Abstract
Mitochondrial depletion syndromes (MDS) are a class of mitochondrial diseases characterized by reduction of mitochondrial DNA (mtDNA) content in muscle and/or liver as well as encephalomyopathy or hepatoencephalopathy. Mutations in SUCLG1 or SUCLA2, which encode the a and the ADP-specific b isoforms, respectively, of Succinyl-CoA Synthetase (SCS) and cause MDS associated with mild methylmalonic acidemia. SCS deficiency is speculated to cause mtDNA depletion through perturbation of mitochondrial nucleotide pools by disruption of its interaction with mitochondrial nucleotide diphosphate kinase (NDPK). Development and study of models of SCS deficiency are required to better understand the pathogenesis of SCS-dependent MDS and to develop novel therapeutic approaches.
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References
Bereiter-Hahn J, Voth M (1994) Dynamics of mitochondria in living cells: Shape changes, dislocations, fusion, and fission of mitochondria. Microsc Res Tech 27(3):198–219
Rambold AS, Lippincott-Schwartz J (2011) Mechanisms of mitochondria and autophagy crosstalk. Cell Cycle 10(23):4032–4038
Green DR, Galluzzi L, Kroemer G (2011) Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Sci 333(6046):1109–1112
Parone P, Priault M, James D, Nothwehr SF, Martinou JC (2003) Apoptosis: Bombarding the mitochondria. Essays Biochem 39:41–51
Bereiter-Hahn J, Jendrach M (2010) Mitochondrial dynamics. Int Rev Cell Mol Biol 284:1–65
Suzuki T, Nagao A (2011) Human mitochondrial tRNAs: Biogenesis, function, structural aspects, and diseases. Annu Rev Genet 45:299–329
O’Brien TW (2003) Properties of human mitochondrial ribosomes. IUBMB Life 55(9):505–513
Pagliarini DJ, Calvo SE, Chang B et al (2008) A mitochondrial protein compendium elucidates complex I disease biology. Cell 134(1):112–123
Spinazzola A, Invernizzi F, Carrara F et al (2009) Clinical and molecular features of mitochondrial DNA depletion syndromes. J Inherit Metab Dis 32(2):143–158
Buck D, Spencer ME, Guest JR (1985) Primary structure of the succinyl-CoA synthetase of Escherichia coli. Biochem 24(22):6245–6252
Weitzman PD, Kinghorn HA (1978) Occurrence of ‘large’ or ‘small’ forms of succinate thiokinase in diverse organisms. FEBS Lett 88(2):255–258
Joyce MA, Fraser ME, James MN, Bridger WA, Wolodko WT (2000) ADP-binding site of Escherichia coli succinyl-CoA synthetase revealed by x-ray crystallography. Biochem 39(1):17–25
Fraser ME, James MN, Bridger WA, Wolodko WT (1999) A detailed structural description of Escherichia coli succinyl-CoA synthetase. J Mol Biol 285(4):1633–1653
Fraser ME, Joyce MA, Ryan DG, Wolodko WT (2002) Two glutamate residues, Glu 208 alpha and Glu 197 beta, are crucial for phosphorylation and dephosphorylation of the active-site histidine residue in succinyl-CoA synthetase. Biochem 41(2):537–546
Johnson JD, Mehus JG, Tews K, Milavetz BI, Lambeth DO (1998) Genetic evidence for the expression of ATP- and GTP-specific succinyl-CoA synthetases in multicellular eucaryotes. J Biol Chem 273(42):27580–27586
Bailey DL, Wolodko WT, Bridger WA (1993) Cloning, characterization, and expression of the beta subunit of pig heart succinyl-CoA synthetase. Protein Sci 2(8):1255–1262
Sanadi DR, Gibson M, Ayengar P (1954) Guanosine triphosphate, the primary product of phosphorylation coupled to the breakdown of succinyl coenzyme A. Biochim Biophys Acta 14(3):434–436
Ayengar P, Gibson DM, Sanadi DR (1954) A new coenzyme for phosphorylation. Biochim Biophys Acta 13(2):309–310
Hansford RG (1973) An adenine nucleotide-linked succinic thiokinase of animal origin. FEBS Lett 31(3):317–320
Allen DA, Ottaway JH (1986) Succinate thiokinase in pigeon breast muscle mitochondria. FEBS Lett 194(1):171–175
Severin SE, Feigina MM (1976) alpha-keto acid dehydrogenases and acyl-CoA synthetases from pigeon breast muscle. Adv Enzyme Regul 15:1–21
Johnson JD, Muhonen WW, Lambeth DO (1998) Characterization of the ATP- and GTP-specific succinyl-CoA synthetases in pigeon. The enzymes incorporate the same alpha-subunit. J Biol Chem 273(42):27573–27579
Lambeth DO, Tews KN, Adkins S, Frohlich D, Milavetz BI (2004) Expression of two succinyl-CoA synthetases with different nucleotide specificities in mammalian tissues. J Biol Chem 279(35):36621–36624
Elpeleg O, Miller C, Hershkovitz E et al (2005) Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. Am J Hum Genet 76(6):1081–1086
Carrozzo R, Dionisi-Vici C, Steuerwald U et al (2007) SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness. Brain 130(Pt 3):862–874
Ostergaard E, Hansen FJ, Sorensen N et al (2007) Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations. Brain 130(Pt 3):853–861
Morava E, Steuerwald U, Carrozzo R et al (2009) Dystonia and deafness due to SUCLA2 defect; Clinical course and biochemical markers in 16 children. Mitochondrion 9(6):438–442
Poulton J, Hirano M, Spinazzola A et al (2009) Collated mutations in mitochondrial DNA (mtDNA) depletion syndrome (excluding the mitochondrial gamma polymerase, POLG1). Biochim Biophys Acta 1792(12):1109–1112
Ostergaard E, Christensen E, Kristensen E et al (2007) Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion. Am J Hum Genet 81(2):383–387
Sakamoto O, Ohura T, Murayama K et al (2011) Neonatal lactic acidosis with methylmalonic aciduria due to novel mutations in the SUCLG1 gene. Pediatr Int 53(6):921–925
Randolph LM, Jackson HA, Wang J et al (2011) Fatal infantile lactic acidosis and a novel homozygous mutation in the SUCLG1 gene: A mitochondrial DNA depletion disorder. Mol Genet Metab 102(2):149–152
Rouzier C, Le Guedard-Mereuze S, Fragaki K et al (2010) The severity of phenotype linked to SUCLG1 mutations could be correlated with residual amount of SUCLG1 protein. J Med Genet 47(10):670–676
Van Hove JL, Saenz MS, Thomas JA et al (2010) Succinyl-CoA ligase deficiency: a mitochondrial hepatoencephalomyopathy. Pediatr Res 68(2):159–164
Rivera H, Merinero B, Martinez-Pardo M et al (2010) Marked mitochondrial DNA depletion associated with a novel SUCLG1 gene mutation resulting in lethal neonatal acidosis, multi-organ failure, and interrupted aortic arch. Mitochondrion 10(4):362–368
Valayannopoulos V, Haudry C, Serre V et al (2010) New SUCLG1 patients expanding the phenotypic spectrum of this rare cause of mild methylmalonic aciduria. Mitochondrion 10(4):335–341
Ostergaard E, Schwartz M, Batbayli M et al (2010) A novel missense mutation in SUCLG1 associated with mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria. Eur J Pediatr 169(2):201–205
Kowluru A, Tannous M, Chen HQ (2002) Localization and characterization of the mitochondrial isoform of the nucleoside diphosphate kinase in the pancreatic beta cell: evidence for its complexation with mitochondrial succinyl-CoA synthetase. Arch Biochem Biophys 398(2):160–169
Miller C, Wang L, Ostergaard E, Dan P, Saada A (2011) The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion. Biochim Biophys Acta 1812(5):625–629
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Hawkins, N., Graham, B. (2013). Depletion of mtDNA with MMA: SUCLA2 and SUCLG1 . In: Wong, LJ. (eds) Mitochondrial Disorders Caused by Nuclear Genes. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3722-2_10
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DOI: https://doi.org/10.1007/978-1-4614-3722-2_10
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