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Mitochondrial genome and human mitochondrial diseases

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Abstract

Today there are described more than 400 point mutations and more than hundred of structural rearrangements of mitochondrial DNA associated with characteristic neuromuscular and other mitochondrial syndromes, from lethal in the neonatal period of life to the disease with late onset. The defects of oxidative phosphorylation are the main reasons of mitochondrial disease development. Phenotypic diversity and phenomenon of heteroplasmy are the hallmark of mitochondrial human diseases. It is necessary to assess the amount of mutant mtDNA accurately, since the level of heteroplasmy largely determines the phenotypic manifestation. In spite of tremendous progress in mitochondrial biology since the cause-and-effect relations between mtDNA mutation and the human diseases was established over 20 years ago, there is still no cure for mitochondrial diseases.

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References

  1. Sukernik R.I., Derbeneva O.A., Starikovskaia E.B., Volodko N.V., Mikhailovskaia I.E., Bychkov I.Yu, Lott M., Brown M., and Wallace D. 2002. The mitochondrial genome and human mitochondrial diseases. Russ. J. Genet. 38, 161–170.

    Article  CAS  Google Scholar 

  2. DiMauro S., Schon E.A. 2008. Mitochondrial disorders in the nervous system. Annu. Rev. Neurosci. 31, 91–123.

    Article  PubMed  CAS  Google Scholar 

  3. Di Donato S. 2009. Multisystem manifestations of mitochondrial disorders. J. Neurol. 256, 693–710.

    Article  PubMed  Google Scholar 

  4. Ernster L., Ikkos D., Luft R. 1959. Enzymic activities of human skeletal muscle mitochondria: A tool in clinical metabolic research. Nature. 184, 1851–1854.

    Article  PubMed  CAS  Google Scholar 

  5. Luft R., Ikkos D., Palmieri G., Ernster L., Afzelius B. 1962. A case of severe hypermetabolism of monthyroid origin with a defect in the maintenance of mitochondrial respiratory control: A correlated clinical, biochemical, and morphological study. J. Clin. Ivest. 41, 1776–1804.

    Article  CAS  Google Scholar 

  6. Holt I.J., Harding A.E., Morgan Hughes J.A. 1988. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature. 331, 717–719.

    Article  PubMed  CAS  Google Scholar 

  7. Wallace D.C., Singh G., Lott M.T., Hodge J.A., Shurr T.G., Lezza A.M., Elsas L.J. 2nd, Nikoskelainen E.K. 1988. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science. 242, 1427–1430.

    Article  PubMed  CAS  Google Scholar 

  8. van den Ouweland J.M., Lemkes H.H., Ruitenbeek W., Sandkuijl L.A., de Vijlder M.F., Struyvenberg P.A., van de Kamp J.J., Maassen J.A. 1992. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nature Genet. 1, 368–371.

    Article  PubMed  Google Scholar 

  9. Tatuch Y., Christodoulou J., Feigenbaum A., Clarke J.T., Wherret J., Smith C., Rudd N., Petrova-Benedict R., Robinson B.H. 1992. Heteroplasmic mtDNA mutation (T—G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am. J. Hum. Genet. 50, 852–858.

    PubMed  CAS  Google Scholar 

  10. MITOMAP: A Human Mitochondrial Genome Database. http://www.mitomap.org, 2009.

  11. Schaefer A.M., McFarland R., Blakely E.L., He L., Whittaker R.G., Taylor R.W., Chinnery P.F., Turnbull D.M. 2008. Prevalence of mitochondrial DNA disease in adults. Ann. Neurol. 63, 35–39.

    Article  PubMed  CAS  Google Scholar 

  12. Anderson S., Bankier A.T., Barrell B.G., de Bruijn M.H., Coulson A.R., Drouin J., Eperon I.C., Nierlich D.P., Roe B.A., Sanger F., Schreier P.H., Smith A.J., Staden R., Young I.G. 1981. Sequence and organization of the human mitochondrial genome. Nature. 290, 457–465.

    Article  PubMed  CAS  Google Scholar 

  13. Spelbrink J.N. 2010. Functional organization of mammalian mitochondrial DNA in nucleoids: History, recent developments, and future challenges. IUBMB Life. 62, 19–32.

    PubMed  CAS  Google Scholar 

  14. Iborra F.J., Kimura H., Cook P.R. 2004. The functional organization of mitochondrial genomes in human cells. BMC Biol. 24, 2–9.

    Google Scholar 

  15. Holt I.J., He J., Mao C.C., Boyd-Kirkup J.D., Martinsson P., Sembongi H., Reyes A., Spelbrink J.N. 2007. Mammalian mitochondrial nucleoids: Organizing an independently minded genome. Mitochondrion. 7, 311–321.

    Article  PubMed  CAS  Google Scholar 

  16. Bogenhagen D.F., Rousseau D., Burke S. 2008. The layered structure of human mitochondrial DNA nucleoids. J. Biol. Chem. 8, 3665–3675.

    Google Scholar 

  17. He J., Mao C.C., Reyes A., Sembongi H., Di Re M., Granycome C., Clippingdale A.B., Fearnley I.M., Harbour M., Robinson A.J., Reichelt S., Spelbrink J.N., Walker J.E., Holt I.J. 2007. The AAA+ protein ATAD3 has displacement loop binding properties and is involved in mitochondrial nucleoid organization. J. Cell. Biol. 15, 141–146.

    Article  CAS  Google Scholar 

  18. Di Re M., Sembongi H., He J., Reyes A., Yasukawa T., Martinsson P., Bailey L.J., Goffart S., Boyd-Kirkup J.D., Wong T.S., Fersht A.R., Spelbrink J.N., Holt I.J. 2009. Nucleic Acids Res. 37, 5701–5713.

    Article  PubMed  CAS  Google Scholar 

  19. Gilkerson R.W., Schon E.A., Hernandez E., Davidson M.M. 2008. Mitochondrial nucleoids maintain genetic autonomy but allow for functional complementation. J. Cell. Biol. 30, 1117–1128.

    Article  Google Scholar 

  20. Jacobs H.T., Lehtinen S.N., Spelbrink J.N. 2000. No sex please, we’re mitochondria: A hypothesis on the somatic unit of inheritance of mammalian mtDNA. BioEssays. 22, 564–572.

    Article  PubMed  CAS  Google Scholar 

  21. D’Aurelio M., Gajewski C.D., Lin M.T., Mauck W.M., Shao L.Z., Lenaz G., Moraes C.T., Manfredi G. 2004. Heterologous mitochondrial DNA recombination in human cells. Hum. Mol. Genet. 15, 3171–3179.

    Article  CAS  Google Scholar 

  22. Clayton D.A. 1982. Replication of animal mitochondrial DNA. Cell. 28, 693–705.

    Article  PubMed  CAS  Google Scholar 

  23. Clayton D.A. 2003. Mitochondrial DNA replication: what we know. IUBMB Life. 55, 213–217.

    Article  PubMed  CAS  Google Scholar 

  24. Holt I.J., Lorimer H.E., Jacobs H. T. 2000. Coupled leading- and lagging-strand synthesis of mammalian mitochondrial DNA. Cell. 100, 515–524.

    Article  PubMed  CAS  Google Scholar 

  25. Fish J., Raule N., Attardi G. 2004. Discovery of a major D-loop replication origin reveals two modes of human mtDNA synthesis. Science. 306, 2098–2101.

    Article  PubMed  CAS  Google Scholar 

  26. Korhonen J.A., Pham X.H., Pellegrini M., Falkenberg M. 2004. Reconstitution of a minimal mtDNA replisome in vitro. in vitro. EMBO J. 23, 2423–2429.

    Article  PubMed  CAS  Google Scholar 

  27. Holt I. 2009. Mitochondrial DNA replication and repair: All a flap. Trends Biochem. Sci. 34, 358–365.

    Article  PubMed  CAS  Google Scholar 

  28. Ojala D., Montoya J., Attardi G. 1981. tRNA punctuation model of RNA processing in human mitochondria. Nature. 290, 470–474.

    Article  PubMed  CAS  Google Scholar 

  29. Nagaike T., Suzuki T., Ueda T. 2008. Polyadenylation in mammalian mitochondria: Insights from recent studies. Biochim. Biophys. Acta. 1779, 266–269.

    PubMed  CAS  Google Scholar 

  30. Asin-Cayuela J., Gustafsson C.M. 2007. Mitochondrial transcription and its regulation in mammalian cells. Trends Biochem. Sci. 32, 111–117.

    Article  PubMed  CAS  Google Scholar 

  31. Scarpulla R. C. 2008. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol. Rev. 88, 611–638.

    Article  PubMed  CAS  Google Scholar 

  32. Sologub M.Yu., Kochetkov S.N., Temiakov D.E. 2009. Transcription and its regulation in mammalian and human mitochondria. Mol. Biol. 43, 198–210.

    Article  CAS  Google Scholar 

  33. Spremulli L.L., Coursey A., Navratil T., Hunter S.E. 2004. Initiation and elongation factors in mammalian mitochondrial protein biosynthesis. Prog. Nucleic Acids Res. Mol. Biol. 77, 211–261.

    Article  CAS  Google Scholar 

  34. Coenen M.J., Antonicka H., Ugalde C., Sasarman F., Rossi R., Heister J.G., Newbold R.F., Trijbels F.J., van den Heuvel L.P., Shoubridge E.A., Smeitink J.A. 2004. Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency. N. Engl. J. Med. 351, 2080–2086.

    Article  PubMed  CAS  Google Scholar 

  35. Rorbach J., Soleimanpour-Lichaei R., Lightowlers R.N., Chrzanowska-Lightowlers Z.M. 2007. How do mammalian mitochondria synthesize proteins? Biochem. Soc. Trans. 35, 1290–1291.

    Article  PubMed  CAS  Google Scholar 

  36. Hatefi Y. 1985. The mitochondrial electron transport and oxidative phosphorylation system. Annu. Rev. Biochem. 54, 1015–1069.

    Article  PubMed  CAS  Google Scholar 

  37. Moser C.C., Farid T.A., Chobot S.E., Dutton P.L. 2006. Electron tunneling chains of mitochondria. Biochim. Biophys. Acta. 1757, 1096–1109.

    Article  PubMed  CAS  Google Scholar 

  38. Lenaz G., Genova M.L. 2010. Structure and organization of mitochondrial respiratory complexes: A new understanding of an old subject. Antioxid. Redox Signal. 12, 961–1008.

    Article  PubMed  CAS  Google Scholar 

  39. Zickermann V., Dröse S., Tocilescu M.A., Zwicker K., Kerscher S., Brandt U. 2008. Challenges in elucidating structure and mechanism of proton pumping NADH:ubiquinone oxidoreductase (complex I). J. Bioenerg. Biomembr. 40, 475–483.

    Article  PubMed  CAS  Google Scholar 

  40. Hunte C., Palsdottir H., Trumpower B.L. 2003. Protonmotive pathways and mechanisms in the cytochrome bc1 complex. FEBS Lett. 12, 39–46.

    Article  CAS  Google Scholar 

  41. Belevich I., Verkhovsky M.I. 2008. Molecular mechanism of proton translocation by cytochrome c oxidase. Antioxid. Redox Signal. 10, 1–29.

    Article  PubMed  CAS  Google Scholar 

  42. von Ballmoos C., Wiedenmann A., Dimroth P. 2009. Essentials for ATP synthesis by F1F0 ATP synthases. Annu. Rev. Biochem. 78, 649–672.

    Article  CAS  Google Scholar 

  43. Schaegger H. 2001. Respiratory Chain Supercomplexes. IUBMB Life. 52, 119–128.

    Article  Google Scholar 

  44. Wittig I., Carrozzo R., Santorelli F.M., Schägger H. 2006. Supercomplexes and subcomplexes of mitochondrial oxidative phosphorylation. Biochim. Biophys. Acta. 1757, 1066–1072.

    Article  PubMed  CAS  Google Scholar 

  45. Schäfer E., Dencher N.A., Vonck J., Parcej D.N. 2007. Three-dimensional structure of the respiratory chain supercomplex I1III2IV1 from bovine heart mitochondria. Biochemistry. 46, 12579–12585.

    Article  PubMed  CAS  Google Scholar 

  46. Vonck J., Schaefer E. 2009. Supramolecular organization of protein complexes in the mitochondrial inner membrane. Biochim. Biophys. Acta. 1793, 117–124.

    Article  PubMed  CAS  Google Scholar 

  47. Wittig I., Schaegger H. 2009. Supramolecular organization of ATP synthase and respiratory chain in mitochondrial membranes. Biochim. Biophys. Acta. 1787, 672–680.

    Article  PubMed  CAS  Google Scholar 

  48. Lenaz G., Genova M.L. 2009. Structural and functional organization of the mitochondrial respiratory chain: A dynamic super-assembly. Int. J. Biochem. Cell. Biol. 41, 1750–1772.

    Article  PubMed  CAS  Google Scholar 

  49. Dudkina N.V., Kouřil R., Peters K., Braun H.P., Boekema E.J. 2010. Structure and function of mitochondrial supercomplexes. Biochim. Biophys. Acta. In press.

  50. Acín-Pérez R., Fernández-Silva P., Peleato M.L., Pérez-Martos A., Enriquez J.A. 2008. Respiratory active mitochondrial supercomplexes. Mol. Cell. 32, 529–539.

    Article  PubMed  CAS  Google Scholar 

  51. Ko Y.H., Delannoy M., Hullihen J., Chiu W., Pedersen P.L. 2003. Mitochondrial ATP synthasome: Cristae-enriched membranes and a multiwell detergent screening assay yield dispersed single complexes containing the ATP synthase and carriers for Pi and ADP/ATP. J. Biol. Chem. 278, 12305–12309.

    Article  PubMed  CAS  Google Scholar 

  52. Chen C., Ko Y., Delannoy M., Ludtke S.J., Chiu W., Pedersen P.L. 2004. Mitochondrial ATP synthasome: Three-dimensional structure by electron microscopy of the ATP synthase in complex formation with carriers for Pi and ADP/ATP. J. Biol. Chem. 279, 31761–31768.

    Article  PubMed  CAS  Google Scholar 

  53. Chinopoulos C., Adam-Vizi V. 2010. Mitochondria as ATP consumers in cellular pathology. Biochim. Biophys. Acta. 1802, 221–227.

    PubMed  CAS  Google Scholar 

  54. Mitchell P. 1961. Coupling of phosphorylation to electron and hydrogen by a chemi-osmotic type of mechanism. Nature. 191, 144–148.

    Article  PubMed  CAS  Google Scholar 

  55. Murphy M. P. 2009. How mitochondria produce reactive oxygen species. Biochem. J. 417, 1–13.

    Article  PubMed  CAS  Google Scholar 

  56. Poyton R.O., Ball K.A., Castello P.R. 2009. Mitochondrial generation of free radicals and hypoxic signaling. Trends Endocrinol. Metab. 20, 332–340.

    Article  PubMed  CAS  Google Scholar 

  57. Poyton R.O., Castello P.R., Ball K.A., Woo D.K., Pan N. 2009. Mitochondria and hypoxic signaling: A new view. Ann. NY. Acad. Sci. 1177, 48–56.

    Article  PubMed  CAS  Google Scholar 

  58. St-Pierre J., Buckingham J.A., Roebuck S.J., Brand M.D. 2002. Topology of superoxide production from different sites in the mitochondrial electron transport chain. J. Biol. Chem. 277, 44784–44790.

    Article  PubMed  CAS  Google Scholar 

  59. Sun J., Trumpower B.L. 2003. Superoxide anion generation by the cytochrome bc1 complex. Arch. Biochem. Biophys. 419, 198–206.

    Article  PubMed  CAS  Google Scholar 

  60. Giulivi C. 2003. Characterization and function of mitochondrial nitric-oxide synthase. Free Radic. Biol. Med. 34, 397–408.

    Article  PubMed  CAS  Google Scholar 

  61. Giulivi C. 2007. Mitochondria as generators and targets of nitric oxide. Novartis Fdn Symp. 287, 92–100.

    Article  CAS  Google Scholar 

  62. Melov S., Coskun P., Patel M., Tuinstra R., Cottrell B., Jun A.S., Zastawny T.H., Dizdaroglu M., Goodman S.I., Huang T.T., Miziorko H., Epstein C.J., Wallace D.C. 1999. Mitochondrial disease in superoxide dismutase 2 mutant mice. Proc. Natl. Acad. Sci. USA. 96, 846–851.

    Article  PubMed  CAS  Google Scholar 

  63. Andreyev A.Y., Kushnareva Y.E., Starkov A.A. 2005. Mitochondrial metabolism of reactive oxygen species. Biokhimiya. 70, 200–214.

    CAS  Google Scholar 

  64. Fariss M.W., Chan C.B., Patel M., van Houten B., Orrenius S. 2005. Role of mitochondria in toxic oxidative stress. Mol. Interv. 5, 94–111.

    Article  PubMed  CAS  Google Scholar 

  65. Yamakura F., Taka H., Fujimura T., Murayama K. 1998. Inactivation of human manganese-superoxide dismutase by peroxynitrite is caused by exclusive nitration of tyrosine 34 to 3-nitrotyrosine. J. Biol. Chem. 273, 14085–14089.

    Article  PubMed  CAS  Google Scholar 

  66. Riobó N.A., Clementi E., Melani M., Boveris A., Cadenas E., Moncada S., Poderoso J.J. 2001. Nitric oxide inhibits mitochondrial NADH:ubiquinone reductase activity through peroxynitrite formation. Biochem. J. 359, 139–145.

    Article  PubMed  Google Scholar 

  67. Clementi E., Brown G.C., Feelisch M., Moncada S. 1998. Persistent inhibition of cell respiration by nitric oxide: Crucial role of S-nitrosylation of mitochondrial complex I and protective action of glutathione. Proc. Natl. Acad. Sci. USA. 95, 7631–7636.

    Article  PubMed  CAS  Google Scholar 

  68. Kroemer G., Petit P., Zamzami N., Vayssière J.L., Mignotte B. 1995. The biochemistry of programmed cell death. FASEB J. 9, 1277–1287.

    PubMed  CAS  Google Scholar 

  69. Perkins G., Bossy-Wetzel E., Ellisman M.H. 2009. New insights into mitochondrial structure during cell death. Exp. Neurol. 218, 183–192.

    Article  PubMed  CAS  Google Scholar 

  70. Scorrano L. 2009. Opening the doors to cytochrome c: Changes in mitochondrial shape and apoptosis. Int. J. Biochem. Cell. Biol. 41, 1875–1883.

    Article  PubMed  CAS  Google Scholar 

  71. Wallace D.C., Ye J.H., Neckelmann S.N., Singh G., Webster K.A., Greenberg B.D. 1987. Sequence analysis of cDNAs for the human and bovine ATP synthase beta subunit: mitochondrial DNA genes sustain seventeen times more mutations. Curr. Genet. 12, 81–90.

    Article  PubMed  CAS  Google Scholar 

  72. Todorov I.N., Todorov G.I. 2009. The multifactor nature of high mutation frequency in mtDNA of mammalian somatic cells. Biokhimiya. 74, 1184–1194.

    Google Scholar 

  73. Turnbull H.E., Lax N.Z., Diodato D., Ansorge O., Turnbull D.M. 2010. The mitochondrial brain: From mitochondrial genome to neurodegeneration. Biochim. Biophys. Acta. 1802, 111–121.

    PubMed  CAS  Google Scholar 

  74. Abramov A.Y., Smulders-Srinivasan T.K., Kibry D.M., Acin-Perez R., Enriquez J.A., Lightowlers R.N., Duchen M.R., Turnbull D.M. 2010. Mechanism of neurodegeneration of neurons with mitochondrial DNA mutations. Brain. 133, 797–807.

    Article  PubMed  Google Scholar 

  75. Munnich A., Rustin P. 2001. Clinical spectrum and diagnosis of mitochondrial disorders. Am. J. Med. Genet. 106, 4–17.

    Article  PubMed  CAS  Google Scholar 

  76. Taylor R.W., Schaefer A.M., Barron M.J., McFarland R., Turnbull D.M. 2004. The diagnosis of mitochondrial muscle disease. Neuromuscul. Disord. 14, 237–245.

    Article  PubMed  Google Scholar 

  77. Haas R.H., Parikh S., Falk M.J., Saneto R.P., Wolf N.I., Darin N., Cohen B.H. 2007. Mitochondrial disease: A practical approach for primary care physicians. Pediatrics. 120, 1326–1333.

    Article  PubMed  Google Scholar 

  78. Haas R.H., Parikh S., Falk M.J., Saneto R.P., Wolf N.I., Darin N., Wong L.J., Cohen B.H., Naviaux R.K. 2008. The in-depth evaluation of suspected mitochondrial disease. Mol. Genet. Metab. 94, 16–37.

    Article  PubMed  CAS  Google Scholar 

  79. Rahman S., Hanna M.G. 2009. Diagnosis and therapy in neuromuscular disorders: Diagnosis and new treatments in mitochondrial diseases. J. Neurol. Neurosurg. Psychiatry. 80, 943–953.

    Article  PubMed  CAS  Google Scholar 

  80. McFarland R., Turnbull D.M. 2009. Batteries not included: Diagnosis and management of mitochondrial disease. J. Intern. Med. 265, 210–228.

    Article  PubMed  CAS  Google Scholar 

  81. Wong L.J. 2007. Pathogenic mitochondrial DNA mutations in protein-coding genes. Muscle Nerve. 36, 279–293.

    Article  PubMed  CAS  Google Scholar 

  82. Rotig A. 2010. Genetic bases of mitochondrial respiratory chain disorders. Diabetes Metab. 36, 97–107.

    Article  PubMed  CAS  Google Scholar 

  83. Carelli V., La Morgia C., Valentino M.L., Barboni P., Ross-Cisneros F.N., Sadun A.A. 2009. Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders. Biochim. Biophys. Acta. 1787, 518–528.

    Article  PubMed  CAS  Google Scholar 

  84. Yu-Wai-Man P., Griffiths P.G., Hudson G., Chinnery P.F. 2009. Inherited mitochondrial optic neuropathies. J. Med. Genet. 46, 145–158.

    Article  PubMed  CAS  Google Scholar 

  85. Brown M.D., Starikovskaya E., Derbeneva O., Hosseini S., Allen J.C., Mikhailovskaya I.E., Sukernik R.I., Wallace D.C. 2002. The role of mtDNA background in disease expression: A new primary LHON mutation associated with Western Eurasian haplogroup J. Hum. Genet. 110, 130–138.

    Article  CAS  Google Scholar 

  86. Hudson G., Carelli V., Spruijt L., Gerards M., Mowbray C., Achilli A., Pyle A., Elson J., Howell N., La Morgia C., Valentino M.L., Huoponen K., Savontaus M.L., Nikoskelainen E., Sadun A.A., Salomao S.R., Belfort R.Jr., Griffiths P., Man P.Y., de Coo R.F., Horvath R., Zeviani M., Smeets H.J., Torroni A., Chinnery P.F. 2007. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am. J. Hum. Genet. 81, 228–233.

    Article  PubMed  CAS  Google Scholar 

  87. Volodko N.V, L’vova M.A, Starikovskaya E.B., Derbeneva O.A., Bychkov I.Yu., Mikhailovskaya I.E., Pogozheva I.V., Fedotov F.F., Soyan G.V., Procaccio V., Wallace D.C., Sukernik R.I. 2006. Spectrum of pathogenic mtDNA mutations in Leber’s hereditary optic neuropathy families from Siberia. Genetika. 42, 78–87.

    Google Scholar 

  88. Finsterer J. 2008. Leigh and Leigh-like syndrome in children and adults. Pediatr. Neurol. 39, 223–235.

    Article  PubMed  Google Scholar 

  89. Johns D.R., Neufeld M.J. 1991. Cytochrome b mutations in Leber hereditary optic neuropathy. Biochem. Biophys. Res. Commun. 181, 1358–1364.

    Article  PubMed  CAS  Google Scholar 

  90. Valnot I., Kassis J., Chretien D., de Lonlay P., Parfait B., Munnich A., Kachaner J., Rustin P., Rötig A. 1999. A mitochondrial cytochrome b mutation but no mutations of nuclearly encoded subunits in ubiquinol cytochrome c reductase (complex III) deficiency. Hum. Genet. 104, 460–466.

    Article  PubMed  CAS  Google Scholar 

  91. Abu-Amero K.K., Bosley T.M. 2006. Mitochondrial abnormalities in patients with LHON-like optic neuropathies. Invest. Ophthalmol. Vis. Sci. 47, 4211–4220.

    Article  PubMed  Google Scholar 

  92. Lévêque M., Marlin S., Jonard L., Procaccio V., Reynier P., Amati-Bonneau P., Baulande S., Pierron D., Lacombe D., Duriez F., Francannet C., Mom T., Journel H., Catros H., Drouin-Garraud V., Obstoy M.F., Dollfus H., Eliot M.M., Faivre L., Duvillard C., Couderc R., Garabedian E.N., Petit C., Feldmann D., Denoyelle F. 2007. Whole mitochondrial genome screening in maternally inherited non-syndromic hearing impairment using a microarray resequencing mitochondrial DNA chip. Eur. J. Hum. Genet. 15, 1145–1155.

    Article  PubMed  CAS  Google Scholar 

  93. Petros J.A., Baumann A.K., Ruiz-Pesini E., Amin M.B., Sun C.Q., Hall J., Lim S., Issa M.M., Flanders W.D., Hosseini S.H., Marshall F.F., Wallace D. C. 2005. mtDNA mutations increase tumorigenicity in prostate cancer. Proc. Natl. Acad. Sci. USA. 102, 719–724.

    Article  PubMed  CAS  Google Scholar 

  94. Perucca-Lostanlen D., Narbonne H., Hernandez J.B., Staccini P., Saunieres A., Paquis-Flucklinger V., Vialettes B., Desnuelle C. 2000. Mitochondrial DNA variations in patients with maternally inherited diabetes and deafness syndrome. Biochem. Biophys. Res. Commun. 3, 771–775.

    Article  CAS  Google Scholar 

  95. Schon E.A., Santra S., Pallotti F., Girvin M.E. 2001. Pathogenesis of primary defects in mitochondrial ATP synthesis. Semin. Cell. Dev. Biol. 12, 441–448.

    Article  PubMed  CAS  Google Scholar 

  96. Solaini G., Harris D.A., Lenaz G., Sgarbi G., Baracca A. 2008. The study of the pathogenic mechanism of mitochondrial diseases provides information on basic bioenergetics. Biochim. Biophys. Acta. 1777, 941–945.

    Article  PubMed  CAS  Google Scholar 

  97. D’Aurelio M., Vives-Bauza C., Davidson M.M., Manfredi G. 2010. Mitochondrial DNA background modifies the bioenergetics of NARP/MILS ATP6 mutant cells. Hum. Mol. Genet. 19, 374–386.

    Article  PubMed  CAS  Google Scholar 

  98. Cortopassi G., Hutchin T. 1994. A molecular and cellular hypothesis for aminoglycoside-induced deafness. Hear Res. 78, 27–30.

    Article  PubMed  CAS  Google Scholar 

  99. Kokotas H., Petersen M.B., Willems P.J. 2007. Mitochondrial deafness. Clin. Genet. 71, 379–391.

    Article  PubMed  CAS  Google Scholar 

  100. Finsterer J. 2007. Genetic, pathogenetic, and phenotypic implications of the mitochondrial A3243G tRNALeu(UUR) mutation. Acta Neurol. Scand. 116, 1–14.

    Article  PubMed  CAS  Google Scholar 

  101. Ma Y., Fang F., Yang Y., Zou L., Zhang Y., Wang S., Xu Y., Pei P., Qi Y. 2009. The study of mitochondrial A3243G mutation in different samples. Mitochondrion. 9, 139–143.

    Article  PubMed  CAS  Google Scholar 

  102. Sue C.M., Quigley A., Katsabanis S., Kapsa R., Crimmins D.S., Byrne E., Morris J.G. 1998. Detection of MELAS A3243G point mutation in muscle, blood and hair follicles. J. Neurol. Sci. 161, 36–39.

    Article  PubMed  CAS  Google Scholar 

  103. Silvestri G., Ciafaloni E., Santorelli F.M., Shanske S., Servidei S., Graf W.D., Sumi M., DiMauro S. 1993. Clinical features associated with the A G transition at nucleotide 8344 of mtDNA (“MERRF mutation”). Neurology. 43, 1200–1206.

    PubMed  CAS  Google Scholar 

  104. Shoffner J.M., Lott M.T., Lezza A.M., Seibel P., Ballinger S.W., Wallace D. C. 1990. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell. 6, 931–937.

    Article  Google Scholar 

  105. Krishnan K.J., Reeve A.K., Samuels D.C., Chinnery P.F., Blackwood J.K., Taylor R.W., Wanrooij S., Spelbrink J.N., Lightowlers R.N., Turnbull D.M. 2008. What causes mitochondrial DNA deletions in human cells? Nature Genet. 40, 275–279.

    Article  PubMed  CAS  Google Scholar 

  106. Chinnery P.F., DiMauro S., Shanske S., Schon E.A., Zeviani M., Mariotti C., Carrara F., Lombes A., Laforet P., Ogier H., Jaksch M., Lochmüller H., Horvath R., Deschauer M., Thorburn D.R., Bindoff L.A., Poulton J., Taylor R.W., Matthews J.N., Turnbull D.M. 2004. Risk of developing a mitochondrial DNA deletion disorder. Lancet. 364, 592–596.

    Article  PubMed  CAS  Google Scholar 

  107. Maceluch J.A., Niedziela M. 2006. The clinical diagnosis and molecular genetics of Kearns-Sayre syndrome: A complex mitochondrial encephalomyopathy. Pediatr. Endocrinol. Rev. 4, 117–137.

    PubMed  Google Scholar 

  108. van Goethem G., Martin J.J., Van Broeckhoven C. 2003. Progressive external ophthalmoplegia characterized by multiple deletions of mitochondrial DNA: Unraveling the pathogenesis of human mitochondrial DNA instability and the initiation of a genetic classification. Neuromolecular Med. 3, 129–146.

    Article  PubMed  Google Scholar 

  109. Rötig A., Cormier V., Blanche S., Bonnefont J.P., Ledeist F., Romero N., Schmitz J., Rustin P., Fischer A., Saudubray J.M. 1990. Pearson’s marrow-pancreas syndrome. A multisystem mitochondrial disorder in infancy. J. Clin. Invest. 86, 1601–1608.

    Article  PubMed  Google Scholar 

  110. Lee H.F., Lee H.J., Chi C.S., Tsai C.R., Chang T.K., Wang C.J. 2007. The neurological evolution of Pearson syndrome: Case report and literature review. Eur. J. Paediatr. Neurol. 11, 208–214.

    Article  PubMed  Google Scholar 

  111. López-Gallardo E., López-Pérez M.J., Montoya J., Ruiz-Pesini E. 2009. CPEO and KSS differ in the percentage and location of the mtDNA deletion. Mitochondrion. 9, 314–317.

    Article  PubMed  CAS  Google Scholar 

  112. Dimmer K.S., Rapaport D. 2008. Proteomic view of mitochondrial function. Genome Biol. 9, 209.

    Article  PubMed  CAS  Google Scholar 

  113. Ruiz-Romeo C., Blanco F.J. 2009. Mitochondrial proteomics and its application in biomedical research. Mol. BioSyst. 5, 1130–1142.

    Article  CAS  Google Scholar 

  114. Jacobs H.T, Turnbull D.M. 2005. Nuclear genes and mitochondrial translation: A new class of genetic disease. Trends Genet. 21, 312–314.

    Article  PubMed  CAS  Google Scholar 

  115. Zhu X., Peng X., Guan M-X., Yan Q. 2009. Pathogenic mutations of nuclear genes associated with mitochondrial disorders. Acta Biochim. Biophys. Sinica. 41, 179–187.

    Article  CAS  Google Scholar 

  116. Kmiec B., Woloszynska M., Janska H. 2006. Heteroplasmy as a common state of mitochondrial genetic information in plants and animals. Curr. Genet. 50, 149–159.

    Article  PubMed  CAS  Google Scholar 

  117. Wonnapinij P., Chinnery P.F., Samuels D. C. 2008. The distribution of mitochondrial DNA heteroplasmy due to random genetic drift. Am. J. Hum. Genet. 83, 582–593.

    Article  PubMed  CAS  Google Scholar 

  118. Gilkerson R.W., Schon E.A. 2008. Nucleoid autonomy: An underlying mechanism of mitochondrial genetics with therapeutic potential. Commun. Integr. Biol. 1, 34–36.

    Article  PubMed  CAS  Google Scholar 

  119. Gilkerson R.W. 2009. Mitochondrial DNA nucleoids determine mitochondrial genetics and dysfunction. Int. J. Biochem. Cell Biol. 41, 1899–1906.

    Article  PubMed  CAS  Google Scholar 

  120. Lightowlers R.N., Chinnery P.F., Turnbull D.M., Howell N. 1997. Mammalian mitochondrial genetics: Heredity, heteroplasmy and disease. Trends Genet. 13, 450–455.

    Article  PubMed  CAS  Google Scholar 

  121. DiMauro S., Schon E.A. 2001. Mitochondrial DNA mutations in human disease. Am. J. Med. Genet. 106, 18–26.

    Article  PubMed  CAS  Google Scholar 

  122. van Blerkom J. 2008. Mitochondria as regulatory forces in oocytes, preimplantation embryos and stem cells. Reprod. Biomed. Online. 16, 553–569.

    Article  PubMed  Google Scholar 

  123. van Blerkom J. 2009. Mitochondria in early mammalian development. Semin. Cell Dev. Biol. 20, 354–364.

    Article  PubMed  CAS  Google Scholar 

  124. Ramalho-Santos J., Varum S., Amaral S., Mota P.C., Sousa A.P., Amaral A. 2009. Mitochondrial functionality in reproduction: from gonads and gametes to embryos and embryonic stem cells. Hum. Reprod. Update. 15, 553–572.

    Article  PubMed  CAS  Google Scholar 

  125. Hauswirth W.W., Laipis P.J. 1982. Mitochondrial DNA polymorphism in a maternal lineage of Holstein cows. Proc. Natl. Acad. Sci. USA. 79, 4686–4690.

    Article  PubMed  CAS  Google Scholar 

  126. Jansen R.P., de Boer K. 1998. The bottleneck: Mitochondrial imperatives in oogenesis and ovarian follicular fate. Mol. Cell. Endocrinol. 145, 81–88.

    Article  PubMed  CAS  Google Scholar 

  127. Shoubridge E.A., Wai T. 2007. Mitochondrial DNA and the mammalian oocyte. Curr. Top. Dev. Biol. 77, 87–111.

    Article  PubMed  CAS  Google Scholar 

  128. Cao L., Shitara H., Horii T., Nagao Y., Imai H., Abe K., Hara T., Hayashi J., Yonekawa H. 2007. The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells. Nature Genet. 39, 386–390.

    Article  PubMed  CAS  Google Scholar 

  129. Cree L.M., Samuels D.C., de Sousa Lopes S.C., Rajasimha H.K., Wonnapinij P., Mann J.R., Dahl H.H., Chinnery P.F. 2008. A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nature Genet. 40, 249–254.

    Article  PubMed  CAS  Google Scholar 

  130. Stewart J.B., Freyer C., Elson J.L., Larsson N.G. 2008. Purifying selection of mtDNA and its implications for understanding evolution and mitochondrial disease. Nature Rev. Genet. 9, 657–662.

    Article  CAS  Google Scholar 

  131. Wai T., Teoli D., Shoubridge E.A. 2008. The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes. Nature Genet. 40, 1484–1488.

    Article  PubMed  CAS  Google Scholar 

  132. Cummins J.M. 2001. Mitochondria: Potential roles in embryogenesis and nucleocytoplasmic transfer. Hum. Reprod. Update. 7, 217–228.

    Article  PubMed  CAS  Google Scholar 

  133. Kurelac I., Lang M., Zuntini R., Bartoletti S.A., Santamaria M., Attimonelli M., Gasparre G., Romeo G. 2009. Experimental and critical assessment of six methodological approaches to quantify heteroplasmy of mitochondrial mutations. Abstr. Eur. Hum. Genet. Conf., Vienna, Austria, May 23–26, 2009.

  134. Wong L.J., Bai R.K. 2006. Real-time quantitative polymerase chain reaction analysis of mitochondrial DNA point mutation. Methods Mol. Biol. 335, 187–200.

    PubMed  CAS  Google Scholar 

  135. Poe B.G., Navratil M., Arriaga E.A. 2007. Absolute quantitation of a heteroplasmic mitochondrial DNA deletion using a multiplex three-primer real-time PCR assay. Anal. Biochem. 362, 193–200.

    Article  PubMed  CAS  Google Scholar 

  136. Bai R.K., Wong L.J. 2006. Detection and quantification of heteroplasmic mutant mitochondrial DNA by real-time amplification refractory mutation system quantitative PCR analysis: A single-step approach. Clin. Chem. 50, 996–1001.

    Article  CAS  Google Scholar 

  137. Thèves C., Keyser-Tracqui C., Crubézy E., Salles J.P., Ludes B., Telmon N. 2006. Detection and quantification of the age-related point mutation A189G in the human mitochondrial DNA. J. Forensic Sci. 51, 865–873.

    Article  PubMed  CAS  Google Scholar 

  138. Alvarez-Iglesias V., Barros F., Carracedo A., Salas A. 2008. Minisequencing mitochondrial DNA pathogenic mutations. BMC Med. Genet. 10, 9–26.

    Google Scholar 

  139. White H.E., Durston V.J., Seller A., Fratter C., Harvey J.F., Cross N. C. 2005. Accurate detection and quantitation of heteroplasmic mitochondrial point mutations by pyrosequencing. Genet. Test. 9, 190–199.

    Article  PubMed  CAS  Google Scholar 

  140. Mashima Y., Nagano M., Funayama T., Zhang Q., Egashira T., Kudho J., Shimizu N., Oguchi Y. 2003. Rapid quantification of the heteroplasmy of mutant mitochondrial DNAs in Leber’s hereditary optic neuropathy using the Invader technology. Clin. Biochem. 37, 268–276.

    Article  CAS  Google Scholar 

  141. Pati N., Schowinsky V., Kokanovic O., Magnuson V., Ghosh S. 2004. A comparison between SNaPshot, pyrosequencing, and biplex invader SNP genotyping methods: Accuracy, cost, and throughput. J. Biochem. Biophys. Methods. 60, 1–12.

    Article  PubMed  CAS  Google Scholar 

  142. Du W., Li W., Chen G., Cao H., Tang H., Tang X., Jin Q., Sun Z., Zhao H., Zhou W., He S., Lv Y., Zhao J., Zhang X. 2009. Detection of known base substitution mutations in human mitochondrial DNA of MERRF and MELAS by biochip technology. Biosens. Bioelectron. 24, 2371–2376.

    Article  PubMed  CAS  Google Scholar 

  143. Nishigaki Y., Ueno H., Coku J., Koga Y., Fujii T., Sahashi K., Nakano K., Yoneda M., Nonaka M., Tang L., Liou C.W., Paquis-Flucklinger V., Harigaya Y., Ibi T., Goto Y.I., Hosoya H., Dimauro S., Hirano M., Tanaka M. 2010. Extensive screening system using suspension array technology to detect mitochondrial DNA point mutations. Mitochondrion. 10, 300–308.

    Article  PubMed  CAS  Google Scholar 

  144. Chinnery P., Majamaa K., Turnbull D., Thorburn D. 2006. Treatment for mitochondrial disorders. Cochrane. Database. Syst. Rev. 1, CD004426.

    PubMed  Google Scholar 

  145. Dimauro S., Rustin P. 2009. A critical approach to the therapy of mitochondrial respiratory chain and oxidative phosphorylation diseases. Biochim. Biophys. Acta. 1792, 1159–1167.

    PubMed  CAS  Google Scholar 

  146. Parikh S., Saneto R., Falk M.J., Anselm I., Cohen B.H., Haas R., Medicine Society TM. 2009. A modern approach to the treatment of mitochondrial disease. Curr. Treat. Options Neurol. 11, 414–430.

    Article  PubMed  Google Scholar 

  147. Finsterer J. 2010. Treatment of mitochondrial disorders. Eur. J. Paediatr. Neurol. 14, 29–44.

    Article  PubMed  Google Scholar 

  148. Finsterer J., Segall L. 2010. Drugs interfering with mitochondrial disorders. Drug. Chem. Toxicol. 33, 138–151.

    Article  PubMed  CAS  Google Scholar 

  149. Kerr D. S. 2010. Treatment of mitochondrial electron transport chain disorders: A review of clinical trials over the past decade. Mol. Genet. Metab. 99, 246–255.

    Article  PubMed  CAS  Google Scholar 

  150. Taivassalo T., Haller R.G. 2004. Implications of exercise training in mtDNA defects: Use it or lose it? Biochim. Biophys. Acta. 1659, 221–231.

    Article  PubMed  CAS  Google Scholar 

  151. Taivassalo T., Haller R.G. 2005. Exercise and training in mitochondrial myopathies. Med. Sci. Sports Exerc. 37, 2094–2101.

    Article  PubMed  CAS  Google Scholar 

  152. Gardner J.L., Craven L., Turnbull D.M., Taylor R.W. 2007. Experimental strategies towards treating mitochondrial DNA disorders. Biosci. Rep. 27, 139–150.

    Article  PubMed  CAS  Google Scholar 

  153. Edmonds J.L. Jr. 2004. Surgical and anesthetic management of patients with mitochondrial dysfunction. Mitochondrion. 4, 543–548.

    Article  PubMed  CAS  Google Scholar 

  154. Footitt E.J., Sinha M.D., Raiman J.A., Dhawan A., Moganasundram S., Champion M. P. 2008. Mitochondrial disorders and general anaesthesia: A case series and review. Br. J. Anaesth. 100, 436–441.

    Article  PubMed  CAS  Google Scholar 

  155. Chinnery P.F., Bindoff L.A., Europen neuromuscular center. 2003. 116th ENMC international workshop: The treatment of mitochondrial disorders, 14th–16th March 2003, Naarden, The Netherlands. Neuromuscul. Disord. 13, 757–764.

    Article  PubMed  CAS  Google Scholar 

  156. Oca-Cossio J., Kenyon L., Hao H., Moraes C. T. 2003. Limitations of allotopic expression of mitochondrial genes in mammalian cells. Genetics. 165, 707–720.

    PubMed  CAS  Google Scholar 

  157. Manfredi G., Fu J., Ojaimi J., Sadlock J.E., Kwong J.Q., Guy J., Schon E.A. 2002. Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus. Nature Genet. 30, 394–399.

    Article  PubMed  CAS  Google Scholar 

  158. Guy J., Qi X., Pallotti F., Schon E.A., Manfredi G., Carelli V., Martinuzzi A., Hauswirth W.W., Lewin A.S. 2002. Rescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy. Ann. Neurol. 52, 534–542.

    Article  PubMed  CAS  Google Scholar 

  159. Zullo S.J., Parks W.T., Chloupkova M., Wei B., Weiner H., Fenton W.A., Eisenstadt J.M., Merril C.R. 2005. Stable transformation of CHO Cells and human NARP cybrids confers oligomycin resistance (oli(r)) following transfer of a mitochondrial DNA-encoded oli(r) ATPase6 gene to the nuclear genome: A model system for mtDNA gene therapy. Rejuvenation Res. 8, 18–28.

    Article  PubMed  CAS  Google Scholar 

  160. Bonnet C., Augustin S., Ellouze S., Bénit P., Bouaita A., Rustin P., Sahel J.A., Corral-Debrinski M. 2008. The optimized allotopic expression of ND1 or ND4 genes restores respiratory chain complex I activity in fibro-blasts harboring mutations in these genes. Biochim. Biophys. Acta. 1783, 1707–1717.

    Article  PubMed  CAS  Google Scholar 

  161. Bonnet C., Kaltimbacher V., Ellouze S., Augustin S., Bénit P., Forster V., Rustin P., Sahel J.A., Corral-Debrinski M. 2007. Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts harboring mitochondrial DNA mutations affecting complex I or V subunits. Rejuvenation Res. 10, 127–144.

    Article  PubMed  CAS  Google Scholar 

  162. Ellouze S., Augustin S., Bouaita A., Bonnet C., Simonutti M., Forster V., Picaud S., Sahel J.A., Corral-Debrinski M. 2008. Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am. J. Hum. Genet. 83, 373–387.

    Article  PubMed  CAS  Google Scholar 

  163. Seo B.B., Wang J., Flotte T.R., Yagi T., Matsuno-Yagi A. 2000. Use of the NADH-quinone oxidoreductase (NDI1) gene of Saccharomyces cerevisiae as a possible cure for complex I defects in human cells. J. Biol. Chem. 275, 37774–37778.

    Article  PubMed  CAS  Google Scholar 

  164. Park J.S., Li Y.F., Bai Y. 2007. Yeast NDI1 improves oxidative phosphorylation capacity and increases protection against oxidative stress and cell death in cells carrying a Leber’s hereditary optic neuropathy mutation. Biochim. Biophys. Acta. 1772, 533–542.

    PubMed  CAS  Google Scholar 

  165. Marella M., Seo B.B., Yagi T., Matsuno-Yagi A. 2009. Parkinson’s disease and mitochondrial complex I: A perspective on the Ndi1 therapy. J. Bioenerg. Biomembr. 41, 493–497.

    Article  PubMed  CAS  Google Scholar 

  166. Hakkaart G.A., Dassa E.P., Jacobs H.T., Rustin P. 2006. Allotopic expression of a mitochondrial alternative oxidase confers cyanide resistance to human cell respiration. EMBO Rep. 7, 341–345.

    Article  PubMed  CAS  Google Scholar 

  167. Kolesnikova O.A., Entelis N.S., Mireau H., Fox T.D., Martin R.P., Tarassov I.A. 2000. Suppression of mutations in mitochondrial DNA by tRNAs imported from the cytoplasm. Science. 289, 1931–1933.

    Article  PubMed  CAS  Google Scholar 

  168. Entelis N.S., Kolesnikova O.A., Martin R.P., Tarassov I.A. 2001. RNA delivery into mitochondria. Adv. Drug. Deliv. Rev. 49, 199–215.

    Article  PubMed  CAS  Google Scholar 

  169. Kolesnikova O.A., Entelis N.S., Jacquin-Becker C., Goltzene F., Chrzanowska-Lightowlers Z.M., Lightowlers R.N., Martin R.P., Tarassov I. 2004. Nuclear DNA-encoded tRNAs targeted into mitochondria can rescue a mitochondrial DNA mutation associated with the MERRF syndrome in cultured human cells. Hum. Mol. Genet. 13, 2519–2534.

    Article  PubMed  CAS  Google Scholar 

  170. Mahata B., Mukherjee S., Mishra S., Bandyopadhyay A., Adhya S. 2006. Functional delivery of a cytosolic tRNA into mutant mitochondria of human cells. Science. 314, 471–474.

    Article  PubMed  CAS  Google Scholar 

  171. Mukherjee S., Mahata B., Mahato B., Adhya S. 2008. Targeted mRNA degradation by complex-mediated delivery of antisense RNAs to intracellular human mitochondria. Hum. Mol. Genet. 17, 1292–1298.

    Article  PubMed  CAS  Google Scholar 

  172. Ling J., Roy H., Qin D., Rubio M.A., Alfonzo J.D., Fredrick K., Ibba M. 2007. Pathogenic mechanism of a human mitochondrial tRNAPhe mutation associated with myoclonic epilepsy with ragged red fibers syndrome. Proc. Natl. Acad. Sci. USA. 104, 15299–15304.

    Article  PubMed  Google Scholar 

  173. Rorbach J., Soleimanpour-Lichaei R., Lightowlers R.N., Chrzanowska-Lightowlers Z.M. 2007. How do mammalian mitochondria synthesize proteins? Biochem. Soc. Trans. 35, 1290–1291.

    Article  PubMed  CAS  Google Scholar 

  174. Park H., Davidson E., King M. P. 2008. Overexpressed mitochondrial leucyl-tRNA synthetase suppresses the A3243G mutation in the mitochondrial tRNA(Leu(UUR)) gene. RNA. 14, 2407–2416.

    Article  PubMed  CAS  Google Scholar 

  175. Tanaka M., Borgeld H.J., Zhang J., Muramatsu S., Gong J.S., Yoneda M., Maruyama W., Naoi M., Ibi T., Sahashi K., Shamoto M., Fuku N., Kurata M., Yamada Y., Nishizawa K., Akao Y., Ohishi N., Miyabayashi S., Umemoto H., Muramatsu T., Furukawa K., Kikuchi A., Nakano I., Ozawa K., Yagi K. 2002. Gene therapy for mitochondrial disease by delivering restriction endonuclease SmaI into mitochondria. J. Biomed. Sci. 9, 534–541.

    PubMed  CAS  Google Scholar 

  176. Bacman S.R., Williams S.L., Hernandez D., Moraes C.T. 2007. Modulating mtDNA heteroplasmy by mitochondria-targeted restriction endonucleases in a’ differential multiple cleavage-site’ model. Gene Ther. 14, 1309–1318.

    PubMed  CAS  Google Scholar 

  177. Taylor R.W., Chinnery P.F., Turnbull D.M., Lightowlers R.N. 1997. Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids. Nature Genet. 15, 212–215.

    Article  PubMed  CAS  Google Scholar 

  178. Chinnery P.F., Taylor R.W., Diekert K., Lill R., Turnbull D.M., Lightowlers R.N. 1999. Peptide nucleic acid delivery to human mitochondria. Gene Ther. 6, 1919–1928.

    Article  PubMed  CAS  Google Scholar 

  179. Muratovska A., Lightowlers R.N., Taylor R.W., Turnbull D.M., Smith R.A., Wilce J.A., Martin S.W., Murphy M. P. 2001. Targeting peptide nucleic acid (PNA) oligomers to mitochondria within cells by conjugation to lipophilic cations: Implications for mitochondrial DNA replication, expression and disease. Nucleic Acids Res. 29, 1852–1863.

    Article  PubMed  CAS  Google Scholar 

  180. Taylor R.W., Wardell T.M., Smith P.M., Muratovska A., Murphy M.P., Turnbull D.M., Lightowlers R.N. 2001. An antigenomic strategy for treating heteroplasmic mtDNA disorders. Adv. Drug. Deliv. Rev. 49, 121–125.

    Article  PubMed  CAS  Google Scholar 

  181. Flierl A., Jackson C., Cottrell B., Murdock D., Seibel P., Wallace D. C. 2003. Targeted delivery of DNA to the mitochondrial compartment via import sequence-conjugated peptide nucleic acid. Mol. Ther. 7, 550–557.

    Article  PubMed  CAS  Google Scholar 

  182. Kyriakouli D.S., Boesch P., Taylor R.W., Lightowlers R.N. 2008. Progress and prospects: gene therapy for mitochondrial DNA disease. Gene Ther. 15, 1017–1023.

    Article  PubMed  CAS  Google Scholar 

  183. Minczuk M., Papworth M.A., Kolasinska P., Murphy M.P., Klug A. 2006. Sequence-specific modification of mitochondrial DNA using a chimeric zinc finger methylase. Proc. Natl. Acad. Sci. USA. 103, 19689–19694.

    Article  PubMed  CAS  Google Scholar 

  184. Spees J.L., Olson S.D., Whitney M.J., Prockop D.J. 2005. Mitochondrial transfer between cells can rescue aerobic respiration. Proc. Natl. Acad. Sci. USA. 103, 1283–1238.

    Article  CAS  Google Scholar 

  185. Csordás A. 2006. Mitochondrial transfer between eukaryotic animal cells and its physiologic role. Rejuvenation Res. 9, 450–454.

    Article  PubMed  Google Scholar 

  186. Dani M.A., Dani S.U. 2010. Improving upon nature’s somatic mitochondrial DNA therapies. Med. Hypotheses. 74, 1021–1025.

    Article  PubMed  CAS  Google Scholar 

  187. Yamada Y., Harashima H. 2008. Mitochondrial drug delivery systems for macromolecule and their therapeutic application to mitochondrial diseases. Adv. Drug. Deliv. Rev. 60, 1439–1462.

    Article  PubMed  CAS  Google Scholar 

  188. Boddapati S.V., D’souza G.G., Weissig V. 2010. Liposomes for drug delivery to mitochondria. Methods Mol. Biol. 605, 295–303.

    Article  PubMed  CAS  Google Scholar 

  189. Brown D.T., Herbert M., Lamb V.K., Chinnery P.F., Taylor R.W., Lightowlers R.N., Craven L., Cree L., Gardner J.L., Turnbull D.M. 2006. Transmission of mitochondrial DNA disorders: Possibilities for the future. Lancet. 368, 87–89.

    Article  PubMed  CAS  Google Scholar 

  190. Poulton J., Kennedy S., Oakeshott P., Wells D. 2009. Preventing transmission of maternally inherited mitochondrial DNA diseases. Br. Med. J. 338, b94.

    Article  Google Scholar 

  191. South S.T., Chen Z., Brothman A.R. 2008. Genomic medicine in prenatal diagnosis. Clin. Obstet. Gynecol. 51, 62–73.

    Article  PubMed  Google Scholar 

  192. Poulton J., Turnbull D.M. 2000. 74th ENMC international workshop: Mitochondrial diseases. 19–20 November 1999, Naarden, the Netherlands. Neuromuscul. Disord. 10, 460–462.

    Article  PubMed  CAS  Google Scholar 

  193. Geraedts J.P., De Wert G.M. 2009. Preimplantation genetic diagnosis. Clin. Genet. 76, 315–325.

    Article  PubMed  CAS  Google Scholar 

  194. Dean N.L., Battersby B.J., Ao A., Gosden R.G., Tan S.L., Shoubridge E.A., Molnar M.J. 2003. Prospect of preimplantation genetic diagnosis for heritable mitochondrial DNA diseases. Mol. Hum. Reprod. 9, 631–638.

    Article  PubMed  CAS  Google Scholar 

  195. Bickerstaff H., Flinter F., Yeong C.T., Braude P. 2001. Clinical application of preimplantation genetic diagnosis. Hum. Fertil. (Cambridge). 4, 24–30.

    Article  CAS  Google Scholar 

  196. Steffann J., Frydman N., Gigarel N., Burlet P., Ray P.F., Fanchin R., Feyereisen E., Kerbrat V., Tachdjian G., Bonnefont J.P., Frydman R., Munnich A. 2006. Analysis of mtDNA variant segregation during early human embryonic development: A tool for successful NARP preimplantation diagnosis. J. Med. Genet. 43, 244–247.

    Article  PubMed  CAS  Google Scholar 

  197. Bredenoord A.L., Dondorp W., Pennings G., De Die-Smulders C.E., De Wert G. 2008. PGD to reduce reproductive risk: The case of mitochondrial DNA disorders. Hum. Reprod. 23, 2392–2401.

    Article  PubMed  CAS  Google Scholar 

  198. Bredenoord A.L., Pennings G., Smeets H.J., de Wert G. 2008. Dealing with uncertainties: Ethics of prenatal diagnosis and preimplantation genetic diagnosis to prevent mitochondrial disorders. Hum. Reprod. Update. 14, 83–94.

    Article  PubMed  CAS  Google Scholar 

  199. Bredenoord A., Dondorp W., Pennings G., de Die-Smulders C., Smeets B., de Wert G. 2009. Preimplantation genetic diagnosis for mitochondrial DNA disorders: ethical guidance for clinical practice. Eur. J. Hum. Genet. 17, 1550–1559.

    Article  PubMed  CAS  Google Scholar 

  200. Brenner C.A., Barritt J.A., Willadsen S., Cohen J. 2000. Mitochondrial DNA heteroplasmy after human ooplasmic transplantation. Fertil. Steril. 74, 573–578.

    Article  PubMed  CAS  Google Scholar 

  201. Cohen J., Scott R., Alikani M., Schimmel T., Munné S., Levron J., Wu L., Brenner C., Warner C., Willadsen S. 1998. Ooplasmic transfer in mature human oocytes. Mol. Hum. Reprod. 4, 269–280.

    Article  PubMed  CAS  Google Scholar 

  202. Barritt J.A., Brenner C.A., Malter H.E., Cohen J. 2001. Mitochondria in human offspring derived from ooplasmic transplantation. Hum. Reprod. 16, 513–516.

    Article  PubMed  CAS  Google Scholar 

  203. Hawes S.M., Sapienza C., Latham K.E. 2002. Ooplasmic donation in humans: The potential for epigenic modifications. Hum. Reprod. 17, 850–852.

    Article  PubMed  Google Scholar 

  204. Harvey A.J., Gibson T.C., Quebedeaux T.M., Brenner C.A. 2007. Impact of assisted reproductive technologies: A mitochondrial perspective of cytoplasmic transplantation. Curr. Top. Dev. Biol. 77, 229–249.

    Article  PubMed  CAS  Google Scholar 

  205. Taylor R.W., Turnbull D.M. 2005. Mitochondrial DNA mutations in human disease. Nature Rev. Genet. 5, 389–402.

    Article  CAS  Google Scholar 

  206. Fulka H., Fulka J. Jr. 2007. The use of micromanipulation methods as a tool to prevention of transmission of mutated mitochondrial DNA. Curr. Top. Dev. Biol. 77, 187–211.

    Article  PubMed  CAS  Google Scholar 

  207. Fulka J. Jr., Fulka H., John J. C. 2007. Transmission of mitochondrial DNA disorders: Possibilities for the elimination of mutated mitochondria. Cloning Stem Cells. 9, 47–50.

    Article  PubMed  CAS  Google Scholar 

  208. Bredenoord A.L., Pennings G., de Wert G. 2008. Ooplasmic and nuclear transfer to prevent mitochondrial DNA disorders: Conceptual and normative issues. Hum. Reprod. Update. 14, 669–678.

    Article  PubMed  CAS  Google Scholar 

  209. Fulka H., Langerova A., Barnetova I., Novakova Z., Mosko T., Fulka J. Jr. 2009. How to repair the oocyte and zygote? J. Reprod. Dev. 55, 583–587.

    Article  PubMed  Google Scholar 

  210. Tachibana M., Sparman M., Sritanaudomchai H., Ma H., Clepper L., Woodward J., Li Y., Ramsey C., Kolotushkina O., Mitalipov S. 2009. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature. 461, 367–372.

    Article  PubMed  CAS  Google Scholar 

  211. Khan S.M., Smigrodzki R.M., Swerdlow R.H. 2007. Cell and animal models of mtDNA biology: progress and prospects. Am. J. Physiol. Cell. Physiol. 292, 658–669.

    Article  CAS  Google Scholar 

  212. Vempati U.D., Torraco A., Moraes C.T. 2008. Mouse models of oxidative phosphorylation dysfunction and disease. Methods. 46, 241–247.

    Article  PubMed  CAS  Google Scholar 

  213. Wallace D.C., Fan W. 2009. The pathophysiology of mitochondrial disease as modeled in the mouse. Genes Dev. 23, 1714–1736.

    Article  PubMed  CAS  Google Scholar 

  214. Lim K.S., Naviaux R.K., Wong S., Haas R.H. 2008. Pitfalls in the denaturing high-performance liquid chromatography analysis of mitochondrial DNA mutation. J. Mol. Diagn. 10, 102–108.

    Article  PubMed  CAS  Google Scholar 

  215. Dobrowolski S.F., Hendrickx A.T., van den Bosch B.J., Smeets H.J., Gray J., Miller T., Sears M. 2009. Identifying sequence variants in the human mitochondrial genome using high-resolution melt (HRM) profiling. Hum. Mutat. 30, 891–898.

    Article  PubMed  CAS  Google Scholar 

  216. Ojaimi J., Pan J., Santra S., Snell W.J., Schon E.A. An algal nucleus-encoded subunit of mitochondrial ATP synthase rescues a defect in the analogous human mitochondrial-encoded subunit. Mol. Biol. Cell. 13, 3836–3844.

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    I. O. Mazunin, N. V. Volodko, E. B. Starikovskaya & R. I. Sukernik

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  2. N. V. Volodko
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  3. E. B. Starikovskaya
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  4. R. I. Sukernik
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Correspondence to I. O. Mazunin.

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Original Russian Text © I.O. Mazunin, N.V. Volodko, E.B. Starikovskaya, R.I. Sukernik, 2010, published in Molekulyarnaya Biologiya, 2010, Vol. 44, No. 5, pp. 755–772.

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Mazunin, I.O., Volodko, N.V., Starikovskaya, E.B. et al. Mitochondrial genome and human mitochondrial diseases. Mol Biol 44, 665–681 (2010). https://doi.org/10.1134/S0026893310050018

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  • DOI: https://doi.org/10.1134/S0026893310050018

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