Abstract This article reviews the structure and function of mitochondrial respiratory chain complex Ⅱ, and the clinical features, diagnosis, treatment and genetic analysis of mitochondrial respiratory chain complex Ⅱ deficiency. Mitochondrial complex Ⅱ, known as succinate dehydrogenase, is a part of the mitochondrial respiratory chain. It plays an important role in cellular oxidative phosphorylation. It is associated with oxidative stress and is a sensitive target for toxic substances and abnormal metabolin in cells. Clinical manifestations of respiratory chain complex Ⅱ deficiency are characterized by a wide variety of abnormalities. Progressive neuromuscular dysfunction is the most common syndrome. Cardiomyopathy, episodic vomit and hemolytic uremic syndrome are also encountered in a few cases. A precise diagnosis is dependent on enzyme activities assay of respiratory chain complexes and genetic analysis. Complex Ⅱ activities decreased in affected tissues. Pathogenic mutations in SDHA gene and SDHAF1 gene encoding assembly factor have been found so far. Clinical treatment aims at improving the mitochondrial function.
［1］Ghezzi D, Goffrini P, Uziel G, Horvath R, Klopstock T, Lochmuller H, et al. SDHAF1, encoding a LYR complex-Ⅱ specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy［J］. Nat Genet, 2009, 41 (6): 654-656.
［2］Loveland BE, Johns TG, Mackay IR, Vaillant F, Wang ZX, Hertzog PJ. Validation of the MTT dye assay for enumeration of cells in proliferative and antiproliferative assays［J］. Biochem Int, 1992, 27 (3): 501-510.
［3］Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, et al. Crystal structure of mitochondrial respiratory membrane protein complex Ⅱ［J］. Cell, 2005, 121 (7): 1043-1057.
［4］Kolker S, Schwab M, Horster F, Sauer S, Hinz A, Wolf NI, et al. Methylmalonic acid, a biochemical hallmark of methylmalonic acidurias but no inhibitor of mitochondrial respiratory chain［J］. J Biol Chem, 2003, 278 (48): 47388-47393.
［5］Mbaya E, Oules B, Caspersen C, Tacine R, Massinet H, Pennuto M, et al. Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain complex Ⅱ deficiency［J］. Cell Death Differ, 2010, 17 (12): 1855-1866.
［6］Schafer E, Seelert H, Reifschneider NH, Krause F, Dencher NA, Vonck J. Architecture of active mammalian respiratory chain supercomplexes［J］. J Biol Chem, 2006, 281 (22): 15370-15375.
［7］Parfait B, de Lonlay P, von KJC, Cormier-Daire V, Chretien D, Rotig A, et al. The neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome mtDNA mutation (T8993G) triggers muscle ATPase deficiency and hypocitrullinaemia［J］. Eur J Pediatr, 1999, 158 (1): 55-58.
［8］van den Heuvel L, Smeitink J. The oxidative phosphorylation (OXPHOS) system: nuclear genes and human genetic diseases［J］. Bioessays, 2001, 23 (6): 518-525.
［9］Rustin P, Bourgeron T, Parfait B, Chretien D, Munnich A, Rotig A. Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human［J］. Biochim Biophys Acta, 1997, 1361 (2): 185-197.
［10］Bugiani M, Lamantea E, Invernizzi F, Moroni I, Bizzi A, Zeviani M, et al. Effects of riboflavin in children with complex Ⅱ deficiency［J］. Brain Dev, 2006, 28 (9): 576-581.
［11］Brockmann K, Bjornstad A, Dechent P, Korenke CG, Smeitink J, Trijbels JM, et al. Succinate in dystrophic white matter: a proton magnetic resonance spectroscopy finding characteristic for complex Ⅱ deficiency［J］. Ann Neurol, 2002, 52 (1): 38-46.
［12］Burgeois M, Goutieres F, Chretien D, Rustin P, Munnich A, Aicardi J. Deficiency in complex Ⅱ of the respiratory chain, presenting as a leukodystrophy in two sisters with Leigh syndrome［J］. Brain Dev, 1992, 14 (6): 404-408.
［13］Rivner MH, Shamsnia M, Swift TR, Trefz J, Roesel RA, Carter AL, et al. Kearns-Sayre syndrome and complex Ⅱ deficiency［J］. Neurology, 1989, 39 (5): 693-696.
［14］Davili Z, Johar S, Hughes C, Kveselis D, Hoo J. Succinate dehydrogenase deficiency associated with dilated cardiomyopathy and ventricular noncompaction［J］. Eur J Pediatr, 2007, 166 (8): 867-870.
［15］Linderholm H, Essen-Gustavsson B, Thornell LE. Low succinate dehydrogenase (SDH) activity in a patient with a hereditary myopathy with paroxysmal myoglobinuria［J］. J Intern Med, 1990, 228 (1): 43-52.
［16］Taylor RW, Birch-Machin MA, Schaefer J, Taylor L, Shakir R, Ackrell BA, et al. Deficiency of complex Ⅱ of the mitochondrial respiratory chain in late-onset optic atrophy and ataxia［J］. Ann Neurol, 1996, 39 (2): 224-232.
［17］Sugimoto J, Shimohira M, Osawa Y, Matsubara M, Yamamoto H, Goto Y, et al. A patient with mitochondrial myopathy associated with isolated succinate dehydrogenase deficiency［J］. Brain Dev, 2000, 22 (3): 158-162.
［18］Horvath R, Abicht A, Holinski-Feder E, Laner A, Gempel K, Prokisch H, et al. Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA)［J］. J Neurol Neurosurg Psychiatry, 2006, 77 (1): 74-76.
［19］Parfait B, Chretien D, Rotig A, Marsac C, Munnich A, Rustin P. Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex Ⅱ in a patient with Leigh syndrome［J］. Hum Genet, 2000, 106 (2): 236-243.
［21］Micheletti MV, Lavoratti G, Gasperini S, Donati MA, Pela I. Hemolytic uremic syndrome and rhabdomyolysis in a patient with succinate coenzyme Q reductase (complex Ⅱ) deficiency［J］. Clin Nephrol, 2011, 76 (1): 68-73.
［22］Ma YY, Zhang XL, Wu TF, Liu YP, Wang Q, Zhang Y, et al. Analysis of the mitochondrial complex I-V enzyme activities of peripheral leukocytes in oxidative phosphorylation disorders［J］. J Child Neurol, 2011, 26 (8): 974-979.
［24］Yang YL, Sun F, Zhang Y, Qian N, Yuan Y, Wang ZX, et al. Clinical and laboratory survey of 65 Chinese patients with Leigh syndrome［J］. Chin Med J (Engl), 2006, 119 (5): 373-377.
［25］Bourgeron T, Rustin P, Chretien D, Birch-Machin M, Bourgeois M, Viegas-Pequignot E, et al. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency［J］. Nat Genet, 1995, 11 (2): 144-149.
［26］Levitas A, Muhammad E, Harel G, Saada A, Caspi VC, Manor E, et al. Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase［J］. Eur J Hum Genet, 2010, 18 (10): 1160-1165.
［27］Manthey KC, Rodriguez-Melendez R, Hoi JT, Zempleni J. Riboflavin deficiency causes protein and DNA damage in HepG2 cells, triggering arrest in G1 phase of the cell cycle［J］. J Nutr Biochem, 2006, 17 (4): 250-256.
［28］Pinard JM, Marsac C, Barkaoui E, Desguerre I, Birch-Machin M, Reinert P, et al. Leigh syndrome and leukodystrophy due to partial succinate dehydrogenase deficiency: regression with riboflavin［J］. Arch Pediatr, 1999, 6 (4): 421-426.
［29］Di Rocco M, Lamba LD, Minniti G, Caruso U, Naito E. Outcome of thiamine treatment in a child with Leigh disease due to thiamine-responsive pyruvate dehydrogenase deficiency［J］. Eur J Paediatr Neurol, 2000, 4 (3): 115-117.
