Neurochemical Research

, Volume 29, Issue 3, pp 589–600 | Cite as

Mitochondrial Disease: Mutations and Mechanisms

  • Matthew McKenzie
  • Danae Liolitsa
  • Michael G. Hanna


The mitochondrial diseases encompass a diverse group of disorders that can exhibit various combinations of clinical features. Defects in mitochondrial DNA (mtDNA) have been associated with these diseases, and studies have been able to assign biochemical defects. Deficiencies in mitochondrial oxidative phosphorylation appear to be the main pathogenic factors, although recent studies suggest that other mechanisms are involved. Reactive oxygen species (ROS) generation has been implicated in a wide variety of neurodegenerative diseases, and mitochondrial ROS generation may be an important factor in mitochondrial disease pathogenesis. Altered apoptotic signaling as a consequence of defective mitochondrial function has also been observed in both in vitro and in vivo disease models. Our current understanding of the contribution of these various mechanisms to mitochondrial disease pathophysiology will be discussed.

Mitochondria DNA mutation reactive oxygen species apoptosis 


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  1. 1.
    Wallace, D. C., Singh, G., Lott, M. T., Hodge, J. A., Schurr, T. G., Lezza, A. M., Elsas, L. J., 2nd, and Nikoskelainen, E. K. 1988. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242:1427–1430.PubMedGoogle Scholar
  2. 2.
    Holt, I. J., Harding, A. E., and Morgan-Hughes, J. A. 1988. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331:717–719.PubMedGoogle Scholar
  3. 3.
    Moraes, C. T., DiMauro, S., Zeviani, M., Lombes, A., Shanske, S., Miranda, A. F., Nakase, H., Bonilla, E., Werneck, L. C., and Servidei, S. 1989. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N. Engl. J. Med. 320:1293–1299.PubMedGoogle Scholar
  4. 4.
    Zeviani, M., Moraes, C. T., DiMauro, S., Nakase, H., Bonilla, E., Schon, E. A., and Rowland, L. P. 1988. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 38:1339–1346.PubMedGoogle Scholar
  5. 5.
    Servidei, S. 2000. Mitochondrial encephalomyopathies: Gene mutation. Neuromuscul. Disord. 10:X–XV.Google Scholar
  6. 6.
    Clayton, D. A. 2000. Transcription and replication of mitochondrial DNA. Hum. Repord. 15(Suppl 2):11–17.Google Scholar
  7. 7.
    Saraste, M. 1999. Oxidative phosphorylation at the fin de siecle. Science 283:1488–1493.PubMedGoogle Scholar
  8. 8.
    Richter, C., Park, J. W., and Ames, B. N. 1988. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc. Natl. Acad. Sci. USA 85:6465–6467.PubMedGoogle Scholar
  9. 9.
    Clayton, D. A., Doda, J. N., and Friedberg, E. C. 1974. The absence of a pyrimidine dimer repair mechanism in mammalian mitochondria. Proc. Natl. Acad. Sci. USA 71:2777–2781.PubMedGoogle Scholar
  10. 10.
    Croteau, D. L., Stierum, R. H., and Bohr, V. A. 1999. Mitochondrial DNA repair pathways. Mutat. Res. 434:137–148.PubMedGoogle Scholar
  11. 11.
    Giles, R. E., Blanc, H., Cann, H. M., and Wallace, D. C. 1980. Maternal inheritance of human mitochondrial DNA. Proc. Natl. Acad. Sci. USA 77:6715–6719.PubMedGoogle Scholar
  12. 12.
    Hammans, S. R., Sweeney, M. G., Brockington, M., Lennox, G. G., Lawton, N. F., Kennedy, C. R., Morgan-Hughes, J. A., and Harding, A. E. 1993. The mitochondrial DNA transfer RNA(Lys)A → G(8344) mutation and the syndrome of myoclonic epilepsy with ragged red fibres (MERRF): Relationship of clinical phenotype to proportion of mutant mitochondrial DNA. Brain 116(Pt 3):617–632.PubMedGoogle Scholar
  13. 13.
    Harding, A. E., Sweeney, M. G., Govan, G. G., and Riordan-Eva, P. 1995. Pedigree analysis in Leber hereditary optic neuropathy families with a pathogenic mtDNA mutation. Am. J. Hum. Genet. 57:77–86.PubMedGoogle Scholar
  14. 14.
    Chen, X., Prosser, R., Simonetti, S., Sadlock, J., Jagiello, G., and Schon, E. A. 1995. Rearranged mitochondrial genomes are present in human oocytes. Am. J. Hum. Genet. 57:239–247PubMedGoogle Scholar
  15. 15.
    Zeviani, M., Gellera, C., Pannacci, M., Uziel, G., Prelle, A., Servidei, S., and DiDonato, S. 1990. Tissue distribution and transmission of mitochondrial DNA deletions in mitochondrial myopathies. Ann. Neurol. 28:94–97.PubMedGoogle Scholar
  16. 16.
    Dunbar, D. R., Moonie, P. A., Swingler, R. J., Davidson, D., Roberts, R., and Holt, I. J. 1993. Maternally transmitted partial direct tandem duplication of mitochondrial DNA associated with diabetes mellitus. Hum. Mol. Genet. 2:1619–1624.PubMedGoogle Scholar
  17. 17.
    Rotig, A., Bessis, J. L., Romero, N., Cormier, V., Saudubray, J. M., Narcy, P., Lenoir, G., Rustin, P., and Munnich, A. 1992. Maternally inherited duplication of the mitochondrial genome in a syndrome of proximal tubulopathy, diabetes mellitus, and cerebellar ataxia. Am. J. Hum. Genet. 50:364–370.PubMedGoogle Scholar
  18. 18.
    Manfredi, G., Vu, T., Bonilla, E., Schon, E. A., DiMauro, S., Arnaudo, E., Zhang, L., Rowland, L. P., and Hirano, M. 1997. Association of myopathy with large-scale mitochondrial DNA duplications and deletions: Which is pathogenic? Ann. Neurol. 42:180–188.PubMedGoogle Scholar
  19. 19.
    Tully, L. A., Parsons, T. J., Steighner, R. J., Holland, M. M., Marino, M. A., and Prenger, V. L. 2000. A sensitive denaturing gradient-gel electrophoresis assay reveals a high frequency of heteroplasmy in hypervariable region 1 of the human mtDNA control region. Am. J. Hum. Genet. 67:432–443.PubMedGoogle Scholar
  20. 20.
    Huoponen, K., Vilkki, J., Aula, P., Nikoskelainen, E. K., and Savontaus, M. L. 1991. A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Am. J. Hum. Genet. 48:1147–1153.PubMedGoogle Scholar
  21. 21.
    Prezant, T. R., Agapian, J. V., Bohlman, M. C., Bu, X., Oztas, S., Qiu, W. Q., Arnos, K. S., Cortopassi, G. A., Jaber, L., Rotter, J. I., Shohat, M., and Fischel-Ghodsian, N. 1993. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat. Genet. 4:289–294.PubMedGoogle Scholar
  22. 22.
    Vernham, G. A., Reid, F. M., Rundle, P. A., and Jacobs, H. T. 1994. Bilateral sensorineural hearing loss in members of a maternal lineage with mitochondrial point mutation. Clin. Otolaryngol. 19:314–319.PubMedGoogle Scholar
  23. 23.
    Novotny, E. J. Jr., Singh, G., Wallace, D. C., Dorfman, L. J., Louis, A., Sogg, R. L., and Steinman, L. 1986. Leber's disease and dystonia: A mitochondrial disease. Neurology 36:1053–1060.PubMedGoogle Scholar
  24. 24.
    Tatuch, Y., Christodoulou, J., Feigenbaum, A., Clarke, J. T., Wherret, J., Smith, C., Rudd, N., Petrova-Benedict, R., and 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.PubMedGoogle Scholar
  25. 25.
    Chomyn, A., Martinuzzi, A., Yoneda, M., Daga, A., Hurko, O., Johns, D., Lai, S. T., Nonaka, I., Angelini, C., and Attardi, G. 1992. MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts. Proc. Natl. Acad. Sci. USA 89:4221–4225.PubMedGoogle Scholar
  26. 26.
    Hanna, M. G., Nelson, I. P., Morgan-Hughes, J. A., and Harding, A. E. 1995. Impaired mitochondrial translation in human myoblasts harbouring the mitochondrial DNA tRNA lysine 8344 A → G (MERRF) mutation: Relationship to proportion of mutant mitochondrial DNA. J. Neurol. Sci. 130:154–160.PubMedGoogle Scholar
  27. 27.
    Bourgeron, T., Chretien, D., Rotig, A., Munnich, A., and Rustin, P. 1993. Fate and expression of the deleted mitochondrial DNA differ between human heteroplasmic skin fibroblast and Epstein-Barr virus-transformed lymphocyte cultures. J. Biol. Chem. 268:19369–19376.PubMedGoogle Scholar
  28. 28.
    Jenuth, J. P., Peterson, A. C., Fu, K., and Shoubridge, E. A. 1996. Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA. Nat. Genet. 14:146–151.PubMedGoogle Scholar
  29. 29.
    Battersby, B. J., Loredo-Osti, J. C., and Shoubridge, E. A. 2003. Nuclear genetic control of mitochondrial DNA segregation. Nat. Genet. 33:183–186.PubMedGoogle Scholar
  30. 30.
    Jenuth, J. P., Peterson, A. C., and Shoubridge, E. A. 1997. Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice. Nat. Genet. 16:93–95.PubMedGoogle Scholar
  31. 31.
    Brown, M. D., Voljavec, A. S., Lott, M. T., Torroni, A., Yang, C. C., and Wallace, D. C. 1992. Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy. Genetics 130:163–173.PubMedGoogle Scholar
  32. 32.
    Brown, M. D., Yang, C. C., Trounce, I., Torroni, A., Lott, M. T., and Wallace, D. C. 1992. A mitochondrial DNA variant, identified in Leber hereditary optic neuropathy patients, which extends the amino acid sequence of cytochrome c oxidase subunit I. Am. J. Hum. Genet. 51:378–385.PubMedGoogle Scholar
  33. 33.
    Jun, A. S., Brown, M. D., and Wallace, D. C. 1994. A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia. Proc. Natl. Acad. Sci. USA 91:6206–6210.PubMedGoogle Scholar
  34. 34.
    Johns, D. R., Neufeld, M. J., and Park, R. D. 1992. An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem. Biophys. Res. Commun. 187:1551–1557.PubMedGoogle Scholar
  35. 35.
    Howell, N., Bindoff, L. A., McCullough, D. A., Kubacka, I., Poulton, J., Mackey, D., Taylor, L., and Turnbull, D. M. 1991. Leber hereditary optic neuropathy: Identification of the same mitochondrial ND1 mutation in six pedigrees. Am. J. Hum. Genet. 49:939–950.PubMedGoogle Scholar
  36. 36.
    Shoffner, J. M., Brown, M. D., Stugard, C., Jun, A. S., Pollock, S., Haas, R. H., Kaufman, A., Koontz, D., Kim, Y., Graham, J. R., Smith, E., Dixon, J., and Wallace, D. C. 1995. Leber's hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation. Ann. Neurol. 38:163–169.PubMedGoogle Scholar
  37. 37.
    Wallace, D. C., Bunn, C. L., and Eisenstadt, J. M. 1975. Cytoplasmic transfer of chloramphenicol resistance in human tissue culture cells. J. Cell Biol. 67:174–188.PubMedGoogle Scholar
  38. 38.
    King, M. P. and Attardi, G. 1989. Human cells lacking mtDNA: Repopulation with exogenous mitochondria by complementation. Science 246:500–503.PubMedGoogle Scholar
  39. 39.
    Jun, A. S., Trounce, I. A., Brown, M. D., Shoffner, J. M., and Wallace, D. C. 1996. Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes Leber hereditary optic neuropathy and dystonia. Mol. Cell Biol. 16:771–777.PubMedGoogle Scholar
  40. 40.
    Brown, M. D., Trounce, I. A., Jun, A. S., Allen, J. C., and Wallace, D. C. 2000. Functional analysis of lymphoblast and cybrid mitochondria containing the 3460, 11778, or 14484 Leber's hereditary optic neuropathy mitochondrial DNA mutation. J. Biol. Chem. 275:39831–39836.PubMedGoogle Scholar
  41. 41.
    Hofhaus, G., Johns, D. R., Hurko, O., Attardi, G., and Chomyn, A. 1996. Respiration and growth defects in transmitochondrial cell lines carrying the 11778 mutation associated with Leber's hereditary optic neuropathy. J. Biol. Chem. 271:13155–13161.PubMedGoogle Scholar
  42. 42.
    Johns, D. R., Heher, K. L., Miller, N. R., and Smith, K. H. 1993. Leber's hereditary optic neuropathy: Clinical manifestations of the 14484 mutation. Arch. Ophthalmol. 111:495–498.PubMedGoogle Scholar
  43. 43.
    Wong, A., Cavelier, L., Collins-Schramm, H. E., Seldin, M. F., McGrogan, M., Savontaus, M. L., and Cortopassi, G. A. 2002. Differentiation-specific effects of LHON mutations introduced into neuronal NT2 cells. Hum. Mol. Genet. 11:431–438.PubMedGoogle Scholar
  44. 44.
    Danielson, S. R., Wong, A., Carelli, V., Martinuzzi, A., Schapira, A. H., and Cortopassi, G. A. 2002. Cells bearing mutations causing Leber's hereditary optic neuropathy are sensitized to Fas-induced apoptosis. J. Biol. Chem. 277:5810–5815.PubMedGoogle Scholar
  45. 45.
    Harding, A. E., Sweeney, M. G., Miller, D. H., Mumford, C. J., Kellar-Wood, H., Menard, D., McDonald, W. I., and Compston, D. A. 1992. Occurrence of a multiple sclerosis-like illness in women who have a Leber's hereditary optic neuropathy mitochondrial DNA mutation. Brain 115:979–989.PubMedGoogle Scholar
  46. 46.
    Kellar-Wood, H., Robertson, N., Govan, G. G., Compston, D. A., and Harding, A. E. 1994. Leber's hereditary optic neuropathy mitochondrial DNA mutations in multiple sclerosis. Ann. Neurol. 36:109–112.PubMedGoogle Scholar
  47. 47.
    Brown, M. D., Starikovskaya, E., Derbeneva, O., Hosseini, S., Allen, J. C., Mikhailovskaya, I. E., Sukernik, R. I., and 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.Google Scholar
  48. 48.
    Holt, I. J., Harding, A. E., Petty, R. K., and Morgan-Hughes, J. A. 1990. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am. J. Hum. Genet. 46:428–433.PubMedGoogle Scholar
  49. 49.
    Trounce, I., Neill, S., and Wallace, D. C. 1994. Cytoplasmic transfer of the mtDNA nt 8993 T → G (ATP6) point mutation associated with Leigh syndrome into mtDNA-less cells demonstrates cosegregation with a decrease in state III respiration and ADP/O ratio. Proc. Natl. Acad. Sci. USA 91:8334–8338.PubMedGoogle Scholar
  50. 50.
    Nijtmans, L. G., Henderson, N. S., Attardi, G., and Holt, I. J. 2001. Impaired ATP synthase assembly associated with a mutation in the human ATP synthase subunit 6 gene. J. Biol. Chem. 276:6755–6762.PubMedGoogle Scholar
  51. 51.
    Garcia, J. J., Ogilvie, I., Robinson, B. H., and Capaldi, R. A. 2000. Structure, functioning, and assembly of the ATP synthase in cells from patients with the T8993G mitochondrial DNA mutation: Comparison with the enzyme in Rho(0) cells completely lacking mtDNA. J. Biol. Chem. 275:11075–11081.PubMedGoogle Scholar
  52. 52.
    Ortiz, R. G., Newman, N. J., Shoffner, J. M., Kaufman, A. E., Koontz, D. A., and Wallace, D. C. 1993. Variable retinal and neurologic manifestations in patients harboring the mitochondrial DNA 8993 mutation. Arch. Ophthalmol. 111:1525–1530.PubMedGoogle Scholar
  53. 53.
    Shoffner, J. M., Fernhoff, P. M., Krawiecki, N. S., Caplan, D. B., Holt, P. J., Koontz, D. A., Takei, Y., Newman, N. J., Ortiz, R. G., Polak, M., Ballinger, S. W., Lott, M. T. and Walllace, D. C. 1992. Subacute necrotizing encephalopathy: Oxidative phosphorylation defects and the ATPase 6 point mutation. Neurology 42:2168–2174.PubMedGoogle Scholar
  54. 54.
    Liolitsa, D., Rahman, S., Benton, S., Carr, L. J., and Hanna, M. G. 2003. Is the mitochondrial complex I ND5 gene a hot-spot for MELAS causing mutations? Ann Neurol. 53:128–132.PubMedGoogle Scholar
  55. 55.
    Manfredi, G., Schon, E. A., Moraes, C. T., Bonilla, E., Berry, G. T., Sladky, J. T., and DiMauro, S. 1995. A new mutation associated with MELAS is located in a mitochondrial DNA polypeptide-coding gene. Neuromuscul. Disord. 5:391–398.PubMedGoogle Scholar
  56. 56.
    Pulkes, T., Eunson, L., Patterson, V., Siddiqui, A., Wood, N. W., Nelson, I. P., Morgan-Hughes, J. A., and Hanna, M. G. 1999. The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS overlap syndrome and may be a frequent cause of MELAS. Ann. Neurol. 46:916–919.PubMedGoogle Scholar
  57. 57.
    Santorelli, F. M., Tanji, K., Kulikova, R., Shanske, S., Vilarinho, L., Hays, A. P., and DiMauro, S. 1997. Identification of a novel mutation in the mtDNA ND5 gene associated with MELAS. Biochem. Biophys. Res. Commun. 238:326–328.PubMedGoogle Scholar
  58. 58.
    De Coo, I. F., Renier, W. O., Ruitenbeek, W., Ter Laak, H. J., Bakker, M., Schagger, H., Van Oost, B. A., and Smeets, H. J. 1999. A 4-base pair deletion in the mitochondrial cytochrome b gene associated with parkinsonism/MELAS overlap syndrome. Ann. Neurol. 45:130–133.PubMedGoogle Scholar
  59. 59.
    Andreu, A. L., Checcarelli, N., Iwata, S., Shanske, S., and DiMauro, S. 2000. A missense mutation in the mitochondrial cytochrome b gene in a revisited case with histiocytoid cardiomyopathy. Pediatr. Res. 48:311–314.PubMedGoogle Scholar
  60. 60.
    Valnot, I., Kassis, J., Chretien, D., de Lonlay, P., Parfait, B., Munnich, A., Kachaner, J., Rustin, P., and Rotig, 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.PubMedGoogle Scholar
  61. 61.
    Andreu, A. L., Hanna, M. G., Reichmann, H., Bruno, C., Penn, A. S., Tanji, K., Pallotti, F., Iwata, S., Bonilla, E., Lach, B., Morgan-Hughes, J., and DiMauro, S. 1999. Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N. Engl. J. Med. 341:1037–1044.PubMedGoogle Scholar
  62. 62.
    Andreu, A. L., Tanji, K., Bruno, C., Hadjigeorgiou, G. M., Sue, C. M., Jay, C., Ohnishi, T., Shanske, S., Bonilla, E., and DiMauro, S. 1999. Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene. Ann. Neurol. 45:820–823.PubMedGoogle Scholar
  63. 63.
    Karadimas, C. L., Greenstein, P., Sue, C. M., Joseph, J. T., Tanji, K., Haller, R. G., Taivassalo, T., Davidson, M. M., Shanske, S., Bonilla, E., and DiMauro, S. 2000. Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA. Neurology 55:644–649.PubMedGoogle Scholar
  64. 64.
    Keightley, J. A., Hoffbuhr, K. C., Burton, M. D., Salas, V. M., Johnston, W. S., Penn, A. M., Buist, N. R., and Kennaway, N. G. 1996. A microdeletion in cytochrome c oxidase (COX) subunit III associated with COX deficiency and recurrent myoglobinuria. Nat. Genet. 12:410–416.PubMedGoogle Scholar
  65. 65.
    Musumeci, O., Andreu, A. L., Shanske, S., Bresolin, N., Comi, G. P., Rothstein, R., Schon, E. A., and DiMauro, S. 2000. Intragenic inversion of mtDNA: A new type of pathogenic mutation in a patient with mitochondrial myopathy. Am. J. Hum. Genet. 66:1900–1904.PubMedGoogle Scholar
  66. 66.
    Rahman, S., Taanman, J. W., Cooper, J. M., Nelson, I., Hargreaves, I., Meunler, B., Hanna, M. G., Garcia, J. J., Capaldi, R. A., Lake, B. D., Leonard, J. V., and Schapira, A. H. 1999. A missense mutation of cytochrome oxidase subunit II causes defective assembly and myopathy. Am. J. Hum. Genet. 65:1030–1039.PubMedGoogle Scholar
  67. 67.
    Dumoulin, R., Sagnol, I., Ferlin, T., Bozon, D., Stepien, G., and Mousson, B. 1996. A novel gly290asp mitochondrial cytochrome b mutation linked to a complex III deficiency in progressive exercise intolerance. Mol. Cell Probes 10:389–391.PubMedGoogle Scholar
  68. 68.
    Engel, W. K. and Cunnigham, C. G. 1963. Rapid examination of muscle tissue: An improved trichrome stain method for fresh-frozen biopsy sections. Neurology 13:919–923.PubMedGoogle Scholar
  69. 69.
    DiMauro, S., Bonilla, E., Davidson, M., Hirano, M., and Schon, E. A. 1998. Mitochondria in neuromuscular disorders. Biochim. Biophys. Acta 1366:199–210.PubMedGoogle Scholar
  70. 70.
    Wallace, D. C. 1995. 1994 William Allan Award Address: Mitochondrial DNA variation in human evolution, degenerative disease, and aging. Am. J. Hum. Genet. 57:201–223.PubMedGoogle Scholar
  71. 71.
    Goto, Y., Nonaka, I., and Horai, S. 1990. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348:651–653.PubMedGoogle Scholar
  72. 72.
    Goto, Y., Horai, S., Matsuoka, T., Koga, Y., Nihei, K., Kobayashi, M., and Nonaka, I. 1992. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): A correlative study of the clinical features and mitochondrial DNA mutation. Neurology 42:545–550.PubMedGoogle Scholar
  73. 73.
    Hammans, S. R., Sweeney, M. G., Hanna, M. G., Brockington, M., Morgan-Hughes, J. A., and Harding, A. E. 1995. The mitochondrial DNA transfer RNALeu(UUR) A → G(3243) mutation: A clinical and genetic study. Brain 118(Pt 3):721–734.PubMedGoogle Scholar
  74. 74.
    Gerbitz, K. D., van den Ouweland, J. M., Maassen, J. A., and Jaksch, M. 1995. Mitochondrial diabetes mellitus: A review. Biochim. Biophys. Acta 1271:253–260.PubMedGoogle Scholar
  75. 75.
    Goto, Y. 1995. Clinical features of MELAS and mitochondrial DNA mutations. Muscle Nerve 3:S107–S112.PubMedGoogle Scholar
  76. 76.
    Chinnery, P. F., Taylor, D. J., Brown, D. T., Manners, D., Styles, P., and Lodi, R. 2000. Very low levels of the mtDNA A3243G mutation associated with mitochondrial dysfunction in vivo. Ann. Neurol. 47:381–384.PubMedGoogle Scholar
  77. 77.
    King, M. P., Koga, Y., Davidson, M., and Schon, E. A. 1992. Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA(Leu(UUR)) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Mol. Cell Biol. 12:480–490.PubMedGoogle Scholar
  78. 78.
    Muller-Hocker, J., Hubner, G., Bise, K., Forster, C., Hauck, S., Paetzke, I., Pongratz, D., and Kadenbach, B. 1993. Generalized mitochondrial microangiopathy and vascular cytochrome c oxidase deficiency: Occurrence in a case of MELAS syndrome with mitochondrial cardiomyopathy-myopathy and combined complex I/IV deficiency. Arch. Pathol. Lab. Med. 117:202–210.PubMedGoogle Scholar
  79. 79.
    Flierl, A., Reichmann, H., and Seibel, P. 1997. Pathophysiology of the MELAS 3243 transition mutation. J. Biol. Chem. 272: 27189–27196.PubMedGoogle Scholar
  80. 80.
    James, A. M., Wei, Y. H., Pang, C. Y., and Murphy, M. P. 1996. Altered mitochondrial function in fibroblasts containing MELAS or MERRF mitochondrial DNA mutations. Biochem. J. 318:401–407.PubMedGoogle Scholar
  81. 81.
    Moudy, A. M., Handran, S. D., Goldberg, M. P., Ruffin, N., Karl, I., Kranz-Eble, P., DeVivo, D. C., and Rothman, S. M. 1995. Abnormal calcium homeostasis and mitochondrial polarization in a human encephalomyopathy. Proc. Natl. Acad. Sci. USA 92:729–733.PubMedGoogle Scholar
  82. 82.
    Helm, M., Florentz, C., Chomyn, A., and Attardi, G. 1999. Search for differences in post-transcriptional modification patterns of mitochondrial DNA-encoded wild-type and mutant human tRNALys and tRNALeu(UUR). Nucleic Acids Res. 27:756–763.PubMedGoogle Scholar
  83. 83.
    Janssen, G. M., Maassen, J. A., and van Den Ouweland, J. M. 1999. The diabetes-associated 3243 mutation in the mitochondrial tRNA(Leu(UUR)) gene causes severe mitochondrial dysfunction without a strong decrease in protein synthesis rate. J. Biol. Chem. 274:29744–29748.PubMedGoogle Scholar
  84. 84.
    El Meziane, A., Lentinen, S. K., Hance, N., Nijtmans, L. G., Dunbar, D., Holt, I. J., and Jacobs, H. T. 1998. A tRNA suppressor mutation in human mitochondria. Nat. Genet. 18:350–353.PubMedGoogle Scholar
  85. 85.
    Shoffner, J. M., Lott, M. T., Lezza, A. M., Seibel, P., Ballinger, S. W., and Wallace, D. C. 1990. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell 61:931–937.PubMedGoogle Scholar
  86. 86.
    Byrne, E., Trounce, I., Marzuki, S., Dennett, X., Berkovic, S. F., Davis, S., Tanaka, M., and Ozawa, T. 1991. Functional respiratory chain studies in mitochondrial cytopathies: Support for mitochondrial DNA heteroplasmy in myoclonus epilepsy and ragged red fibers (MERRF) syndrome. Acta Neuropathol. (Berl.) 81:318–323.Google Scholar
  87. 87.
    Masucci, J. P., Davidson, M., Koga, Y., Schon, E. A., and King, M. P. 1995. In vitro analysis of mutations causing myoclonus epilepsy with ragged-red fibers in the mitochondrial tRNA(Lys)gene: Two genotypes produce similar phenotypes. Mol. Cell Biol. 15: 2872–2881.PubMedGoogle Scholar
  88. 88.
    Villani, G. and Attardi, G. 1997. In vivo control of respiration by cytochrome c oxidase in wild-type and mitochondrial DNA mutation-carrying human cells. Proc. Natl. Acad. Sci. USA 94:1166–1171.PubMedGoogle Scholar
  89. 89.
    Enriquez, J. A., Chomyn, A., and Attardi, G. 1995. MtDNA mutation in MERRF syndrome causes defective aminoacylation of tRNA(Lys) and premature translation termination. Nat. Genet. 10:47–55.PubMedGoogle Scholar
  90. 90.
    Pulkes, T., Sweeney, M. G., and Hanna, M. G. 2000. Increased risk of stroke in patients with the A12308G polymorphism in mitochondria. Lancet 356:2068–2069.PubMedGoogle Scholar
  91. 91.
    Schon, E. A., Bonilla, E., and DiMauro, S. 1997. Mitochondrial DNA mutations and pathogenesis. J. Bioenerg. Biomembr. 29:131–149.PubMedGoogle Scholar
  92. 92.
    Petruzzella, V., Moraes, C. T., Sano, M. C., Bonilla, E., DiMauro, S., and Schon, E. A. 1994. Extremely high levels of mutant mtDNAs co-localize with cytochrome c oxidase-negative ragged-red fibers in patients harboring a point mutation at nt 3243. Hum. Mol. Genet. 3:449–454.PubMedGoogle Scholar
  93. 93.
    Ballinger, S. W., Shoffner, J. M., Gebhart, S., Koontz, D. A., and Wallace, D. C. 1994. Mitochondrial diabetes revisited. Nat. Genet. 7:458–459.PubMedGoogle Scholar
  94. 94.
    Ballinger, S. W., Shoffner, J. M., Hedaya, E. V., Trounce, I., Polak, M. A., Koontz, D. A., and Wallace, D. C. 1992. Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion. Nat. Genet. 1:11–15.PubMedGoogle Scholar
  95. 95.
    Rotig, A., Colonna, M., Bonnefont, J. P., Blanche, S., Fischer, A., Saudubray, J. M., and Munnich, A. 1989. Mitochondrial DNA deletion in Pearson's marrow/pancreas syndrome. Lancet 1:902–903.Google Scholar
  96. 96.
    Larsson, N. G., Holme, E., Kristiansson, B., Oldfors, A., and Tulinius, M. 1990. Progressive increase of the mutated mitochondrial DNA fraction in Kearns-Sayre syndrome. Pediatr. Res. 28:131–136.PubMedGoogle Scholar
  97. 97.
    Holt, I. J., Harding, A. E., Cooper, J. M., Schapira, A. H., Toscano, A., Clark, J. B., and Morgan-Hughes, J. A. 1989. Mitochondrial myopathies: Clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA. Ann. Neurol. 26:699–708.PubMedGoogle Scholar
  98. 98.
    Wei, Y. H., Lee, C. F., Lee, H. C., Ma, Y. S., Wang, C. W., Lu, C. Y., and Pang, C. Y. 2001. Increases of mitochondrial mass and mitochondrial genome in association with enhanced oxidative stress in human cells harboring 4,977 BP-deleted mitochondrial DNA. Ann. NY Acad. Sci. 928:97–112.PubMedGoogle Scholar
  99. 99.
    Porteous, W. K., James, A. M., Sheard, P. W., Porteous, C. M., Packer, M. A., Hyslop, S. J., Melton, J. V., Pang, C. Y., Wei, Y. H., and Murphy, M. P. 1998. Bioenergetic consequences of accumulating the common 4977-bp mitochondrial DNA deletion. Eur. J. Biochem. 257:192–201.PubMedGoogle Scholar
  100. 100.
    Chance, B., Sies, H., and Boveris, A. 1979. Hydroperoxide metabolism in mammalian organs. Physiol. Rev. 59:527–605.PubMedGoogle Scholar
  101. 101.
    Richter, C. 1988. Do mitochondrial DNA fragments promote cancer and aging? FEBS Lett. 241:1–5.PubMedGoogle Scholar
  102. 102.
    Boveris, A. 1977. Mitochondrial production of superoxide radical and hydrogen peroxide. In: Tissue hypoxia and ischemia (eds. Reivich, M., Coburn, R., Lahiri, S., and Chance, B.), pp. 67–82. Plenum Press, New York.Google Scholar
  103. 103.
    Liu, Y., Fiskum, G., and Schubert, D. 2002. Generation of reactive oxygen species by the mitochondrial electron transport chain. J. Neurochem. 80:780–787.PubMedGoogle Scholar
  104. 104.
    Fridovich, I. 1995. Superoxide radical and superoxide dismutases. Annu. Rev. Biochem. 64:97–112.PubMedGoogle Scholar
  105. 105.
    Flint, D. H., Tuminello, J. F., and Emptage, M. H. 1993. The inactivation of Fe-S cluster containing hydro-lyases by superoxide. J. Biol. Chem. 268:22369–22376.PubMedGoogle Scholar
  106. 106.
    Gardner, P. R., Raineri, I., Epstein, L. B., and White, C. W. 1995. Superoxide radical and iron modulate aconitase activity in mammalian cells. J. Biol. Chem. 270:13399–13405.PubMedGoogle Scholar
  107. 107.
    Raha, S. and Robinson, B. H. 2000. Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem. Sci. 25:502–508.PubMedGoogle Scholar
  108. 108.
    Boveris, A., Oshino, N., and Chance, B. 1972. The cellular production of hydrogen peroxide. Biochem. J. 128:617–630.PubMedGoogle Scholar
  109. 109.
    Kwong, L. K. and Sohal, R. S. 1998. Substrate and site specificity of hydrogen peroxide generation in mouse mitochondria. Arch. Biochem. Biophys. 350:118–126.PubMedGoogle Scholar
  110. 110.
    Garcia-Ruiz, C., Colell, A., Mari, M., Morales, A., and Fernandez-Checa, J. C. 1997. Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species: Role of mitochondrial glutathione. J. Biol. Chem. 272: 11369–11377.PubMedGoogle Scholar
  111. 111.
    Luo, X., Pitkanen, S., Kassovska-Bratinova, S., Robinson, B. H., and Lehotay, D. C. 1997. Excessive formation of hydroxyl radicals and aldehydic lipid peroxidation products in cultured skin fibroblasts from patients with complex I deficiency. J. Clin. Invest. 99:2877–2882.PubMedGoogle Scholar
  112. 112.
    Pitkanen, S., Merante, F., McLeod, D. R., Applegarth, D., Tong, T., and Robinson, B. H. 1996. Familial cardiomyopathy with cataracts and lactic acidosis: A defect in complex I (NADH-dehydrogenase) of the mitochondria respiratory chain. Pediatr. Res. 39:513–521.PubMedGoogle Scholar
  113. 113.
    Pitkanen, S. and Robinson, B. H. 1996. Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase. J. Clin. Invest. 98:345–351.PubMedGoogle Scholar
  114. 114.
    Robinson, B. H. 1998. Human complex I deficiency: Clinical spectrum and involvement of oxygen free radicals in the pathogenicity of the defect. Biochim. Biophys. Acta 1364:271–286.PubMedGoogle Scholar
  115. 115.
    Rana, M., de Coo, I., Diaz, F., Smeets, H., and Moraes, C. T. 2000. An out-of-frame cytochrome b gene deletion from a patient with parkinsonism is associated with impaired complex III assembly and an increase in free radical production. Ann. Neurol. 48:774–781.PubMedGoogle Scholar
  116. 116.
    Rusanen, H., Majamaa, K., and Hassinen, I. E. 2000. Increased activities of antioxidant enzymes and decreased ATP concentration in cultured myoblasts with the 3243A → G mutation in mitochondrial DNA. Biochim. Biophys. Acta 1500:10–16.PubMedGoogle Scholar
  117. 117.
    Geromel, V., Kadhom, N., Cebalos-Picot, I., Ouari, O., Polidori, A., Munnich, A., Rotig, A., and Rustin, R. 2001. Superoxide-induced massive apoptosis in cultured skin fibroblasts harboring the neurogenic ataxia retinitis pigmentosa (NARP) mutation in the ATPase-6 gene of the mitochondrial DNA. Hum. Mol. Genet. 10: 1221–1228.PubMedGoogle Scholar
  118. 118.
    Graham, B. H., Waymire, K. G., Cottrell, B., Trounce, I. A., MacGregor, G. R., and Wallace, D. C. 1997. A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator. Nat. Genet. 16:226–234.PubMedGoogle Scholar
  119. 119.
    Esposito, L. A., Melov, S., Panov, A., Cottrell, B. A., and Wallace, D. C. 1999. Mitochondrial disease in mouse results in increased oxidative stress. Proc. Natl. Acad. Sci. USA 96:4820–4825.PubMedGoogle Scholar
  120. 120.
    Hockenbery, D., Nunez, G., Milliman, C., Schreiber, R. D., and Korsmeyer, S. J. 1990. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348:334–336.PubMedGoogle Scholar
  121. 121.
    Nguyen, M., Millar, D. G., Yong, V. W., Korsmeyer, S. J., and Shore, G. C. 1993. Targeting of Bcl-2 to the mitochondrial outer membrane by a COOH- terminal signal anchor sequence. J. Biol. Chem. 268:25265–25268.PubMedGoogle Scholar
  122. 122.
    Liu, X., Kim, C. N., Yang, J., Jemmerson, R., and Wang, X. 1996. Induction of apoptotic program in cell-free extracts: Requirement for dATP and cytochrome c. Cell. 86:147–157.PubMedGoogle Scholar
  123. 123.
    Finkel, E. 2001. The mitochondrion: Is it central to apoptosis? Science 292:624–626.PubMedGoogle Scholar
  124. 124.
    Green, D. R. and Reed, J. C. 1998. Mitochondria and apoptosis. Science 281:1309–1312.PubMedGoogle Scholar
  125. 125.
    Joza, N., Susin, S. A., Daugas, E., Stanford, W. L., Cho, S. K., Li, C. Y., Sasaki, T., Elia, A. J., Cheng, H. Y., Ravagnan, L., Ferri, K. F., Zamzami, N., Wakeham, A., Hakem, R., Yoshida, H., Kong, Y. Y., Mak, T. W., Zuniga-Pflucker, J. C., Kroemer, G., and Penninger, J. M. 2001. Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 410:549–554.PubMedGoogle Scholar
  126. 126.
    Kroemer, G., Zamzami, N., and Susin, S. A. 1997. Mitochondrial control of apoptosis. Immunol. Today 18:44–51.PubMedGoogle Scholar
  127. 127.
    Marchetti, P., Castedo, M., Susin, S. A., Zamzami, N., Hirsch, T., Macho, A., Haeffner, A., Hirsch, F., Geuskens, M., and Kroemer, G. 1996. Mitochondrial permeability transition is a central coordinating event of apoptosis. J. Exp. Med. 184:1155–1160.PubMedGoogle Scholar
  128. 128.
    Zamzami, N., Susin, S. A., Marchetti, P., Hirsch, T., Gomez-Monterrey, I., Castedo, M., and Kroemer, G. 1996. Mitochondrial control of nuclear apoptosis. J. Exp. Med. 183:1533–1544.PubMedGoogle Scholar
  129. 129.
    Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S. M., Ahmad, M., Alnemri, E. S., and Wang, X. 1997. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489.PubMedGoogle Scholar
  130. 130.
    Hengartner, M. O. 2000. The biochemistry of apoptosis. Nature 407:770–776.PubMedGoogle Scholar
  131. 131.
    Li, L. Y., Luo, X., and Wang, X. 2001. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412:95–99.PubMedGoogle Scholar
  132. 132.
    Kharbanda, S., Pandey, P., Schofield, L., Israels, S., Roncinske, R., Yoshida, K., Bharti, A., Yuan, Z. M., Saxena, S., Weichselbaum, R., Nalin, C., and Kufe, D. 1997. Role for Bcl-xL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis. Proc. Natl. Acad. Sci. USA 94:6939–6942.PubMedGoogle Scholar
  133. 133.
    Kluck, R. M., Bossy-Wetzel, E., Green, D. R., and Newmeyer, D. D. 1997. The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis. Science 275:1132–1136.PubMedGoogle Scholar
  134. 134.
    Yang, J., Liu, X., Bhalla, K., Kim, C. N., Ibrado, A. M., Cai, J., Peng, T. I., Jones, D. P., and Wang, X. 1997. Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science 275:1129–1132.PubMedGoogle Scholar
  135. 135.
    Goping, I. S., Gross, A., Lavoie, J. N., Nguyen, M., Jemmerson, R., Roth, K., Korsmeyer, S. J., and Shore, G. C. 1998. Regulated targeting of BAX to mitochondria. J. Cell Biol. 143:207–215.PubMedGoogle Scholar
  136. 136.
    Jacobson, M. D., Burne, J. F., King, M. P., Miyashita, T., Reed, J. C., and Raff, M. C. 1993. Bcl-2 blocks apoptosis in cells lacking mitochondrial DNA. Nature 361:365–369.PubMedGoogle Scholar
  137. 137.
    Dey, R. and Moraes, C. T. 2000. Lack of oxidative phosphorylation and low mitochondrial membrane potential decrease susceptibility to apoptosis and do not modulate the protective effect of Bcl-x(L) in osteosarcoma cells. J. Biol. Chem. 275:7087–7094.PubMedGoogle Scholar
  138. 138.
    Wang, J., Silva, J. P., Gustafsson, C. M., Rustin, P., and Larsson, N. G. 2001. Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression. Proc. Natl. Acad. Sci. USA 98:4038–4043.PubMedGoogle Scholar
  139. 139.
    Hail, N. Jr. and Lotan, R. 2001. Mitochondrial respiration is uniquely associated with the prooxidant and apoptotic effects of N-(4-hydroxyphenyl) retinamide. J. Biol. Chem. 276:45614–45621.PubMedGoogle Scholar
  140. 140.
    Guidarelli, A., Clementi, E., De Nadai, C., Bersacchi, R., and Cantoni, O. 2001. TNFalpha enhances the DNA single-strand breakage induced by the short-chain lipid hydroperoxide analogue tert-butylhydroperoxide via ceramide-dependent inhibition of complex III followed by enforced superoxide and hydrogen peroxide formation. Exp. Cell Res. 270:56–65.PubMedGoogle Scholar
  141. 141.
    Higuchi, M., Aggarwal, B. B., and Yeh, E. T. 1997. Activation of CPP32-like protease in tumor necrosis factor-induced apoptosis is dependent on mitochondrial function. J. Clin. Invest. 99:1751–1758.PubMedGoogle Scholar
  142. 142.
    Larsson, N. G., Wang, J., Wilhelmsson, H., Oldfors, A., Rustin, P., Lewandoski, M., Barsh, G. S., and Clayton, D. A. 1998. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat. Genet. 18: 231–236.PubMedGoogle Scholar
  143. 143.
    Sorensen, L., Ekstrand, M., Silva, J. P., Lindqvist, E., Xu, B., Rustin, P., Olson, L., and Larsson, N. G. 2001. Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice. J. Neurosci. 21: 8082–8090.PubMedGoogle Scholar
  144. 144.
    Wang, J., Wilhelmsson, H., Graff, C., Li, H., Oldfors, A., Rustin, P., Bruning, J. C., Kahn, C. R., Clayton, D. A., Barsh, G. S., Thoren, P., and Larsson, N. G. 1999. Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression. Nat. Genet. 21:133–137.PubMedGoogle Scholar
  145. 145.
    Silva, J. P., Kohler, M., Graff, C., Oldfors, A., Magnuson, M. A., Berggren, P. O., and Larsson, N. G. 2000. Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes. Nat. Genet. 26:336–340.PubMedGoogle Scholar
  146. 146.
    Mirabella, M., Di Giovanni, S., Silvestri, G., Tonali, P., and Servidei, S. 2000. Apoptosis in mitochondrial encephalomyopathies with mitochondrial DNA mutations: A potential pathogenic mechanism. Brain 123:93–104.PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 2004

Authors and Affiliations

  • Matthew McKenzie
    • 1
  • Danae Liolitsa
    • 2
  • Michael G. Hanna
    • 2
    • 3
  1. 1.Department of PhysiologyUniversity College LondonLondonUnited Kingdom
  2. 2.Department of Molecular PathogenesisInstitute of NeurologyLondonUnited Kingdom
  3. 3.Centre for Neuromuscular DiseaseNational Hospital for Neurology and Institute of NeurologyLondonUnited Kingdom

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