochondria and peroxisomes are the two organelles that are most affected during adaptation to microoxic or anoxic environments. Mitochondria are known to transform into anaerobic mitochondria, hydrogenosomes, mitosomes, and various transition stages in between, collectively called mitochondrion-related organelles (MROs), which vary in enzymatic capacity. Anaerobic peroxisomes were identified only recently, and their putatively most conserved function seems to be the metabolism of inositol. The group Archamoebae includes anaerobes bearing both anaerobic peroxisomes and MROs, specifically hydrogenosomes in free-living Mastigamoeba balamuthi and mitosomes in the human pathogen Entamoeba histolytica, while the organelles within the third lineage represented by Pelomyxa remain uncharacterized. RESULTS We generated high-quality genome and transcriptome drafts from Pelomyxa schiedti using single-cell omics. These data provided clear evidence for anaerobic derivates of mitochondria and peroxisomes in this species, and corresponding vesicles were tentatively identified in electron micrographs. In silico reconstructed MRO metabolism harbors respiratory complex II, electron-transferring flavoprotein, a partial TCA cycle running presumably in the reductive direction, pyruvate:ferredoxin oxidoreductase, [FeFe]-hydrogenases, a glycine cleavage system, a sulfate activation pathway, and an expanded set of NIF enzymes for iron-sulfur cluster assembly. When expressed in the heterologous system of yeast, some of these candidates localized into mitochondria, supporting their involvement in the MRO metabolism. The putative functions of P. schiedti peroxisomes could be pyridoxal 5'-phosphate biosynthesis, amino acid and carbohydrate metabolism, and hydrolase activities. Unexpectedly, out of 67 predicted peroxisomal enzymes, only four were also reported in M. balamuthi, namely peroxisomal processing peptidase, nudix hydrolase, inositol 2-dehydrogenase, and D-lactate dehydrogenase. Localizations in yeast corroborated peroxisomal functions of the latter two. CONCLUSIONS This study revealed the presence and partially annotated the function of anaerobic derivates of mitochondria and peroxisomes in P. schiedti using single-cell genomics, localizations in yeast heterologous systems, and transmission electron microscopy. The MRO metabolism resembles that of M. balamuthi and most likely reflects the state in the common ancestor of Archamoebae. The peroxisomal metabolism is strikingly richer in P. schiedti. The presence of myo-inositol 2-dehydrogenase in the predicted peroxisomal proteome corroborates the situation in other Archamoebae, but future experimental evidence is needed to verify additional functions of this organelle.
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Affiliation(s)
- Kristína Záhonová
- Department of Parasitology, Faculty of Science, Charles University, BIOCEV, Vestec, Czech Republic.
- Institute of Parasitology, Biology Centre, Czech Academy of Sciences, České Budějovice (Budweis), Czech Republic.
| | | | - Tien Le
- Department of Parasitology, Faculty of Science, Charles University, BIOCEV, Vestec, Czech Republic
| | - Ingrid Škodová-Sveráková
- Institute of Parasitology, Biology Centre, Czech Academy of Sciences, České Budějovice (Budweis), Czech Republic
- Department of Biochemistry, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia
| | - Pavla Hanousková
- Department of Zoology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Ivan Čepička
- Department of Zoology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Jan Tachezy
- Department of Parasitology, Faculty of Science, Charles University, BIOCEV, Vestec, Czech Republic
| | - Vladimír Hampl
- Department of Parasitology, Faculty of Science, Charles University, BIOCEV, Vestec, Czech Republic.
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47
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Curtabbi A, Enríquez JA. The ins and outs of the flavin mononucleotide cofactor of respiratory complex I. IUBMB Life 2022; 74:629-644. [PMID: 35166025 DOI: 10.1002/iub.2600] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 01/23/2022] [Accepted: 01/24/2022] [Indexed: 12/12/2022]
Abstract
The flavin mononucleotide (FMN) cofactor of respiratory complex I occupies a key position in the electron transport chain. Here, the electrons coming from NADH start the sequence of oxidoreduction reactions, which drives the generation of the proton-motive force necessary for ATP synthesis. The overall architecture and the general catalytic proprieties of the FMN site are mostly well established. However, several aspects regarding the complex I flavin cofactor are still unknown. For example, the flavin binding to the N-module, the NADH-oxidizing portion of complex I, lacks a molecular description. The dissociation of FMN from the enzyme is beginning to emerge as an important regulatory mechanism of complex I activity and ROS production. Finally, how mitochondria import and metabolize FMN is still uncertain. This review summarizes the current knowledge on complex I flavin cofactor and discusses the open questions for future research.
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Affiliation(s)
- Andrea Curtabbi
- Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - José Antonio Enríquez
- Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.,Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
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48
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Microenvironmental Metabolites in the Intestine: Messengers between Health and Disease. Metabolites 2022; 12:metabo12010046. [PMID: 35050167 PMCID: PMC8778376 DOI: 10.3390/metabo12010046] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 01/04/2022] [Indexed: 02/01/2023] Open
Abstract
The intestinal mucosa is a highly absorptive organ and simultaneously constitutes the physical barrier between the host and a complex outer ecosystem. Intestinal epithelial cells (IECs) represent a special node that receives signals from the host and the environment and translates them into corresponding responses. Specific molecular communication systems such as metabolites are known to transmit information across the intestinal boundary. The gut microbiota or food-derived metabolites are extrinsic factors that influence the homeostasis of the intestinal epithelium, while mitochondrial and host-derived cellular metabolites determine the identity, fitness, and regenerative capacity of IECs. Little is known, however, about the role of intrinsic and extrinsic metabolites of IECs in the initiation and progression of pathological processes such as inflammatory bowel disease and colorectal cancer as well as about their impact on intestinal immunity. In this review, we will highlight the most recent contributions on the modulatory effects of intestinal metabolites in gut pathophysiology, with a particular focus on metabolites in promoting intestinal inflammation or colorectal tumorigenesis. In addition, we will provide a perspective on the role of newly identified oncometabolites from the commensal and opportunistic microbiota in shaping response and resistance to antitumor therapy.
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49
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Chupin AV, Verdikhanov NI, Golovyuk AL. [Modern conceptions on neck paragangliomas]. Khirurgiia (Mosk) 2022:64-70. [PMID: 35775846 DOI: 10.17116/hirurgia202207164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Neck paragangliomas are orphan diseases with incidence 1:30 000-1:100 000. Life expectancy is poor in patients with distant metastasis (5-year overall survival 11.8%), whereas 5-year overall survival in patients with regional metastasis is 76.8-82.4%. Meanwhile, there is still no any reliable tool for prediction of malignant potential of paraganglioma. Above-mentioned data indicate an importance of early diagnosis and timely treatment of neck paragangliomas. Total resection of tumor in ablastic conditions is a gold standard of treatment. However, surgery is associated with a high risk of neurovascular complications and requires multidisciplinary approach. Nevertheless, new knowledge dedicated to different aspects of pathogenesis of neck paraganglioma, diagnosis and treatment arise every year. This review is devoted to modern data on neck paragangliomas.
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Affiliation(s)
- A V Chupin
- Vishnevsky National Medical Research Center of Surgery, Moscow, Russia
| | - N I Verdikhanov
- Vishnevsky National Medical Research Center of Surgery, Moscow, Russia
| | - A L Golovyuk
- Vishnevsky National Medical Research Center of Surgery, Moscow, Russia
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50
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Gill EL, Patel K, Rakheja D. Oncometabolites and their role in cancer. Cancer Biomark 2022. [DOI: 10.1016/b978-0-12-824302-2.00003-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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