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Gene Review

SDHA  -  succinate dehydrogenase complex, subunit A...

Homo sapiens

Synonyms: CMD1GG, FP, Flavoprotein subunit of complex II, Fp, PGL5, ...
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Disease relevance of SDHA

  • The largest subunit, SDHA, is mutated in patients with Leigh syndrome and late-onset optic atrophy, but has not as yet been identified as a factor in hereditary cancer [1].
  • Here we introduce all reported paraganglioma and pheochromocytoma related sequence variations in these genes, in addition to all reported mutations of SDHA [1].
  • In this study, expression stability of six supposed control genes was evaluated in 64 samples of primary neuroblastoma and HPRT1 and SDHA mRNA levels were shown to exhibit the least expression variability among the samples [2].
  • The amino acid sequence was highly homologous with that of bovine heart Fp (93.2%) and was quite different from the partial sequence of human placental Fp reported previously [Malcovati et al. (1991) in Flavins and Flavoproteins 1990, pp. 727-730], which showed striking homology to that of Bacillus subtilis [3].
  • In conclusion, we have shown a close relationship between eye muscle disease and serum antibodies against the Fp subunit of succinate dehydrogenase in patients with Graves' hyperthyroidism [4].

High impact information on SDHA

  • Complex II is comprised of two hydrophilic proteins, flavoprotein (Fp) and iron-sulfur protein (Ip), and two transmembrane proteins (CybL and CybS), as well as prosthetic groups required for electron transfer from succinate to ubiquinone [5].
  • Amino acid sequence similarities indicate that sdh2, sdh3, and sdh4 were originally encoded in the protomitochondrial genome and have subsequently been transferred to the nuclear genome in most eukaryotes [6].
  • Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions [7].
  • In fibroblasts only SDHA type I is found [7].
  • In paraganglioma cells, two forms of SDHA (type I, II) were found which might preclude significant succinate accumulation in the case of a mutation in either form [7].

Chemical compound and disease context of SDHA


Biological context of SDHA

  • The phenotypic features of complex II gene mutations suggest that whereas the catalytic subunit SDHA mutations may compromise the Krebs cycle, those in other structural subunits may affect oxygen sensing and signaling [10].
  • Each of the two genes contains a single open reading frame (ORF), which are located on different chromosomes, 1860 nucleotides on chromosome 10 for SDHA and 963 nucleotides on chromosome 12 for SDHB [11].
  • Interestingly, a P. falciparum-specific insertion and a unicellular organism-specific deletion were found in the amino acid sequence of Fp [11].
  • Thus, these data indicate that the geometrical mean of HPRT1 and SDHA transcript levels represents a suitable internal control for biological and clinical studies investigating differential gene expression in primary neuroblastoma by real-time RT-PCR [2].
  • Noticeably, the first mutation in a nuclear-encoded respiratory chain component, a mutation in the 5p15 copy of the flavoprotein (Fp) subunit gene of the SDH, was reported 4 years ago in two siblings with LS and SDH deficiency [12].

Anatomical context of SDHA

  • We analyzed mutations in the all four SDH genes, SDHA through SDHD, in a Japanese family with cervical paraganglioma that include a father with bilateral tumors and his daughter with a malignant left carotid body tumor with nodal metastasis [13].
  • Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the flavoprotein (Fp) subunit of liver mitochondria [3].
  • These results indicate that the FP prostanoid receptor gene is transcribed in cultivated human iridial melanocytes of both blue and hazel eyes, whereas the other prostanoid receptor genes seem to be transcribed much less frequently, or not at all [14].
  • E2F also activates expression of Fp in epithelial cells [15].
  • This processed mRNA encoded a chimeric SDH2 (truncated)-RPS14 polypeptide, and we show that this chimeric polypeptide is targeted into isolated plant mitochondria, where it is proteolytically processed in a complex way [16].

Associations of SDHA with chemical compounds

  • Sequencing of the Fp SDH cDNA in the patient only allowed us to identify a heterozygous C to T transition, changing an alanine to a valine in one allele [12].
  • PURPOSE: To determine the distribution of the prostaglandin F2 alpha (FP) receptor within the monkey eye [17].
  • Recent animal studies have indicated that PGF2 alpha (FP) receptor messenger ribonucleic acid (mRNA) is expressed in the corpus luteum [18].
  • 5. It appears that PGF(2alpha) and Butaprost activate Nur77 transcription mechanisms through the activation of FP and EP(2) receptor-coupled signaling pathways, whereas Bimatoprost stimulates neither FP nor EP(2) receptors [19].
  • An increase in the myometrial expression of the prostaglandin (PG) receptors, and especially the PGF(2alpha) receptor (FP), may be an important component of the process initiating preterm labour [20].

Other interactions of SDHA

  • The four peptides of this complex are the flavoprotein (Fp) and iron-sulfur protein (Ip) of the dehydrogenase, and two integral membrane proteins referred to as C(II-3) and C(II-4) [21].
  • SDHA and TBP were the most stably expressed genes, covering higher and lower expression levels [22].
  • In this study, homology probing with mixed primers for the polymerase chain reaction and subsequent sequence analysis were successfully applied to clone cDNA for the flavoprotein (Fp) subunit of human liver complex II [3].

Analytical, diagnostic and therapeutic context of SDHA

  • Reliable transcript quantification by real-time reverse transcriptase-polymerase chain reaction in primary neuroblastoma using normalization to averaged expression levels of the control genes HPRT1 and SDHA [2].
  • Comparison with transcript levels determined by oligonucleotide-array expression analysis revealed that target gene mRNA quantification became most consistent after normalization to averaged expression levels of HPRT1 and SDHA [2].
  • We have used purified beef heart Fp as antigen in an enzyme-linked immunosorbent assay for cross-reactive human autoantibodies [4].
  • The 64-kDa protein is now shown from a partial sequence and by Western blotting using specific antibody probes to be the flavoprotein (Fp) subunit of succinate dehydrogenase and to have a correct molecular mass of 67 kDa [23].
  • Significantly, appearance of anti-Fp antibodies predicted the development of ophthalmopathy in 5 of the 6 patients with Graves' hyperthyroidism, who developed eye muscle dysfunction after treatment of the hyperthyroidism, and coincided with the onset of eye muscle signs in the other patient [4].


  1. The SDH mutation database: an online resource for succinate dehydrogenase sequence variants involved in pheochromocytoma, paraganglioma and mitochondrial complex II deficiency. Bayley, J.P., Devilee, P., Taschner, P.E. BMC Med. Genet. (2005) [Pubmed]
  2. Reliable transcript quantification by real-time reverse transcriptase-polymerase chain reaction in primary neuroblastoma using normalization to averaged expression levels of the control genes HPRT1 and SDHA. Fischer, M., Skowron, M., Berthold, F. The Journal of molecular diagnostics : JMD. (2005) [Pubmed]
  3. Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the flavoprotein (Fp) subunit of liver mitochondria. Hirawake, H., Wang, H., Kuramochi, T., Kojima, S., Kita, K. J. Biochem. (1994) [Pubmed]
  4. Serum antibodies against the flavoprotein subunit of succinate dehydrogenase are sensitive markers of eye muscle autoimmunity in patients with Graves' hyperthyroidism. Gunji, K., De Bellis, A., Kubota, S., Swanson, J., Wengrowicz, S., Cochran, B., Ackrell, B.A., Salvi, M., Bellastella, A., Bizzarro, A., Sinisi, A.A., Wall, J.R. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  5. Crystal structure of mitochondrial respiratory membrane protein complex II. Sun, F., Huo, X., Zhai, Y., Wang, A., Xu, J., Su, D., Bartlam, M., Rao, Z. Cell (2005) [Pubmed]
  6. Genes encoding the same three subunits of respiratory complex II are present in the mitochondrial DNA of two phylogenetically distant eukaryotes. Burger, G., Lang, B.F., Reith, M., Gray, M.W. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  7. Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions. Brière, J.J., Favier, J., Bénit, P., El Ghouzzi, V., Lorenzato, A., Rabier, D., Di Renzo, M.F., Gimenez-Roqueplo, A.P., Rustin, P. Hum. Mol. Genet. (2005) [Pubmed]
  8. Fluorescence spectroscopy and imaging of myocardial apoptosis. Ranji, M., Kanemoto, S., Matsubara, M., Grosso, M.A., Gorman, J.H., Gorman, R.C., Jaggard, D.L., Chance, B. Journal of biomedical optics (2006) [Pubmed]
  9. Role of the prostaglandins in labour and prostaglandin receptor inhibitors in the prevention of preterm labour. Olson, D.M., Ammann, C. Front. Biosci. (2007) [Pubmed]
  10. Phenotypic dichotomy in mitochondrial complex II genetic disorders. Baysal, B.E., Rubinstein, W.S., Taschner, P.E. J. Mol. Med. (2001) [Pubmed]
  11. Succinate dehydrogenase in Plasmodium falciparum mitochondria: molecular characterization of the SDHA and SDHB genes for the catalytic subunits, the flavoprotein (Fp) and iron-sulfur (Ip) subunits. Takeo, S., Kokaze, A., Ng, C.S., Mizuchi, D., Watanabe, J.I., Tanabe, K., Kojima, S., Kita, K. Mol. Biochem. Parasitol. (2000) [Pubmed]
  12. Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome. Parfait, B., Chretien, D., Rötig, A., Marsac, C., Munnich, A., Rustin, P. Hum. Genet. (2000) [Pubmed]
  13. A novel G106D alteration of the SDHD gene in a pedigree with familial paraganglioma. Ogawa, K., Shiga, K., Saijo, S., Ogawa, T., Kimura, N., Horii, A. Am. J. Med. Genet. A (2006) [Pubmed]
  14. Transcription of prostanoid receptor genes and cyclooxygenase enzyme genes in cultivated human iridial melanocytes from eyes of different colours. Wentzel, P., Bergh, K., Wallin, O., Niemelä, P., Stjernschantz, J. Pigment Cell Res. (2003) [Pubmed]
  15. Reciprocal regulation of the Epstein-Barr virus BamHI-F promoter by EBNA-1 and an E2F transcription factor. Sung, N.S., Wilson, J., Davenport, M., Sista, N.D., Pagano, J.S. Mol. Cell. Biol. (1994) [Pubmed]
  16. Transfer of rps14 from the mitochondrion to the nucleus in maize implied integration within a gene encoding the iron-sulphur subunit of succinate dehydrogenase and expression by alternative splicing. Figueroa, P., Gómez, I., Holuigue, L., Araya, A., Jordana, X. Plant J. (1999) [Pubmed]
  17. Localization of the prostaglandin F2 alpha receptor messenger RNA and protein in the cynomolgus monkey eye. Ocklind, A., Lake, S., Wentzel, P., Nistér, M., Stjernschantz, J. Invest. Ophthalmol. Vis. Sci. (1996) [Pubmed]
  18. Regulation of prostaglandin F2 alpha receptor expression in cultured human granulosa-luteal cells. Ristimäki, A., Jaatinen, R., Ritvos, O. Endocrinology (1997) [Pubmed]
  19. Upregulation of orphan nuclear receptor Nur77 following PGF(2alpha), Bimatoprost, and Butaprost treatments. Essential role of a protein kinase C pathway involved in EP(2) receptor activated Nur77 gene transcription. Liang, Y., Li, C., Guzman, V.M., Chang, W.W., Evinger, A.J., Pablo, J.V., Woodward, D.F. Br. J. Pharmacol. (2004) [Pubmed]
  20. Myometrial activation and preterm labour: evidence supporting a role for the prostaglandin F receptor--a review. Olson, D.M., Zaragoza, D.B., Shallow, M.C., Cook, J.L., Mitchell, B.F., Grigsby, P., Hirst, J. Placenta (2003) [Pubmed]
  21. Characterization of the human SDHC gene encoding of the integral membrane proteins of succinate-quinone oxidoreductase in mitochondria. Elbehti-Green, A., Au, H.C., Mascarello, J.T., Ream-Robinson, D., Scheffler, I.E. Gene (1998) [Pubmed]
  22. Identification and validation of suitable endogenous reference genes for gene expression studies of human bladder cancer. Ohl, F., Jung, M., Radonić, A., Sachs, M., Loening, S.A., Jung, K. J. Urol. (2006) [Pubmed]
  23. The 64-kilodalton eye muscle protein is the flavoprotein subunit of mitochondrial succinate dehydrogenase: the corresponding serum antibodies are good markers of an immune-mediated damage to the eye muscle in patients with Graves' hyperthyroidism. Kubota, S., Gunji, K., Ackrell, B.A., Cochran, B., Stolarski, C., Wengrowicz, S., Kennerdell, J.S., Hiromatsu, Y., Wall, J. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
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