Succinate dehydrogenase complex, subunit A, flavoprotein variant is aprotein that in humans is encoded by theSDHAgene.[5] This gene encodes a major catalytic subunit ofsuccinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. SDHA contains theFAD binding site wheresuccinate is deprotonated and converted tofumarate. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. Apseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[6]
TheSDHA gene is located on the p arm ofchromosome 5 at locus 15 and is composed of 17 exons.[6] The SDHAprotein encoded by this gene is 664 amino acids long and weighs 72.7 kDA.[7][8]
SDHA protein has four subdomains, including capping domain, helical domain,C-terminal domain and most notably,β-barrel FAD-binding domain atN-terminus. Therefore, SDHA is aflavoprotein (Fp) due to theprosthetic groupflavin adenine dinucleotide (FAD). Crystal structure suggests that FAD is covalently bound to ahistidine residue (His99) and further coordinated byhydrogen bonds with number of other amino acid residues within the FAD-binding domain. FAD which is derived fromriboflavin (vitamin B2) is thus essential cofactor for SDHA and whole complex II function.[9]
The SDH complex is located on the inner membrane of themitochondria and participates in both thecitric acid cycle and therespiratory chain. Thesuccinate dehydrogenase (SDH) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). Electrons removed from succinate transfer to SDHA, transfer acrossSDHB throughiron sulphur clusters to theSDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane.
Initially, SDHA oxidizessuccinate viadeprotonation at theFAD binding site, formingFADH2 and leavingfumarate, loosely bound to the active site, free to exit the protein. The electrons derived from succinate tunnel along the [Fe-S] relay in theSDHB subunit until they reach the [3Fe-4S]iron sulfur cluster. The electrons are then transferred to an awaitingubiquinone molecule at the Q pool active site in the SDHC/SDHD dimer. The O1carbonyl oxygen of ubiquinone is oriented at the active site byhydrogen bond interactions with Tyr83 ofSDHD. The presence of electrons in the [3Fe-4S] iron sulphur cluster induces the movement of ubiquinone into a second orientation. This facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 ofSDHC. Following the first single electron reduction step, asemiquinone radical species is formed. The second electron arrives from the [3Fe-4S] cluster to provide full reduction of the ubiquinone toubiquinol.[10]
SDHA acts as an intermediate in the basic SDH enzyme action:
Because of the complexity of SDHA's locus, SDHA was rarely analyzed,[11] but in an increasing amount of research, it's been found that mutations in SDHA are pathogenic for a number of conditions, including hereditary pheochromocytoma-paraganglioma (PPGL) syndrome, mitochondrial complex II deficiency, gastrointestinal stromal tumors, Leigh syndrome, dilated cardiomyopathy, and possible relation with pituitary adenomas, adrenal carcinomas, and other neuroendocrine tumors.[12] Hereditary PPGL syndrome associated with mutations in SDHA is called "Paragangliomas 5" with likely lower penetrance than other SDHx mutations.[13]
Bi-allelic mutations in SDHA are known to be pathogenic for infant or early childhoodLeigh syndrome, a progressive brain disorder.[14][15][16] It is not known, however, how mutations in the SDHA gene are related to the specific features of Leigh syndrome. There is some link between Leigh syndrome as a phenotype of mitochondrial complex II deficiency, but both can occur without the other as relating to SDHA mutations.[17]
SDHA is a tumour suppressor gene, and heterozygous carriers have an increased risk ofparagangliomas as well aspheochromocytomas and renal cancer.[18] Risk management for heterozygous carriers of an SDHA mutation typically involve monitoring via annual urine tests for metanephrines and catecholamines as well as non-radiation imaging such as MRIs. PET scans and radiation imaging are used but should be limited to prevent radiation exposure.[19]
^van der Tuin K, Mensenkamp AR, Tops CM, Corssmit EP, Dinjens WN, van de Horst-Schrivers AN, Jansen JC, de Jong MM, Kunst HP, Kusters B, Leter EM, Morreau H, van Nesselrooij BM, Oldenburg RA, Spruijt L, Hes FJ, Timmers HJ (February 2018). "Clinical Aspects of SDHA-Related Pheochromocytoma and Paraganglioma: A Nationwide Study".J Clin Endocrinol Metab.103 (2):438–445.doi:10.1210/jc.2017-01762.PMID29177515. "CORRIGENDUM FOR "Clinical Aspects of SDHA-Related Pheochromocytoma and Paraganglioma: A Nationwide Study"".J Clin Endocrinol Metab.103 (5): 2077. May 2018.doi:10.1210/jc.2018-00533.hdl:1887/79414.PMID29538659.
^"Leigh syndrome".Genetics Home Reference. U.S. National Library of Medicine. Retrieved30 July 2018.
^Pagnamenta AT, Hargreaves IP, Duncan AJ, Taanman JW, Heales SJ, Land JM, et al. (November 2006). "Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II".Molecular Genetics and Metabolism.89 (3):214–21.doi:10.1016/j.ymgme.2006.05.003.PMID16798039.
^Van Coster R, Seneca S, Smet J, Van Hecke R, Gerlo E, Devreese B, et al. (July 2003). "Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II".American Journal of Medical Genetics. Part A.120A (1):13–8.doi:10.1002/ajmg.a.10202.PMID12794685.S2CID30987591.
Eng C, Kiuru M, Fernandez MJ, Aaltonen LA (March 2003). "A role for mitochondrial enzymes in inherited neoplasia and beyond".Nature Reviews. Cancer.3 (3):193–202.doi:10.1038/nrc1013.PMID12612654.S2CID20549458.
Van Coster R, Seneca S, Smet J, Van Hecke R, Gerlo E, Devreese B, et al. (July 2003). "Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II".American Journal of Medical Genetics. Part A.120A (1):13–8.doi:10.1002/ajmg.a.10202.PMID12794685.S2CID30987591.
Sifroni KG, Damiani CR, Stoffel C, Cardoso MR, Ferreira GK, Jeremias IC, et al. (September 2010). "Mitochondrial respiratory chain in the colonic mucosal of patients with ulcerative colitis".Molecular and Cellular Biochemistry.342 (1–2):111–5.doi:10.1007/s11010-010-0474-x.PMID20440543.S2CID34103232.
Ma YY, Wu TF, Liu YP, Wang Q, Li XY, Ding Y, et al. (May 2014). "Two compound frame-shift mutations in succinate dehydrogenase gene of a Chinese boy with encephalopathy".Brain & Development.36 (5):394–8.doi:10.1016/j.braindev.2013.06.003.PMID23849264.S2CID24730430.
