{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T01:44:00Z","timestamp":1791942240580,"version":"4.3.4"},"reference-count":74,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T00:00:00Z","timestamp":1654560000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/genes13061025","type":"journal-article","created":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T00:22:39Z","timestamp":1654820559000},"page":"1025","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Hypothesis: Why Different Types of SDH Gene Variants Cause Divergent Tumor Phenotypes"],"prefix":"10.3390","volume":"13","author":[{"given":"Jean-Pierre","family":"Bayley","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8023-2009","authenticated-orcid":false,"given":"Peter","family":"Devilee","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"},{"name":"Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1056\/NEJMra1806651","article-title":"Pheochromocytoma and Paraganglioma","volume":"381","author":"Neumann","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.bbabio.2012.11.005","article-title":"The role of complex II in disease","volume":"1827","author":"Hoekstra","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4076","DOI":"10.1038\/sj.onc.1207591","article-title":"Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families","volume":"23","author":"Hensen","year":"2004","journal-title":"Oncogene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"38777","DOI":"10.18632\/oncotarget.6091","article-title":"Inactivation of SDH and FH cause loss of 5hmC and increased H3K9me3 in paraganglioma\/pheochromocytoma and smooth muscle tumors","volume":"6","author":"Hoekstra","year":"2015","journal-title":"Oncotarget"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1001\/jama.292.8.943","article-title":"Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations","volume":"292","author":"Neumann","year":"2004","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1210\/jc.2005-1862","article-title":"Clinical presentation and penetrance of pheochromocytoma\/paraganglioma syndromes","volume":"91","author":"Benn","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"T91","DOI":"10.1530\/ERC-15-0268","article-title":"Clinical manifestations of paraganglioma syndromes types 1\u20135","volume":"22","author":"Benn","year":"2015","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1136\/jmedgenet-2019-106214","article-title":"Variant type is associated with disease characteristics in SDHB, SDHC and SDHD-linked phaeochromocytoma-paraganglioma","volume":"57","author":"Bayley","year":"2020","journal-title":"J. Med. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Bayley, J.P., Bausch, B., Jansen, J.C., Hensen, E.F., van der Tuin, K., Corssmit, E.P.M., Devilee, P., and Neumann, H.P.H. (2021). SDHB variant type impacts phenotype and malignancy in pheochromocytoma-paraganglioma. J. Med. Genet.","DOI":"10.1136\/jmedgenet-2020-107656"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1002\/humu.21136","article-title":"Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD","volume":"31","author":"Ricketts","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1136\/jmedgenet-2017-105127","article-title":"Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD","volume":"55","author":"Andrews","year":"2018","journal-title":"J. Med. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E637","DOI":"10.1210\/jc.2011-2597","article-title":"The endemic paraganglioma syndrome type 1: Origin, spread, and clinical expression","volume":"97","author":"Schiavi","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3263","DOI":"10.1093\/hmg\/ddi359","article-title":"Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions","volume":"14","author":"Briere","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1093\/hmg\/ddi227","article-title":"Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations","volume":"14","author":"Pollard","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.ccr.2004.11.022","article-title":"Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase","volume":"7","author":"Selak","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3136","DOI":"10.1093\/hmg\/ddm275","article-title":"Succinate inhibition of alpha-ketoglutarate-dependent enzymes in a yeast model of paraganglioma","volume":"16","author":"Smith","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Cervera, A.M., Bayley, J.P., Devilee, P., and McCreath, K.J. (2009). Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells. Mol. Cancer, 8.","DOI":"10.1186\/1476-4598-8-89"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.ccr.2013.04.018","article-title":"SDH mutations establish a hypermethylator phenotype in paraganglioma","volume":"23","author":"Letouze","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3082","DOI":"10.1091\/mbc.e02-10-0631","article-title":"The tumor suppressor cybL, a component of the respiratory chain, mediates apoptosis induction","volume":"14","author":"Albayrak","year":"2003","journal-title":"Mol. Biol. Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"27518","DOI":"10.1074\/jbc.M700601200","article-title":"Ubiquinone-binding site mutations in the Saccharomyces cerevisiae succinate dehydrogenase generate superoxide and lead to the accumulation of succinate","volume":"282","author":"Szeto","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1128\/MCB.01338-07","article-title":"Loss of the SdhB, but Not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis","volume":"28","author":"Guzy","year":"2008","journal-title":"Mol. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1093\/hmg\/ddp102","article-title":"Functional study in a yeast model of a novel succinate dehydrogenase subunit B gene germline missense mutation (C191Y) diagnosed in a patient affected by a glomus tumor","volume":"18","author":"Goffrini","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kluckova, K., Sticha, M., Cerny, J., Mracek, T., Dong, L., Drahota, Z., Gottlieb, E., Neuzil, J., and Rohlena, J. (2015). Ubiquinone-binding site mutagenesis reveals the role of mitochondrial complex II in cell death initiation. Cell Death Dis., 6.","DOI":"10.1038\/cddis.2015.110"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"R451","DOI":"10.1530\/ERC-20-0346","article-title":"Epigenetic and metabolic reprogramming of SDH-deficient paragangliomas","volume":"27","author":"Moog","year":"2020","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4256","DOI":"10.1074\/jbc.M115.688762","article-title":"Fumarate and Succinate Regulate Expression of Hypoxia-inducible Genes via TET Enzymes","volume":"291","author":"Laukka","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1038\/s41588-018-0170-4","article-title":"Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair","volume":"50","author":"Sulkowski","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3423","DOI":"10.1158\/1078-0432.CCR-17-3406","article-title":"Targeting NAD(+)\/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma","volume":"24","author":"Pang","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1126\/science.1079605","article-title":"Architecture of succinate dehydrogenase and reactive oxygen species generation","volume":"299","author":"Yankovskaya","year":"2003","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.bbrc.2007.08.168","article-title":"A mev-1-like dominant-negative SdhC increases oxidative stress and reduces lifespan in Drosophila","volume":"363","author":"Tsuda","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1158\/0008-5472.203.65.1","article-title":"A mutation in the SDHC gene of complex II increases oxidative stress, resulting in apoptosis and tumorigenesis","volume":"65","author":"Ishii","year":"2005","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/29331","article-title":"A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes [see comments]","volume":"394","author":"Ishii","year":"1998","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"42563","DOI":"10.1074\/jbc.M204958200","article-title":"Mechanism of superoxide and hydrogen peroxide formation by fumarate reductase, succinate dehydrogenase, and aspartate oxidase","volume":"277","author":"Messner","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"27255","DOI":"10.1074\/jbc.M112.374629","article-title":"Mitochondrial Complex II Can Generate Reactive Oxygen Species at High Rates in Both the Forward and Reverse Reactions","volume":"287","author":"Quinlan","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.bbabio.2013.01.004","article-title":"Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning","volume":"1827","author":"Drose","year":"2013","journal-title":"Biochim. Biophys. Acta-Bioenerg."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"47629","DOI":"10.1074\/jbc.M306312200","article-title":"The ubiquinone-binding site of the Saccharomyces cerevisiae succinate-ubiquinone oxidoreductase is a source of superoxide","volume":"278","author":"Guo","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4506","DOI":"10.1096\/fj.12-210146","article-title":"Missense mutations in the human SDHB gene increase protein degradation without altering intrinsic enzymatic function","volume":"26","author":"Yang","year":"2012","journal-title":"FASEB J."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Boonen, R.A.C.M., Rodrigue, A., Stoepker, C., Wiegant, W.W., Vroling, B., Sharma, M., Rother, M.B., Celosse, N., Vreeswijk, M.P.G., and Couch, F. (2019). Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2. Nat. Commun., 10.","DOI":"10.1038\/s41467-019-13194-2"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/humu.22478","article-title":"Functional Assays for Analysis of Variants of Uncertain Significance in BRCA2","volume":"35","author":"Guidugli","year":"2014","journal-title":"Hum. Mutat."},{"key":"ref_39","first-page":"205","article-title":"Mitochondrial acute oxygen sensing and signaling","volume":"57","year":"2021","journal-title":"Crit. Rev. Biochem. Mol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Swiderska, A., Coney, A.M., Alzahrani, A.A., Aldossary, H.S., Batis, N., Ray, C.J., Kumar, P., and Holmes, A.P. (2021). Mitochondrial Succinate Metabolism and Reactive Oxygen Species Are Important but Not Essential for Eliciting Carotid Body and Ventilatory Responses to Hypoxia in the Rat. Antioxidants, 10.","DOI":"10.3390\/antiox10060840"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4524","DOI":"10.1074\/jbc.M610415200","article-title":"Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates\u2014Possible links between cell metabolism and stabilization of HIF","volume":"282","author":"Koivunen","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Imperiale, A., Moussallieh, F.M., Sebag, F., Brunaud, L., Barlier, A., Elbayed, K., Bachellier, P., Goichot, B., Pacak, K., and Namer, I.J. (2013). A New Specific Succinate-Glutamate Metabolomic Hallmark in Sdhx-Related Paragangliomas. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0080539"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3787","DOI":"10.1158\/1078-0432.CCR-12-3922","article-title":"Genotype-Specific Abnormalities in Mitochondrial Function Associate with Distinct Profiles of Energy Metabolism and Catecholamine Content in Pheochromocytoma and Paraganglioma","volume":"19","author":"Rao","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4058","DOI":"10.1158\/0008-5472.CAN-07-5580","article-title":"Cells silenced for SDHB expression display characteristic features of the tumor phenotype","volume":"68","author":"Cervera","year":"2008","journal-title":"Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1113\/jphysiol.1954.sp005143","article-title":"Observations on the Volume of Blood Flow and Oxygen Utilization of the Carotid Body in the Cat","volume":"125","author":"Daly","year":"1954","journal-title":"J. Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/BF02938055","article-title":"Oxygen Usage of the Cat Carotid-Body Perfused with Cell-Free Solutions","volume":"148","author":"Oregan","year":"1979","journal-title":"Irish J. Med. Sci."},{"key":"ref_47","first-page":"H202","article-title":"Cat Carotid-Body Oxygen-Metabolism and Chemoreception Described by a 2-Cytochrome Model","volume":"250","author":"Nair","year":"1986","journal-title":"Am. J. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.cmet.2015.09.004","article-title":"Oxygen Sensing by Arterial Chemoreceptors Depends on Mitochondrial Complex I Signaling","volume":"22","author":"Gao","year":"2015","journal-title":"Cell Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1038\/ncb3233","article-title":"Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis","volume":"17","author":"Cardaci","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Lussey-Lepoutre, C., Hollinshead, K.E., Ludwig, C., Menara, M., Morin, A., Castro-Vega, L.J., Parker, S.J., Janin, M., Martinelli, C., and Ottolenghi, C. (2015). Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism. Nat. Commun., 6.","DOI":"10.1038\/ncomms9784"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/S1470-2045(09)70164-0","article-title":"An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: A retrospective and prospective analysis","volume":"10","author":"Gaal","year":"2009","journal-title":"Lancet Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1158\/1078-0432.CCR-10-0420","article-title":"SDHAF2 (PGL2-SDH5) and Hereditary Head and Neck Paraganglioma","volume":"17","author":"Kunst","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/S1470-2045(10)70007-3","article-title":"SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma","volume":"11","author":"Bayley","year":"2010","journal-title":"Lancet Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1126\/science.1175689","article-title":"SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma","volume":"325","author":"Hao","year":"2009","journal-title":"Science"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1530\/ERC-11-0369","article-title":"Head and neck paragangliomas: Genetic spectrum and clinical variability in 79 consecutive patients","volume":"19","author":"Piccini","year":"2012","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1001\/jamaoncol.2017.0223","article-title":"Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention","volume":"3","author":"Bausch","year":"2017","journal-title":"JAMA Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"E1248","DOI":"10.1210\/jc.2013-1319","article-title":"A Comprehensive Next Generation Sequencing-Based Genetic Testing Strategy To Improve Diagnosis of Inherited Pheochromocytoma and Paraganglioma","volume":"98","author":"Rattenberry","year":"2013","journal-title":"J. Clin. Endocr. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Roose, L.M., Rupp, N.J., Roosli, C., Valcheva, N., Weber, A., Beuschlein, F., and Tschopp, O. (2020). Tinnitus With Unexpected Spanish Roots: Head and Neck Paragangliomas Caused by SDHAF2 Mutation. J. Endocr. Soc., 4.","DOI":"10.1210\/jendso\/bvaa016"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/s41436-018-0106-5","article-title":"Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma","volume":"21","author":"Richter","year":"2019","journal-title":"Genet. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1210\/js.2018-00353","article-title":"A Family With a Carotid Body Paraganglioma and Thyroid Neoplasias With a New SDHAF2 Germline Variant","volume":"3","author":"Wolf","year":"2019","journal-title":"J. Endocr. Soc."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"23548","DOI":"10.1073\/pnas.2007391117","article-title":"The roles of SDHAF2 and dicarboxylate in covalent flavinylation of SDHA, the human complex II flavoprotein","volume":"117","author":"Sharma","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"21414","DOI":"10.1074\/jbc.C116.755017","article-title":"The Assembly Factor SDHAF2 Is Dispensable for Flavination of the Catalytic Subunit of Mitochondrial Complex II in Breast Cancer Cells","volume":"291","author":"Dong","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"8475","DOI":"10.1021\/bi301171u","article-title":"Solution NMR Structure of Yeast Succinate Dehydrogenase Flavinylation Factor Sdh5 Reveals a Putative Sdh1 Binding Site","volume":"51","author":"Eletsky","year":"2012","journal-title":"Biochemistry"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3405","DOI":"10.1111\/j.1742-4658.2009.07053.x","article-title":"What\u2019s in a covalent bond? On the role and formation of covalently bound flavin cofactors","volume":"276","author":"Heuts","year":"2009","journal-title":"Febs J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"13599","DOI":"10.1016\/S0021-9258(18)80039-4","article-title":"Fumarate Reductase Mutants of Escherichia-Coli That Lack Covalently Bound Flavin","volume":"264","author":"Blaut","year":"1989","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1126\/science.abi7495","article-title":"Fumarate is a terminal electron acceptor in the mammalian electron transport chain","volume":"374","author":"Spinelli","year":"2021","journal-title":"Science"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Bisbach, C.M., Hass, D.T., Robbings, B.M., Rountree, A.M., Sadilek, M., Sweet, I.R., and Hurley, J.B. (2020). Succinate Can Shuttle Reducing Power from the Hypoxic Retina to the O-2-Rich Pigment Epithelium. Cell Rep., 31.","DOI":"10.1101\/2020.01.17.909929"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.cmet.2014.05.012","article-title":"SDHAF4 Promotes Mitochondrial Succinate Dehydrogenase Activity and Prevents Neurodegeneration","volume":"20","author":"Bricker","year":"2014","journal-title":"Cell Metab."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Bezawork-Geleta, A., Wen, H., Dong, L.F., Yan, B., Vider, J., Boukalova, S., Krobova, L., Vanova, K., Zobalova, R., and Sobol, M. (2018). Alternative assembly of respiratory complex II connects energy stress to metabolic checkpoints. Nat. Commun., 9.","DOI":"10.1038\/s41467-018-04603-z"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1126\/science.287.5454.848","article-title":"Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma","volume":"287","author":"Baysal","year":"2000","journal-title":"Science"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.gde.2010.02.008","article-title":"Warburg tumours and the mechanisms of mitochondrial tumour suppressor genes. Barking up the right tree?","volume":"20","author":"Bayley","year":"2010","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1096\/fj.201901456R","article-title":"Succinate dehydrogenase deficiency in a chromaffin cell model retains metabolic fitness through the maintenance of mitochondrial NADH oxidoreductase function","volume":"34","author":"Kluckova","year":"2020","journal-title":"FASEB J."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3868","DOI":"10.1158\/1078-0432.CCR-19-2335","article-title":"Therapeutic Targeting of SDHB-Mutated Pheochromocytoma\/Paraganglioma with Pharmacologic Ascorbic Acid","volume":"26","author":"Liu","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3480","DOI":"10.1158\/0008-5472.CAN-20-2936","article-title":"Loss of SDHB Promotes Dysregulated Iron Homeostasis, Oxidative Stress, and Sensitivity to Ascorbate","volume":"81","author":"Goncalves","year":"2021","journal-title":"Cancer Res."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/6\/1025\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:25:22Z","timestamp":1760138722000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/6\/1025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,7]]},"references-count":74,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["genes13061025"],"URL":"https:\/\/doi.org\/10.3390\/genes13061025","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.742209677.793593853","asserted-by":"object"}]},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,7]]}}}