Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the SDHAgene.[5] This gene encodes a major catalytic subunit of succinate-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 the FAD binding site where succinate is deprotonated and converted to fumarate. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[6]
The SDHA gene is located on the p arm of chromosome 5 at locus 15 and is composed of 17 exons.[6] The SDHA protein 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 at N-terminus. Therefore, SDHA is a flavoprotein (Fp) due to the prosthetic groupflavin adenine dinucleotide (FAD). Crystal structure suggests that FAD is covalently bound to a histidine residue (His99) and further coordinated by hydrogen bonds with number of other amino acid residues within the FAD-binding domain. FAD which is derived from riboflavin (vitamin B2) is thus essential cofactor for SDHA and whole complex II function.[9]
The SDH complex is located on the inner membrane of the mitochondria and participates in both the citric acid cycle and the respiratory chain. The succinate dehydrogenase (SDH) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). Electrons removed from succinate transfer to SDHA, transfer across SDHB through iron sulphur clusters to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane.
Initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, forming FADH2 and leaving fumarate, loosely bound to the active site, free to exit the protein. The electrons derived from succinate tunnel along the [Fe-S] relay in the SDHB subunit until they reach the [3Fe-4S] iron sulfur cluster. The electrons are then transferred to an awaiting ubiquinone molecule at the Q pool active site in the SDHC/SDHD dimer. The O1 carbonyl oxygen of ubiquinone is oriented at the active site by hydrogen bond interactions with Tyr83 of SDHD. 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 of SDHC. Following the first single electron reduction step, a semiquinone radical species is formed. The second electron arrives from the [3Fe-4S] cluster to provide full reduction of the ubiquinone to ubiquinol.[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 childhood Leigh 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 of paragangliomas as well as pheochromocytomas 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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Hirawake H, Wang H, Kuramochi T, Kojima S, Kita K (July 1994). "Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the flavoprotein (Fp) subunit of liver mitochondria". Journal of Biochemistry. 116 (1): 221–7. doi:10.1093/oxfordjournals.jbchem.a124497. PMID7798181.
^Wagner, A., Remillard, S., Zhang, YX. et al. Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors. Mod Pathol 26, 289–294 (2013). https://doi.org/10.1038/modpathol.2012.153
^van der Tuin K, Mensenkamp AR, Tops CMJ, Corssmit EPM, Dinjens WN, van de Horst-Schrivers ANA, Jansen JC, de Jong MM, Kunst HPM, Kusters B, Leter EM, Morreau H, van Nesselrooij BMP, Oldenburg RA, Spruijt L, Hes FJ, Timmers HJLM. Clinical Aspects of SDHA-Related Pheochromocytoma and Paraganglioma: A Nationwide Study. J Clin Endocrinol Metab. 2018 Feb 1;103(2):438-445. doi: 10.1210/jc.2017-01762. Erratum in: J Clin Endocrinol Metab. 2018 May 1;103(5):2077. PMID: 29177515.
^"Leigh syndrome". Genetics Home Reference. U.S. National Library of Medicine. Retrieved 30 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.
^Fullerton M, McFarland R, Taylor RW, Alston CL. The genetic basis of isolated mitochondrial complex II deficiency. Mol Genet Metab. 2020 Sep-Oct;131(1-2):53-65. doi: 10.1016/j.ymgme.2020.09.009. Epub 2020 Oct 3. PMID: 33162331; PMCID: PMC7758838.
^Reference, Genetics Home. "SDHA". Genetics Home Reference. Retrieved 2016-08-31.
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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.
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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.
