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SDHA
Identifiers
Aliases	SDHA, CMD1GG, FP, PGL5, SDH1, SDH2, SDHF, succinate dehydrogenase complex flavoprotein subunit A, MC2DN1, NDAXOA
External IDs	OMIM: 600857; MGI: 1914195; HomoloGene: 3073; GeneCards: SDHA; OMA:SDHA - orthologs
Gene location (Human)
Chr.	Chromosome 5 (human)
End	257,082 bp
Gene location (Mouse)
Chr.	Chromosome 13 (mouse)
End	74,498,399 bp
RNA expression pattern
	Top expressed in
	apex of heart; ; left ventricle; ; mucosa of transverse colon; ; right auricle; ; skeletal muscle tissue; ; muscle of thigh; ; duodenum; ; gastrocnemius muscle; ; right lobe of liver; ; right adrenal cortex;
	Top expressed in
	right ventricle; ; sternocleidomastoid muscle; ; digastric muscle; ; temporal muscle; ; right kidney; ; vastus lateralis muscle; ; triceps brachii muscle; ; aortic valve; ; medial head of gastrocnemius muscle; ; supraoptic nucleus;
	More reference expression data
	n/a
Gene ontology
Molecular function	oxidoreductase activity; oxidoreductase activity, acting on the CH-CH group of donors; succinate dehydrogenase activity; protein binding; succinate dehydrogenase (ubiquinone) activity; flavin adenine dinucleotide binding; electron transfer activity;
Cellular component	mitochondrial inner membrane; myelin sheath; mitochondrial respiratory chain complex II, succinate dehydrogenase complex (ubiquinone); membrane; mitochondrion; nucleolus; plasma membrane succinate dehydrogenase complex;
Biological process	succinate metabolic process; tricarboxylic acid cycle; nervous system development; electron transport chain; respiratory electron transport chain; mitochondrial electron transport, succinate to ubiquinone; anaerobic respiration;
	Sources:Amigo / QuickGO
Orthologs
	6389
	66945
	ENSG00000073578
	ENSMUSG00000021577
	P31040
	Q8K2B3
	NM_001294332; NM_004168; NM_001330758
	NM_023281
	NP_001281261; NP_001317687; NP_004159
	NP_075770
	Wikidata
View/Edit Human	View/Edit Mouse

Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the SDHA gene.^[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]

Structure

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 group flavin 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]

Function

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:

SDHA converts succinate to fumarate as part of the citric acid cycle. This reaction also converts FAD to FADH₂.
Electrons from the FADH₂ are transferred to the SDHB subunit iron clusters [2Fe-2S],[4Fe-4S],[3Fe-4S]. This function is part of the Respiratory chain
Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits.

Clinical significance

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]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

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|alt=TCACycle_WP78 edit]]

TCACycle_WP78 edit

^ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78".

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000073578 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000021577 – Ensembl, May 2017
^ "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. PMID 7798181.
^ ^a ^b "Entrez Gene: succinate dehydrogenase complex".
^ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, et al. (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
^ "SDHA - Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
^ Van Vranken JG, Na U, Winge DR, Rutter J (March–April 2015). "Protein-mediated assembly of succinate dehydrogenase and its cofactors". Critical Reviews in Biochemistry and Molecular Biology. 50 (2): 168–80. doi:10.3109/10409238.2014.990556. PMC 4653115. PMID 25488574.
^ Horsefield R, Yankovskaya V, Sexton G, Whittingham W, Shiomi K, Omura S, et al. (March 2006). "Structural and computational analysis of the quinone-binding site of complex II (succinate-ubiquinone oxidoreductase): a mechanism of electron transfer and proton conduction during ubiquinone reduction". The Journal of Biological Chemistry. 281 (11): 7309–16. doi:10.1074/jbc.m508173200. PMID 16407191.
^ Wagner AJ, Remillard SP, Zhang YX, Doyle LA, George S, Hornick JL (February 2013). "Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors". Mod Pathol. 26 (2): 289–94. doi:10.1038/modpathol.2012.153. PMID 22955521.
^ "SDHA[gene] ▶ GRCh37". ClinVar. National Library of Medicine.
^ 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. PMID 29177515.
"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. PMID 29538659.
^ "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. PMID 16798039.
^ 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. PMID 12794685. S2CID 30987591.
^ Fullerton M, McFarland R, Taylor RW, Alston CL (2020). "The genetic basis of isolated mitochondrial complex II deficiency". Mol Genet Metab. 131 (1–2): 53–65. doi:10.1016/j.ymgme.2020.09.009. PMC 7758838. PMID 33162331.
^ Reference, Genetics Home. "SDHA". Genetics Home Reference. Retrieved 2016-08-31.
^ "SDHA, SDHB or SDHC-related familial paraganglioma-phaeochromocytoma – risk management". eviQ Cancer Treatments Online. Cancer Institute NSW. 22 February 2022. 4066 v.3.