Abstract
Mitochondrial succinate dehydrogenase (SDH), complex II, is an important component of both the mitochondrial respiratory chain and the Krebs cycle. This is the only one of the mitochondrial respiratory chain complexes that is completely encoded by nuclear genes; SDHA, B, C, and D. Recently, two nuclear-encoded assembly factors SDHFA1 and 2 have been identified. Mutations in all four subunit genes and the two assembly factors have now been reported. SDHA and SDHFA1 mutations primarily cause encephalomyopathy in childhood while mutations in the other three subunits and SDHFA2 have been associated with tumor formation. SDH oxidizes succinate as part of the Krebs cycle and in tandem effects the transfer of electrons to ubiquinone. Mutations affecting the former function appear to result in encephalomyelopathy, while mutations affecting electron transfer within the complex appear to result in tumor formation. The dual role of SDH thus appears to account for the major differences in the phenotypes associated with SDH deficiency. This chapter explores the structure and function of the different subunits of SDH, their role in mitochondrial function, and how their dysfunction results in disease. Identifying SDH mutations as important underlying causes of disease enables genetic counseling, early diagnosis, and management of at risk relatives.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Sun F et al (2005) Crystal structure of mitochondrial respiratory membrane protein complex II. Cell 121(7):1043–1057
Lancaster CR (2002) Succinate:Quinone oxidoreductases: an overview. Biochim Biophys Acta 1553(1–2):1–6
Rutter J Winge DR, Schiffman JD (2010) Succinate dehydrogenase—assembly, regulation and role in human disease. Mitochondrion 10(4):393–401
Robinson KM et al (1994) The covalent attachment of FAD to the flavoprotein of Saccharomyces cerevisiae succinate dehydrogenase is not necessary for import and assembly into mitochondria. Eur J Biochem 222(3):983–990
Rustin P, Rotig A (2002) Inborn errors of complex II—unusual human mitochondrial diseases. Biochim Biophys Acta 1553(1–2):117–22
Schafer G, Anemuller S, Moll R (2002) Archaeal complex II: ‘Classical’ and ‘non-classical’ succinate:quinone reductases with unusual features. Biochim Biophys Acta 1553(1–2):57–73
Ghezzi D et al (2009) SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy. Nat Genet 41(6):654–656
Hao HX et al (2009) SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325(5944):1139–1142
Sucheta A et al (1992) Diode-like behaviour of a mitochondrial electron-transport enzyme. Nature 356(6367):361–362
Yankovskaya V et al (2003) Architecture of succinate dehydrogenase and reactive oxygen species generation. Science 299(5607):700–704
Finsterer J (2008) Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol 39(4):223–235
Guzy RD et al (2008) Loss of the SdhB, but not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis. Mol Cell Biol 28(2):718–731.
Rivner MH et al (1989) Kearns-Sayre syndrome and complex II deficiency. Neurology 39(5):693–696
Reichmann H, Angelini C (1994) Single muscle fibre analyses in 2 brothers with succinate dehydrogenase deficiency. Eur Neurol 34(2):95–98
Bourgeron T et al (1995) Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet 11(2):144–149
Parfait B et al (2000) Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome. Hum Genet 106(2):236–243
Van Coster R et al (2003) Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II. Am J Med Genet A 120A(1):13–18
Horvath R et al (2006) Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA). J Neurol Neurosurg Psychiatry 77(1):74–76
Taylor RW et al (1996) Deficiency of complex II of the mitochondrial respiratory chain in late-onset optic atrophy and ataxia. Ann Neurol 39(2):224–232
Birch-Machin MA et al (2000) Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene. Ann Neurol 48(3):330–335
Bugiani M et al (2006) Effects of riboflavin in children with complex II deficiency. Brain Dev 28(9):576–581
Brockmann K et al (2002) Succinate in dystrophic white matter: a proton magnetic resonance spectroscopy finding characteristic for complex II deficiency. Ann Neurol 52(1):38–46
Saneto RP, Friedman SD, Shaw DW (2008) Neuroimaging of mitochondrial disease. Mitochondrion 8(5–6):396–413
Moroni I et al (2002) Cerebral white matter involvement in children with mitochondrial encephalopathies. Neuropediatrics 33(2):79–85
Pasini B , Stratakis CA (2009) SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes. J Intern Med 266(1):19–42
Baysal BE (2002) Hereditary paraganglioma targets diverse paraganglia. J Med Genet 39(9):617–622
Heutink P et al (1992) A gene subject to genomic imprinting and responsible for hereditary paragangliomas maps to chromosome 11q23-qter. Hum Mol Genet 1(1):7–10
Mariman EC et al (1995) Fine mapping of a putatively imprinted gene for familial non-chromaffin paragangliomas to chromosome 11q13.1: evidence for genetic heterogeneity. Hum Genet 95(1):56–62
Niemann S et al (2001) Assignment of PGL3 to chromosome 1 (q21-q23) in a family with autosomal dominant non-chromaffin paraganglioma. Am J Med Genet 98(1):32–36
Welander J, Soderkvist P, Gimm O (2011) Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocr Relat Cancer 18(6): R253–R276
Bardella C, Pollard PJ, Tomlinson I (2011) SDH mutations in cancer. Biochim Biophys Acta 1807(11):1432–1443
Muller U (2011) Pathological mechanisms and parent-of-origin effects in hereditary paraganglioma/pheochromocytoma (PGL/PCC). Neurogenetics 12(3):175–181
Baysal BE et al (2000) Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287(5454):848–851
Niemann S, Muller U (2000) Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 26(3):268–270
Astuti D et al (2001) Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69(1):49–54
Burnichon N et al (2010) SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 19(15):3011–3020
Semenza GL (2004) Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology (Bethesda) 19:176–182
Smith TG, Robbins PA, Ratcliffe PJ (2008) The human side of hypoxia-inducible factor. Br J Haematol 141(3):325–334
Baysal BE, Myers EN (2002) Etiopathogenesis and clinical presentation of carotid body tumors. Microsc Res Tech 59(3):256–261
King A, Selak MA, Gottlieb E (2006) Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25(34):4675–82
Fogg VC, Lanning NJ, Mackeigan JP (2011) Mitochondria in cancer: at the crossroads of life and death. Chin J Cancer 30(8):526–539
Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407
Gottlieb E, Tomlinson IP (2005) Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer 5(11):857–66
Lee S et al (2005) Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell 8(2):155–167
Korpershoek E et al (2011) SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab 96(9):E1472–E1476
Douwes Dekker PB et al (2003) SDHD mutations in head and neck paragangliomas result in destabilization of complex II in the mitochondrial respiratory chain with loss of enzymatic activity and abnormal mitochondrial morphology. J Pathol 201(3):480–486
Saldana MJ, Salem LE, Travezan R (1973) High altitude hypoxia and chemodectomas. Hum Pathol 4(2):251–263
Astrom K et al (2003) Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Hum Genet 113(3):228–237
Astuti D et al (2011) Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility. Endocr Relat Cancer 18(1):73–83
Baysal BE (2008) Clinical and molecular progress in hereditary paraganglioma. J Med Genet 45(11):689–694
Cascon A et al (2004) Genetic and epigenetic profile of sporadic pheochromocytomas. J Med Genet 41(3):e30
Pigny P et al (2008) Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation. J Clin Endocrinol Metab 93(5):1609–1615
Hensen EF et al (2004) Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families. Oncogene 23(23):4076–4083
Bayley JP, Devilee P, Taschner PE (2005) The SDH mutation database: an online resource for succinate dehydrogenase sequence variants involved in pheochromocytoma, paraganglioma and mitochondrial complex II deficiency. BMC Med Genet 6:39
Acknowledgements
To all the patients and their families who inspire us every day.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Ganesh, J., Wong, LJ., Gorman, E. (2013). Mitochondrial Respiratory Chain Complex II. In: Wong, LJ. (eds) Mitochondrial Disorders Caused by Nuclear Genes. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3722-2_13
Download citation
DOI: https://doi.org/10.1007/978-1-4614-3722-2_13
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-3721-5
Online ISBN: 978-1-4614-3722-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)