SDHA

Structure

The SDHA gene is located on the p arm of chromosome 5 at locus 15 and is composed of 17 exons. The SDHA protein encoded by this gene is 664 amino acids long and weighs 72.7 kDA.

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.

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.

SDHA acts as an intermediate in the basic SDH enzyme action:

1. SDHA converts succinate to fumarate as part of the citric acid cycle. This reaction also converts FAD to FADH2.
2. 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
3. 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, 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. Hereditary PPGL syndrome associated with mutations in SDHA is called "Paragangliomas 5" with likely lower penetrance than other SDHx mutations.

Bi-allelic mutations in SDHA are known to be pathogenic for infant or early childhood Leigh syndrome, a progressive brain disorder. 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.

SDHA is a tumour suppressor gene, and heterozygous carriers have an increased risk of paragangliomas as well as pheochromocytomas and renal cancer. 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.

Interactive pathway map

References

References

1. (July 1994). "Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the flavoprotein (Fp) subunit of liver mitochondria". Journal of Biochemistry.
2. "Entrez Gene: succinate dehydrogenase complex".
3. (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research.
4. "SDHA - Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
5. (March–April 2015). "Protein-mediated assembly of succinate dehydrogenase and its cofactors". Critical Reviews in Biochemistry and Molecular Biology.
6. (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.
7. (February 2013). "Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors". Mod Pathol.
8. "SDHA[gene] ▶ GRCh37". National Library of Medicine.
9. (February 2018). "Clinical Aspects of SDHA-Related Pheochromocytoma and Paraganglioma: A Nationwide Study". J Clin Endocrinol Metab.
10. "Leigh syndrome". U.S. National Library of Medicine.
11. (November 2006). "Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II". Molecular Genetics and Metabolism.
12. (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.
13. (2020). "The genetic basis of isolated mitochondrial complex II deficiency". Mol Genet Metab.
14. Reference, Genetics Home. "SDHA".
15. (22 February 2022). "SDHA, SDHB or SDHC-related familial paraganglioma-phaeochromocytoma – risk management". Cancer Institute NSW.