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TRENDS IN MOLECULAR MEDICINE

Mechanisms of mitochondrial diseases

&
Pages 41-59 | Received 02 Apr 2011, Accepted 09 Jun 2011, Published online: 02 Aug 2011

References

  • Schaefer AM, Taylor RW, Turnbull DM, Chinnery PF. The epidemiology of mitochondrial disorders—past, present and future. Biochim Biophys Acta. 2004;1659:115–20.
  • Schaefer AM, McFarland R, Blakely EL, He L, Whittaker RG, Taylor RW, . Prevalence of mitochondrial DNA disease in adults. Ann Neurol. 2008;63:35–9.
  • Debray FG, Lambert M, Mitchell GA. Disorders of mitochondrial function. Curr Opin Pediatr. 2008;20:471–82.
  • McFarland R, Taylor RW, Turnbull DM. The neurology of mitochondrial DNA disease. Lancet Neurol. 2002;1:343–51.
  • Chan DC. Mitochondria: dynamic organelles in disease, aging, and development. Cell. 2006;125:1241–52.
  • Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, . Sequence and organization of the human mitochondrial genome. Nature. 1981;290: 457–65.
  • Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong SE, . A mitochondrial protein compendium elucidates complex I disease biology. Cell. 2008;134:112–23.
  • Poulton J, Chiaratti MR, Meirelles FV, Kennedy S, Wells D, Holt IJ. Transmission of mitochondrial DNA diseases and ways to prevent them. PLoS Genet. 2010;6:pii:e1001066.
  • Cree LM, Samuels DC, de Sousa Lopes SC, Rajasimha HK, Wonnapinij P, Mann JR, . A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nat Genet. 2008;40:249–54.
  • Wai T, Teoli D, Shoubridge EA. The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes. Nat Genet. 2008;40:1484–8.
  • Fan W, Waymire KG, Narula N, Li P, Rocher C, Coskun PE, . A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science. 2008;319:958–62.
  • Stewart JB, Freyer C, Elson JL, Wredenberg A, Cansu Z, Trifunovic A, . Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol. 2008;6:e10.
  • Greaves LC, Turnbull DM. Mitochondrial DNA mutations and ageing. Biochim Biophys Acta. 2009;1790:1015–20.
  • Fernandez-Vizarra E, Tiranti V, Zeviani M. Assembly of the oxidative phosphorylation system in humans: what we have learned by studying its defects. Biochim Biophys Acta. 2009;1793:200–11.
  • Carroll J, Fearnley IM, Skehel JM, Shannon RJ, Hirst J, Walker JE. Bovine complex I is a complex of 45 different subunits. J Biol Chem. 2006;281:32724–7.
  • Berrisford JM, Sazanov LA. Structural basis for the mechanism of respiratory complex I. J Biol Chem. 2009;284:29773–83.
  • Efremov RG, Baradaran R, Sazanov LA. The architecture of respiratory complex I. Nature. 2010;465:441–5.
  • Hunte C, Zickermann V, Brandt U. Functional modules and structural basis of conformational coupling in mitochondrial complex I. Science. 2010;329:448–51.
  • Sazanov LA, Hinchliffe P. Structure of the hydrophilic domain of respiratory complex I from Thermus thermophilus. Science. 2006;311:1430–6.
  • Distelmaier F, Koopman WJ, van den Heuvel LP, Rodenburg RJ, Mayatepek E, Willems PH, . Mitochondrial complex I deficiency: from organelle dysfunction to clinical disease. Brain. 2009;132(Pt 4):833–42.
  • Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, . Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science. 1988;242: 1427–30.
  • Antonicka H, Ogilvie I, Taivassalo T, Anitori RP, Haller RG, Vissing J, . Identification and characterization of a common set of complex I assembly intermediates in mitochondria from patients with complex I deficiency. J Biol Chem. 2003;278:43081–8.
  • Ugalde C, Vogel R, Huijbens R, Van Den Heuvel B, Smeitink J, Nijtmans L. Human mitochondrial complex I assembles through the combination of evolutionary conserved modules: a framework to interpret complex I deficiencies. Hum Mol Genet. 2004;13:2461–72.
  • Vogel RO, Dieteren CE, van den Heuvel LP, Willems PH, Smeitink JA, Koopman WJ, . Identification of mitochondrial complex I assembly intermediates by tracing tagged NDUFS3 demonstrates the entry point of mitochondrial subunits. J Biol Chem. 2007;282:7582–90.
  • Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN, . The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature. 2002;419: 367–74.
  • Bourgeron T, Rustin P, Chretien D, Birch-Machin M, Bourgeois M, Viegas-Pequignot E, . Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet. 1995;11: 144–9.
  • Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, . Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet. 2001;69:49–54.
  • Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, . Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000;287:848–51.
  • Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet. 2000;26:268–70.
  • Eng C, Kiuru M, Fernandez MJ, Aaltonen LA. A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer. 2003;3:193–202.
  • Benit P, Lebon S, Rustin P. Respiratory-chain diseases related to complex III deficiency. Biochim Biophys Acta. 2009;1793:181–5.
  • Crofts AR. The cytochrome bc1 complex: function in the context of structure. Annu Rev Physiol. 2004;66:689–733.
  • Acin-Perez R, Bayona-Bafaluy MP, Fernandez-Silva P, Moreno-Loshuertos R, Perez-Martos A, Bruno C, . Respiratory complex III is required to maintain complex I in mammalian mitochondria. Mol Cell. 2004;13:805–15.
  • McKenzie M, Lazarou M, Thorburn DR, Ryan MT. Mitochondrial respiratory chain supercomplexes are destabilized in Barth Syndrome patients. J Mol Biol. 2006;361:462–9.
  • Visapaa I, Fellman V, Vesa J, Dasvarma A, Hutton JL, Kumar V, . GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. Am J Hum Genet. 2002;71:863–76.
  • Hinson JT, Fantin VR, Schonberger J, Breivik N, Siem G, McDonough B, . Missense mutations in the BCS1L gene as a cause of the Bjornstad syndrome. N Engl J Med. 2007;356:809–19.
  • Diaz F. Cytochrome c oxidase deficiency: patients and animal models. Biochim Biophys Acta. 2010;1802:100–10.
  • Antonicka H, Leary SC, Guercin GH, Agar JN, Horvath R, Kennaway NG, . Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. Hum Mol Genet. 2003;12:2693–702.
  • Antonicka H, Mattman A, Carlson CG, Glerum DM, Hoffbuhr KC, Leary SC, . Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy. Am J Hum Genet. 2003;72:101–14.
  • Zhu Z, Yao J, Johns T, Fu K, De Bie I, Macmillan C, . SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet. 1998;20:337–43.
  • Smith D, Gray J, Mitchell L, Antholine WE, Hosler JP. Assembly of cytochrome-c oxidase in the absence of assembly protein Surf1p leads to loss of the active site heme. J Biol Chem. 2005;280:17652–6.
  • Weraarpachai W, Antonicka H, Sasarman F, Seeger J, Schrank B, Kolesar JE, . Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome. Nat Genet. 2009;41:833–7.
  • Ghezzi D, Saada A, D'Adamo P, Fernandez-Vizarra E, Gasparini P, Tiranti V, . FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency. Am J Hum Genet. 2008;83:415–23.
  • Holt IJ, Harding AE, Petty RK, Morgan-Hughes JA. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet. 1990;46:428–33.
  • Houstek J, Pickova A, Vojtiskova A, Mracek T, Pecina P, Jesina P. Mitochondrial diseases and genetic defects of ATP synthase. Biochim Biophys Acta. 2006;1757:1400–5.
  • Wang ZG, White PS, Ackerman SH. Atp11p and Atp12p are assembly factors for the F(1)-ATPase in human mitochondria. J Biol Chem. 2001;276:30773–8.
  • De Meirleir L, Seneca S, Lissens W, De Clercq I, Eyskens F, Gerlo E, . Respiratory chain complex V deficiency due to a mutation in the assembly gene ATP12. J Med Genet. 2004;41:120–4.
  • Mayr JA, Havlickova V, Zimmermann F, Magler I, Kaplanova V, Jesina P, . Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E gene for the F1 epsilon subunit. Hum Mol Genet. 2010;19:3430–9.
  • Copeland WC. Inherited mitochondrial diseases of DNA replication. Annu Rev Med. 2008;59:131–46.
  • Luoma P, Melberg A, Rinne JO, Kaukonen JA, Nupponen NN, Chalmers RM, . Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet. 2004;364: 875–82.
  • Ylikallio E, Tyynismaa H, Tsutsui H, Ide T, Suomalainen A. High mitochondrial DNA copy number has detrimental effects in mice. Hum Mol Genet. 2010;19:2695–705.
  • Wanrooij S, Falkenberg M. The human mitochondrial replication fork in health and disease. Biochim Biophys Acta. 2010;1797:1378–88.
  • Rampazzo C, Miazzi C, Franzolin E, Pontarin G, Ferraro P, Frangini M, . Regulation by degradation, a cellular defense against deoxyribonucleotide pool imbalances. Mutat Res. 2010 28;703:2–10.
  • Chan SS, Copeland WC. DNA polymerase gamma and mitochondrial disease: understanding the consequence of POLG mutations. Biochim Biophys Acta. 2009;1787:312–9.
  • Hakonen AH, Heiskanen S, Juvonen V, Lappalainen I, Luoma PT, Rantamaki M, . Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Am J Hum Genet. 2005;77:430–41.
  • Van Goethem G, Dermaut B, Lofgren A, Martin JJ, Van Broeckhoven C. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet. 2001;28:211–2.
  • Lee YS, Kennedy WD, Yin YW. Structural insight into processive human mitochondrial DNA synthesis and disease-related polymerase mutations. Cell. 2009;139:312–24.
  • Longley MJ, Clark S, Yu Wai Man C, Hudson G, Durham SE, Taylor RW, . Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia. Am J Hum Genet. 2006;78:1026–34.
  • Walter MC, Czermin B, Muller-Ziermann S, Bulst S, Stewart JD, Hudson G, . Late-onset ptosis and myopathy in a patient with a heterozygous insertion in POLG2. J Neurol. 2010;257:1517–23.
  • Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP, Tariq M, . Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet. 2001;28:223–31.
  • Hakonen AH, Isohanni P, Paetau A, Herva R, Suomalainen A, Lonnqvist T. Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion. Brain. 2007;130(Pt 11):3032–40.
  • Sarzi E, Goffart S, Serre V, Chretien D, Slama A, Munnich A, . Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA depletion. Ann Neurol. 2007;62:579–87.
  • Hakonen AH, Goffart S, Marjavaara S, Paetau A, Cooper H, Mattila K, . Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion. Hum Mol Genet. 2008;17:3822–35.
  • Tyynismaa H, Mjosund KP, Wanrooij S, Lappalainen I, Ylikallio E, Jalanko A, . Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice. Proc Natl Acad Sci U S A. 2005;102:17687–92.
  • Goffart S, Cooper HM, Tyynismaa H, Wanrooij S, Suomalainen A, Spelbrink JN. Twinkle mutations associated with autosomal dominant progressive external ophthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling. Hum Mol Genet. 2009;18:328–40.
  • Wanrooij S, Luoma P, van Goethem G, van Broeckhoven C, Suomalainen A, Spelbrink JN. Twinkle and POLG defects enhance age-dependent accumulation of mutations in the control region of mtDNA. Nucleic Acids Res. 2004;32: 3053–64.
  • Srivastava S, Moraes CT. Double-strand breaks of mouse muscle mtDNA promote large deletions similar to multiple mtDNA deletions in humans. Hum Mol Genet. 2005;14: 893–902.
  • Moslemi AR, Melberg A, Holme E, Oldfors A. Clonal expansion of mitochondrial DNA with multiple deletions in autosomal dominant progressive external ophthalmoplegia. Ann Neurol. 1996;40:707–13.
  • Fukui H, Moraes CT. Mechanisms of formation and accumulation of mitochondrial DNA deletions in aging neurons. Hum Mol Genet. 2009;18:1028–36.
  • Reichard P. Interactions between deoxyribonucleotide and DNA synthesis. Annu Rev Biochem. 1988;57:349–74.
  • Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, Shalata A, . The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet. 2001;29:337–41.
  • Saada A, Shaag A, Mandel H, Nevo Y, Eriksson S, Elpeleg O. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet. 2001;29:342–4.
  • Bourdon A, Minai L, Serre V, Jais JP, Sarzi E, Aubert S, . Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat Genet. 2007;39:776–80.
  • Tyynismaa H, Ylikallio E, Patel M, Molnar MJ, Haller RG, Suomalainen A. A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions. Am J Hum Genet. 2009;85:290–5.
  • Dorado B, Area E, Akman HO, Hirano M. Onset and organ specificity of Tk2 deficiency depends on Tk1 down-regulation and transcriptional compensation. Hum Mol Genet. 2010;20:155–64.
  • Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science. 1999;283:689–92.
  • Hirano M, Nishigaki Y, Marti R. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a disease of two genomes. Neurologist. 2004;10:8–17.
  • Ylikallio E, Page JL, Xu X, Lampinen M, Bepler G, Ide T, . Ribonucleotide reductase is not limiting for mitochondrial DNA copy number in mice. Nucleic Acids Res. 2010;38:8208–18.
  • Smits P, Smeitink J, van den Heuvel L. Mitochondrial translation and beyond: processes implicated in combined oxidative phosphorylation deficiencies. J Biomed Biotechnol. 2010; 2010:737385.
  • Spremulli LL, Coursey A, Navratil T, Hunter SE. Initiation and elongation factors in mammalian mitochondrial protein biosynthesis. Prog Nucleic Acid Res Mol Biol. 2004;77: 211–61.
  • Smits P, Smeitink JA, van den Heuvel LP, Huynen MA, Ettema TJ. Reconstructing the evolution of the mitochondrial ribosomal proteome. Nucleic Acids Res. 2007;35: 4686–703.
  • Bykhovskaya Y, Casas K, Mengesha E, Inbal A, Fischel-Ghodsian N. Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA). Am J Hum Genet. 2004;74:1303–8.
  • Bykhovskaya Y, Mengesha E, Fischel-Ghodsian N. Pleiotropic effects and compensation mechanisms determine tissue specificity in mitochondrial myopathy and sideroblastic anemia (MLASA). Mol Genet Metab. 2007;91: 148–56.
  • Zeharia A, Shaag A, Pappo O, Mager-Heckel AM, Saada A, Beinat M, . Acute infantile liver failure due to mutations in the TRMU gene. Am J Hum Genet. 2009;85:401–7.
  • Guan MX, Yan Q, Li X, Bykhovskaya Y, Gallo-Teran J, Hajek P, . Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations. Am J Hum Genet. 2006;79:291–302.
  • Miller C, Saada A, Shaul N, Shabtai N, Ben-Shalom E, Shaag A, . Defective mitochondrial translation caused by a ribosomal protein (MRPS16) mutation. Ann Neurol. 2004;56:734–8.
  • Saada A, Shaag A, Arnon S, Dolfin T, Miller C, Fuchs-Telem D, . Antenatal mitochondrial disease caused by mitochondrial ribosomal protein (MRPS22) mutation. J Med Genet. 2007;44:784–6.
  • Coenen MJ, Antonicka H, Ugalde C, Sasarman F, Rossi R, Heister JG, . Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency. N Engl J Med. 2004;351:2080–6.
  • Valente L, Tiranti V, Marsano RM, Malfatti E, Fernandez-Vizarra E, Donnini C, . Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu. Am J Hum Genet. 2007;80:44–58.
  • Antonicka H, Sasarman F, Kennaway NG, Shoubridge EA. The molecular basis for tissue specificity of the oxidative phosphorylation deficiencies in patients with mutations in the mitochondrial translation factor EFG1. Hum Mol Genet. 2006;15:1835–46.
  • Smeitink JA, Elpeleg O, Antonicka H, Diepstra H, Saada A, Smits P, . Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs. Am J Hum Genet. 2006;79:869–77.
  • Edvardson S, Shaag A, Kolesnikova O, Gomori JM, Tarassov I, Einbinder T, . Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet. 2007;81: 857–62.
  • Scheper GC, van der Klok T, van Andel RJ, van Berkel CG, Sissler M, Smet J, . Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet. 2007;39:534–9.
  • Riley LG, Cooper S, Hickey P, Rudinger-Thirion J, McKenzie M, Compton A, . Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia—MLASA syndrome. Am J Hum Genet. 2010;87:52–9.
  • Belostotsky R, Ben-Shalom E, Rinat C, Becker-Cohen R, Feinstein S, Zeligson S, . Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome. Am J Hum Genet. 2011;88:193–200.
  • Gotz A, Tyynismaa H, Euro L, Ellonen P, Hyotylainen T, Ojala T, . Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. Am J Hum Genet. 2011;88:635–42.
  • Pierce SB, Chisholm KM, Lynch ED, Lee MK, Walsh T, Opitz JM, . Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc Natl Acad Sci U S A. 2011;108:6543–8.
  • DiMauro S, Davidzon G. Mitochondrial DNA and disease. Ann Med. 2005;37:222–32.
  • Scaglia F, Wong LJ. Human mitochondrial transfer RNAs: role of pathogenic mutation in disease. Muscle Nerve. 2008; 37:150–71.
  • Jacobs HT. Disorders of mitochondrial protein synthesis. Hum Mol Genet. 2003;12 Spec No 2:R293–301.
  • Prezant TR, Agapian JV, Bohlman MC, Bu X, Oztas S, Qiu WQ, . Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat Genet. 1993;4:289–94.
  • Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature. 1988;331:717–9.
  • Detmer SA, Chan DC. Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol. 2007;8:870–9.
  • Zuchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, . Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet. 2004;36:449–51.
  • Detmer SA, Chan DC. Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations. J Cell Biol. 2007;176: 405–14.
  • Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A, . OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet. 2000;26:211–5.
  • Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, Belenguer P, . Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet. 2000;26:207–10.
  • Quinzii CM, Hirano M. Coenzyme Q and mitochondrial disease. Dev Disabil Res Rev. 2010;16:183–8.
  • Jin H, May M, Tranebjaerg L, Kendall E, Fontan G, Jackson J, . A novel X-linked gene, DDP, shows mutations in families with deafness (DFN-1), dystonia, mental deficiency and blindness. Nat Genet. 1996;14:177–80.
  • Roesch K, Curran SP, Tranebjaerg L, Koehler CM. Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13 complex. Hum Mol Genet. 2002;11:477–86.
  • Di Fonzo A, Ronchi D, Lodi T, Fassone E, Tigano M, Lamperti C, . The mitochondrial disulfide relay system protein GFER is mutated in autosomal-recessive myopathy with cataract and combined respiratory-chain deficiency. Am J Hum Genet. 2009;84:594–604.
  • Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, . Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell. 1998;93:973–83.
  • Rugarli EI, Langer T. Translating m-AAA protease function in mitochondria to hereditary spastic paraplegia. Trends Mol Med. 2006;12:262–9.
  • Ghezzi D, Sevrioukova I, Invernizzi F, Lamperti C, Mora M, D'Adamo P, . Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor. Am J Hum Genet. 2010;86:639–49.
  • Tiranti V, Viscomi C, Hildebrandt T, Di Meo I, Mineri R, Tiveron C, . Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat Med. 2009;15:200–5.
  • Smeitink JA, Zeviani M, Turnbull DM, Jacobs HT. Mitochondrial medicine: a metabolic perspective on the pathology of oxidative phosphorylation disorders. Cell Metab. 2006;3:9–13.
  • Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell. 2005;120:483–95.
  • Willems PH, Valsecchi F, Distelmaier F, Verkaart S, Visch HJ, Smeitink JA, . Mitochondrial Ca2 + homeostasis in human NADH:ubiquinone oxidoreductase deficiency. Cell Calcium. 2008;44:123–33.
  • Tyynismaa H, Carroll CJ, Raimundo N, Ahola-Erkkila S, Wenz T, Ruhanen H, . Mitochondrial myopathy induces a starvation-like response. Hum Mol Genet. 2010;19:3948–58.
  • Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008;183:795–803.
  • Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, . Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008;27:433–46.
  • Ahola-Erkkilä S, Carroll CJ, Peltola-Mjosund K, Tulkki V, Mattila I, Seppanen-Laakso T, . Ketogenic diet slows down mitochondrial myopathy progression in mice. Hum Mol Genet. 2010;19:1974–84.
  • Zhu X, Peng X, Guan MX, Yan Q. Pathogenic mutations of nuclear genes associated with mitochondrial disorders. Acta Biochim Biophys Sin (Shanghai). 2009;41:179–87.
  • Haack TB, Danhauser K, Haberberger B, Hoser J, Strecker V, Boehm D, . Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nat Genet. 2010;42:1131–4.
  • Ghezzi D, Goffrini P, Uziel G, Horvath R, Klopstock T, Lochmuller H, . SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy. Nat Genet. 2009;41:654–6.
  • Hao HX, Khalimonchuk O, Schraders M, Dephoure N, Bayley JP, Kunst H, . SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 2009;325:1139–42.
  • Barel O, Shorer Z, Flusser H, Ofir R, Narkis G, Finer G, . Mitochondrial complex III deficiency associated with a homozygous mutation in UQCRQ. Am J Hum Genet. 2008;82:1211–6.
  • Ghezzi D, Arzuffi P, Zordan M, Da Re C, Lamperti C, Benna C, . Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies. Nat Genet. 2011;43:259–63.
  • Shteyer E, Saada A, Shaag A, Al-Hijawi FA, Kidess R, Revel-Vilk S, . Exocrine pancreatic insufficiency, dyserythropoeitic anemia, and calvarial hyperostosis are caused by a mutation in the COX4I2 gene. Am J Hum Genet. 2009;84:412–7.
  • Huigsloot M, Nijtmans LG, Szklarczyk R, Baars MJ, van den Brand MA, Hendriksfranssen MG, . A mutation in c2orf64 causes impaired cytochrome C oxidase assembly and mitochondrial cardiomyopathy. Am J Hum Genet. 2011;88:488–93.
  • Jonckheere AI, Hogeveen M, Nijtmans LG, van den Brand MA, Janssen AJ, Diepstra JH, . A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy. J Med Genet. 2008;45:129–33.
  • Cizkova A, Stranecky V, Mayr JA, Tesarova M, Havlickova V, Paul J, . TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy. Nat Genet. 2008;40:1288–90.
  • Kaukonen J, Juselius JK, Tiranti V, Kyttala A, Zeviani M, Comi GP, . Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science. 2000;289:782–5.
  • Elpeleg O, Miller C, Hershkovitz E, Bitner-Glindzicz M, Bondi-Rubinstein G, Rahman S, . Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. Am J Hum Genet. 2005;76:1081–6.
  • Ostergaard E, Christensen E, Kristensen E, Mogensen B, Duno M, Shoubridge EA, . Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion. Am J Hum Genet. 2007;81:383–7.
  • Amati-Bonneau P, Valentino ML, Reynier P, Gallardo ME, Bornstein B, Boissiere A, . OPA1 mutations induce mitochondrial DNA instability and optic atrophy ‘plus’ phenotypes. Brain. 2008;131(Pt 2):338–51.
  • Spinazzola A, Viscomi C, Fernandez-Vizarra E, Carrara F, D'Adamo P, Calvo S, . MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat Genet. 2006;38: 570–5.
  • Antonicka H, Ostergaard E, Sasarman F, Weraarpachai W, Wibrand F, Pedersen AM, . Mutations in C12orf65 in patients with encephalomyopathy and a mitochondrial translation defect. Am J Hum Genet. 2010;87:115–22.

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