Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mitochondrial DNA mutations in human disease

Key Points

  • Mutations in the maternally inherited mitochondrial genome (mtDNA), which contributes essential protein subunits to the enzyme complexes of oxidative phosphorylation, are an important cause of genetic disease.

  • The clinical manifestations of mtDNA disorders are extremely variable; onset of symptoms might occur in infancy or in adulthood and can involve either a single organ or multiple tissues.

  • Multiple copies (several hundreds or thousands) of the mitochondrial genome are present in individual cells. Many pathogenic mutations only affect a subset of mtDNA molecules, and there are differences in the mutation load between tissues that contribute to the observed clinical heterogeneity.

  • Treatment options for mtDNA disorders are extremely limited, although several new approaches are being considered, including methods to prevent the transmission of pathogenic mutations from mother to offspring.

  • Somatic mtDNA mutations in both human tumours and tissues from ageing individuals are increasingly being described. Recent data from a mouse model engineered to lose mtDNA sequence integrity supports a causal link between mtDNA mutations and the ageing process.

Abstract

The human mitochondrial genome is extremely small compared with the nuclear genome, and mitochondrial genetics presents unique clinical and experimental challenges. Despite the diminutive size of the mitochondrial genome, mitochondrial DNA (mtDNA) mutations are an important cause of inherited disease. Recent years have witnessed considerable progress in understanding basic mitochondrial genetics and the relationship between inherited mutations and disease phenotypes, and in identifying acquired mtDNA mutations in both ageing and cancer. However, many challenges remain, including the prevention and treatment of these diseases. This review explores the advances that have been made and the areas in which future progress is likely.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The role of the mitochondrial genome in energy generation.
Figure 2: Cytochrome c oxidase deficiency in mitochondrial DNA-associated disease and ageing.
Figure 3: The mitochondrial genetic bottleneck.
Figure 4: Nuclear transfer techniques.

References

  1. Zeviani, M. & Di Donato, S. Mitochondrial disorders. Brain 127, 2153–2172 (2004).

    Article  PubMed  Google Scholar 

  2. Ivanov, P. L. et al. Mitochondrial DNA sequence heteroplasmy in the Grand Duke of Russia Georgij Romanov establishes the authenticity of the remains of Tsar Nicholas II. Nature Genet. 12, 417–420 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Anderson, S. et al. Sequence and organization of the human mitochondrial genome. Nature 290, 457–465 (1981). This paper describes the sequence and organization of human mtDNA — the first complete mitochondrial genome to be sequenced.

    Article  CAS  PubMed  Google Scholar 

  4. Bibb, M. J., Van Etten, R. A., Wright, C. T., Walberg, M. W. & Clayton, D. A. Sequence and gene organization of mouse mitochondrial DNA. Cell 26, 167–180 (1981).

    Article  CAS  PubMed  Google Scholar 

  5. Anderson, S. et al. Complete sequence of bovine mitochondrial DNA. Conserved features of the mammalian mitochondrial genome. J. Mol. Biol. 156, 683–717 (1982).

    Article  CAS  PubMed  Google Scholar 

  6. Andrews, R. M. et al. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nature Genet. 23, 147 (1999). A re-analysis of the original human placental DNA sample used by Fred Sanger and colleagues, using automated, fluorescent DNA sequencing, which allowed a consensus human mtDNA sequence (the 'revised Cambridge Reference Sequence') to be made available.

    Article  CAS  PubMed  Google Scholar 

  7. Majamaa, K. et al. Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. Am. J. Hum. Genet. 63, 447–454 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Schaefer, A. M., Taylor, R. W., Turnbull, D. M. & Chinnery, P. F. The epidemiology of mitochondrial disorders — past, present and future. Biochim. Biophys. Acta 1659, 115–120 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Wilson, F. H. et al. A cluster of metabolic defects caused by mutation in a mitochondrial tRNA. Science 306, 1190–1194 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004). This report describes a knock-in mouse model that expresses a proof-reading-deficient version of PolgA, the catalytic subunit of mtDNA polymerase, and provides the first in vivo data in mammals to establish a causative link between mtDNA mutations and ageing phenotypes.

    Article  CAS  PubMed  Google Scholar 

  11. Muller-Hocker, J. Cytochrome c oxidase deficient fibres in the limb muscle and diaphragm of man without muscular disease: an age-related alteration. J. Neurol. Sci. 100, 14–21 (1990).

    Article  CAS  PubMed  Google Scholar 

  12. Mootha, V. K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genet. 34, 267–273 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Petersen, K. F. et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300, 1140–1142 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. DiMauro, S. & Schon, E. A. Mitochondrial respiratory-chain diseases. N. Engl. J. Med. 348, 2656–2668 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Shoubridge, E. A. Nuclear genetic defects of oxidative phosphorylation. Hum. Mol. Genet. 10, 2277–2284 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Lang, B. F., Gray, M. W. & Burger, G. Mitochondrial genome evolution and the origin of eukaryotes. Annu. Rev. Genet. 33, 351–397 (1999).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Carrodeguas, J. A., Theis, K., Bogenhagen, D. F. & Kisker, C. Crystal structure and deletion analysis show that the accessory subunit of mammalian DNA polymerase-γ, Pol-γB, functions as a homodimer. Mol. Cell 7, 43–54 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Spelbrink, J. N. et al. Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nature Genet. 28, 223–231 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Clayton, D. A. Replication of animal mitochondrial DNA. Cell 28, 693–705 (1982). This paper outlines the strand-displacement model of mammalian mtDNA replication, in which the two strands of mtDNA are each replicated in a continuous fashion from widely separated origins, requiring extensive displacement of parental DNA strands during leading-strand synthesis.

    Article  CAS  PubMed  Google Scholar 

  21. Holt, I. J., Lorimer, H. E. & Jacobs, H. T. Coupled leading- and lagging-strand synthesis of mammalian mitochondrial DNA. Cell 100, 515–524 (2000). Using two-dimensional agarose gel electrophoresis, the demonstration of duplex replication intermediates led the authors to propose a further mechanism for mammalian mtDNA replication that involves strand-coupled synthesis.

    Article  CAS  PubMed  Google Scholar 

  22. Yang, M. Y. et al. Biased incorporation of ribonucleotides on the mitochondrial L-strand accounts for apparent strand-asymmetric DNA replication. Cell 111, 495–505 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Bowmaker, M. et al. Mammalian mitochondrial DNA replicates bidirectionally from an initiation zone. J. Biol. Chem. 278, 50961–50969 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Bogenhagen, D. F. & Clayton, D. A. The mitochondrial DNA replication bubble has not burst. Trends Biochem. Sci. 28, 357–360 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Holt, I. J. & Jacobs, H. T. Response: The mitochondrial DNA replication bubble has not burst. Trends Biochem. Sci. 28, 355–356 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Bogenhagen, D. F. & Clayton, D. A. Concluding remarks: The mitochondrial DNA replication bubble has not burst. Trends Biochem. Sci. 28, 404–405 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Gaspari, M., Larsson, N. G. & Gustafsson, C. M. The transcription machinery in mammalian mitochondria. Biochim. Biophys. Acta 1659, 148–152 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Clayton, D. A. Replication and transcription of vertebrate mitochondrial DNA. Annu. Rev. Cell Biol. 7, 453–478 (1991).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Falkenberg, M. et al. Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA. Nature Genet. 31, 289–294 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Fernandez-Silva, P., Enriquez, J. A. & Montoya, J. Replication and transcription of mammalian mitochondrial DNA. Exp. Physiol. 88, 41–56 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Gaspari, M., Falkenberg, M., Larsson, N. G. & Gustafsson, C. M. The mitochondrial RNA polymerase contributes critically to promoter specificity in mammalian cells. EMBO J. 23, 4606–4614 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jacobs, H. T. Disorders of mitochondrial protein synthesis. Hum. Mol. Genet. 12, R293–R301 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Miller, C. et al. Defective mitochondrial translation caused by a ribosomal protein (MRPS16) mutation. Ann. Neurol. 56, 734–738 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Coenen, M. J. et al. Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency. N. Engl. J. Med. 351, 2080–2086 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Sciacco, M., Bonilla, E., Schon, E. A., DiMauro, S. & Moraes, C. T. Distribution of wild-type and common deletion forms of mtDNA in normal and respiration-deficient muscle fibers from patients with mitochondrial myopathy. Hum. Mol. Genet. 3, 13–19 (1994). A study of individual muscle fibres from patients with mitochondrial myopathy caused by large-scale mtDNA rearrangements revealed that, in addition to levels of deleted mtDNA that are above a critical threshold, respiratory-deficient fibres exhibit a marked reduction in the absolute amount of wild-type mtDNA.

    Article  CAS  PubMed  Google Scholar 

  38. Coller, H. A. et al. High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection. Nature Genet. 28, 147–150 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Taylor, R. W. et al. Mitochondrial DNA mutations in human colonic crypt stem cells. J. Clin. Invest. 112, 1351–1360 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Giles, R. E., Blanc, H., Cann, H. M. & Wallace, D. C. Maternal inheritance of human mitochondrial DNA. Proc. Natl Acad. Sci. USA 77, 6715–6719 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gyllensten, U., Wharton, D., Josefsson, A. & Wilson, A. C. Paternal inheritance of mitochondrial DNA in mice. Nature 352, 255–257 (1991).

    Article  CAS  PubMed  Google Scholar 

  42. Shitara, H., Hayashi, J. I., Takahama, S., Kaneda, H. & Yonekawa, H. Maternal inheritance of mouse mtDNA in interspecific hybrids: segregation of the leaked paternal mtDNA followed by the prevention of subsequent paternal leakage. Genetics 148, 851–857 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Awadalla, P., Eyre-Walker, A. & Smith, J. M. Linkage disequilibrium and recombination in hominid mitochondrial DNA. Science 286, 2524–2525 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. D'Aurelio, M. et al. Heterologous mitochondrial DNA recombination in human cells. Hum. Mol. Genet. 13, 3171–3179 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Kraytsberg, Y. et al. Recombination of human mitochondrial DNA. Science 304, 981 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Elson, J. L. et al. Analysis of European mtDNAs for recombination. Am. J. Hum. Genet. 68, 145–153 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Schwartz, M. & Vissing, J. Paternal inheritance of mitochondrial DNA. N. Engl. J. Med. 347, 576–580 (2002).

    Article  PubMed  Google Scholar 

  48. Taylor, R. W. et al. Genotypes from patients indicate no paternal mitochondrial DNA contribution. Ann. Neurol. 54, 521–524 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Filosto, M. et al. Lack of paternal inheritance of muscle mitochondrial DNA in sporadic mitochondrial myopathies. Ann. Neurol. 54, 524–526 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Schwartz, M. & Vissing, J. No evidence for paternal inheritance of mtDNA in patients with sporadic mtDNA mutations. J. Neurol. Sci. 218, 99–101 (2004)

    Article  CAS  PubMed  Google Scholar 

  51. Danan, C. et al. Evaluation of parental mitochondrial inheritance in neonates born after intracytoplasmic sperm injection. Am. J. Hum. Genet. 65, 463–473 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Marchington, D. R. et al. No evidence for paternal mtDNA transmission to offspring or extra-embryonic tissues after ICSI. Mol. Hum. Reprod. 8, 1046–1049 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Chinnery, P. F. et al. Risk of developing a mitochondrial DNA deletion disorder. Lancet 364, 592–596 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Man, P. Y. et al. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am. J. Hum. Genet. 72, 333–339 (2003).

    Article  CAS  Google Scholar 

  55. Prezant, T. R. et al. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nature Genet. 4, 289–294 (1993).

    Article  CAS  PubMed  Google Scholar 

  56. Battersby, B. J., Loredo-Osti, J. C. & Shoubridge, E. A. Nuclear genetic control of mitochondrial DNA segregation. Nature Genet. 33, 183–186 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Brown, D. T., Samuels, D. C., Michael, E. M., Turnbull, D. M. & Chinnery, P. F. Random genetic drift determines the level of mutant mtDNA in human primary oocytes. Am. J. Hum. Genet. 68, 533–536 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  60. McFarland, R., Elson, J. L., Taylor, R. W., Howell, N. & Turnbull, D. M. Assigning pathogenicity to mitochondrial tRNA mutations: when 'definitely maybe' is not good enough. Trends Genet. 20, 591–596 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Holt, I. J., Harding, A. E. & Morgan-Hughes, J. A. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331, 717–719 (1988). The first demonstration that heteroplasmic, large-scale rearrangements of the mitochondrial genome could cause human disease.

    Article  CAS  PubMed  Google Scholar 

  62. Wallace, D. C. et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242, 1427–1430 (1988). This paper describes the first example of a single-nucleotide change in the mitochondrial genome (11778G>A) as the cause of a maternally inherited, neurological disorder in multiple families.

    Article  CAS  PubMed  Google Scholar 

  63. Brandon, M. C. et al. MITOMAP: a human mitochondrial genome database — 2004 update. Nucleic Acids Res. 33, D611–D613 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Moraes, C. T. et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns–Sayre syndrome. N. Engl. J. Med. 320, 1293–1299 (1989).

    Article  CAS  PubMed  Google Scholar 

  65. Rotig, A., Cormier, V., Blanche, S., Bonnefont, J. -P. & Ledeist, F. Pearson's marrow pancreas syndrome. A multisystem mitochondrial disorder of infancy. J. Clin. Invest. 86, 1601–1608 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. McFarland, R. et al. De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency. Ann. Neurol. 55, 58–64 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. de Vries, D. D., van Engelen, B. G., Gabreels, F. J., Ruitenbeek, W. & van Oost, B. A. A second missense mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome. Ann. Neurol. 34, 410–412 (1993).

    Article  CAS  PubMed  Google Scholar 

  68. Andreu, A. L. et al. Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N. Engl. J. Med. 341, 1037–1044 (1999).

    Article  CAS  PubMed  Google Scholar 

  69. Lowell, B. B. & Shulman, G. I. Mitochondrial dysfunction and type 2 diabetes. Science 307, 384–387 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Maassen, J. A. et al. Mitochondrial diabetes: molecular mechanisms and clinical presentation. Diabetes 53 (Suppl. 1), 103–109 (2004).

    Article  Google Scholar 

  71. Saker, P. J. et al. UKPDS 21: low prevalence of the mitochondrial transfer RNA gene (tRNALeu(UUR)) mutation at position 3243bp in UK Caucasian type 2 diabetic patients. Diabet. Med. 14, 42–45 (1997).

    Article  CAS  PubMed  Google Scholar 

  72. Ohkubo, K. et al. Mitochondrial gene mutations in the tRNALeu(UUR) region and diabetes: prevalence and clinical phenotypes in Japan. Clin. Chem. 47, 1641–1648 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Kearney, P. M. et al. Global burden of hypertension: analysis of worldwide data. Lancet 365, 217–223 (2005).

    Article  PubMed  Google Scholar 

  74. Chinnery, P. F. et al. The epidemiology of pathogenic mitochondrial DNA mutations. Ann. Neurol. 48, 188–193 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Choo-Kang, A. T. et al. Defining the importance of mitochondrial gene defects in maternally inherited diabetes by sequencing the entire mitochondrial genome. Diabetes 51, 2317–2320 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Wallace, D. C. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 256, 628–632 (1992).

    Article  CAS  PubMed  Google Scholar 

  77. Herrnstadt, C. et al. Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups. Am. J. Hum. Genet. 70, 1152–1171 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Khogali, S. S. et al. A common mitochondrial DNA variant associated with susceptibility to dilated cardiomyopathy in two different populations. Lancet 357, 1265–1267 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Poulton, J. et al. Type 2 diabetes is associated with a common mitochondrial variant: evidence from a population-based case-control study. Hum. Mol. Genet. 11, 1581–1583 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Torroni, A. et al. Classification of European mtDNAs from an analysis of three European populations. Genetics 144, 1835–1850 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chagnon, P. et al. Phylogenetic analysis of the mitochondrial genome indicates significant differences between patients with Alzheimer disease and controls in a French-Canadian founder population. Am. J. Med. Genet. 85, 20–30 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. van der Walt, J. M. et al. Analysis of European mitochondrial haplogroups with Alzheimer disease risk. Neurosci. Lett. 365, 28–32 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Ross, O. A. et al. mt4216C variant in linkage with the mtDNA TJ cluster may confer a susceptibility to mitochondrial dysfunction resulting in an increased risk of Parkinson's disease in the Irish. Exp. Gerontol. 38, 397–405 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. van der Walt, J. M. et al. Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. Am. J. Hum. Genet. 72, 804–811 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Helgason, A., Yngvadóttir, B., Hrafnkelsson, B., Gulcher, J. & Stefánsson, K. An Icelandic example of the impact of population structure on association studies. Nature Genet. 37, 90–95 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. King, M. P. & Attardi, G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246, 500–503 (1989). This paper highlights the technology that has made trans mitochondrial cybrids — which are generated by fusing human cell lines that lack mtDNA to enucleated cytoplasts from patients' cells that harbour mtDNA mutations and then growing them under selection — such an elegant cell culture system to study the bioenergetic and cellular consequences of pathogenic mtDNA mutations.

    Article  CAS  PubMed  Google Scholar 

  87. Chomyn, A. et al. 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 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Hayashi, J. et al. Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction. Proc. Natl Acad. Sci. USA 88, 10614–10618 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Tiranti, V. et al. Maternally inherited hearing loss, ataxia and myoclonus associated with a novel point mutation in mitochondrial tRNASer(UCN) gene. Hum. Mol. Genet. 4, 1421–1427 (1995).

    Article  CAS  PubMed  Google Scholar 

  90. Taanman, J. W. et al. Molecular mechanisms in mitochondrial DNA depletion syndrome. Hum. Mol. Genet. 6, 935–942 (1997).

    Article  CAS  PubMed  Google Scholar 

  91. Dunbar, D. R., Moonie, P. A., Jacobs, H. T. & Holt, I. J. Different cellular backgrounds confer a marked advantage to either mutant or wild-type mitochondrial genomes. Proc. Natl Acad. Sci. USA 92, 6562–6566 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. El Meziane, A. et al. A tRNA supressor mutation in human mitochondria. Nature Genet. 18, 350–353 (1998).

    Article  CAS  PubMed  Google Scholar 

  93. Jenuth, J., Peterson, A. C., Fu, K. & Shoubridge, E. A. Random genetic drift in the female germ line explains the rapid segregation of mammalian mitochondrial DNA. Nature Genet. 14, 146–151 (1996). By generating heteroplasmic mice for two (neutral) mtDNA genotypes, the authors demonstrated that random genetic drift in early oogenesis was the reason for the observed rapid segregation of mtDNA sequence variants that occurs between generations.

    Article  CAS  PubMed  Google Scholar 

  94. Jenuth, J. P., Peterson, A. C. & Shoubridge, E. A. Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice. Nature Genet. 16, 93–95 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Marchington, D. R., Barlow, D. & Poulton, J. Transmitochondrial mice carrying resistance to chloramphenicol on mitochondrial DNA: developing the first mouse model of mitochondrial DNA disease. Nature Med. 5, 957–960 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Sligh, J. E. et al. Maternal germ-line transmission of mutant mtDNAs from embryonic stem cell-derived chimeric mice. Proc. Natl Acad. Sci. USA 97, 14461–14466 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Inoue, K. et al. Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes. Nature Genet. 26, 176–181 (2000). By isolating mouse cybrid clones with high levels of a somatic mtDNA rearrangement and fusing these with fertilized mouse eggs, these authors generated the first mouse model of a pathogenic mtDNA mutation (mtDNA deletion or duplication), which was transmitted from mother to offspring.

    Article  CAS  PubMed  Google Scholar 

  98. Nakada, K. et al. Inter-mitochondrial complementation: mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA. Nature Med. 7, 934–940 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Larsson, N. G. et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nature Genet. 18, 231–236 (1998). The first Tfam knockout mouse model that demonstrates a role for the TFAM nuclear protein in maintaining mtDNA copy number.

    Article  CAS  PubMed  Google Scholar 

  100. Silva, J. P. et al. Impaired insulin secretion and β-cell loss in tissue-specific knockout mice with mitochondrial diabetes. Nature Genet. 26, 336–340 (2000).

    Article  CAS  PubMed  Google Scholar 

  101. Sorensen, L. et al. Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice. J. Neurosci. 21, 8082–8090 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wredenberg, A. et al. Increased mitochondrial mass in mitochondrial myopathy mice. Proc. Natl Acad. Sci. USA 99, 15066–15071 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wang, J. et al. Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression. Nature Genet. 21, 133–137 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Chinnery, P. F. & Bindoff, L. A. 116th ENMC international workshop: the treatment of mitochondrial disorders, 14th–16th March 2003, Naarden, The Netherlands. Neuromuscul. Disord. 13, 757–764 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Taivassalo, T. et al. Gene shifting: a novel therapy for mitochondrial myopathy. Hum. Mol. Genet. 8, 1047–1052 (1999).

    Article  CAS  PubMed  Google Scholar 

  106. Clark, K. M. et al. Reversal of a mitochondrial DNA defect in human skeletal muscle. Nature Genet. 16, 222–224 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Fu, K. et al. A novel heteroplasmic tRNAleu(CUN) mtDNA point mutation in a sporadic patient with mitochondrial encephalomyopathy segregates rapidly in skeletal muscle and suggests an approach to therapy. Hum. Mol. Genet. 5, 1835–1840 (1996).

    Article  CAS  PubMed  Google Scholar 

  108. Taivassalo, T. et al. Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects. Ann. Neurol. 50, 133–141 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Manfredi, G. et al. Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus. Nature Genet. 30, 394–399 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. Guy, J. et al. Rescue of a mitochondrial deficiency causing Leber Hereditary Optic Neuropathy. Ann. Neurol. 52, 534–542 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Kolesnikova, O. A. et al. Suppression of mutations in mitochondrial DNA by tRNAs imported from the cytoplasm. Science 289, 1931–1933 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Kolesnikova, O. A. et al. 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 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  114. Tanaka, M. et al. Gene therapy for mitochondrial disease by delivering restriction endonuclease SmaI into mitochondria. J. Biomed. Sci. 9, 534–541 (2002).

    CAS  PubMed  Google Scholar 

  115. Srivastava, S. & Moraes, C. T. Manipulating mitochondrial DNA heteroplasmy by a mitochondrially targeted restriction endonuclease. Hum. Mol. Genet. 10, 3093–3099 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Manfredi, G. et al. Oligomycin induces a decrease in the cellular content of a pathogenic mutation in the human mitochondrial ATPase 6 gene. J. Biol. Chem. 274, 9386–9381 (1999).

    Article  CAS  PubMed  Google Scholar 

  117. Santra, S., Gilkerson, R. W., Davidson, M. & Schon, E. A. Ketogenic treatment reduces deleted mitochondrial DNAs in cultured human cells. Ann. Neurol. 56, 662–669 (2004).

    Article  CAS  PubMed  Google Scholar 

  118. Feuermann, M. et al. The yeast counterparts of human 'MELAS' mutations cause mitochondrial dysfunction that can be rescued by overexpression of the mitochondrial translation factor EF-Tu. EMBO Rep. 4, 53–58 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Harding, A. E., Holt, I. J., Sweeney, M. G., Brockington, M. & Davis, M. B. Prenatal diagnosis of mitochondrial DNA 8993T>G disease. Am. J. Hum. Genet. 50, 629–633 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Leshinsky-Silver, E. et al. Prenatal exclusion of Leigh syndrome due to T8993C mutation in the mitochondrial DNA. Prenat. Diagn. 23, 31–33 (2003).

    Article  CAS  PubMed  Google Scholar 

  121. Jacobs, L. J. et al. Transmission and prenatal diagnosis of the T9176C mitochondrial DNA mutation. Mol. Hum. Reprod. 11, 223–228 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Weber, K. et al. A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle. Am. J. Hum. Genet. 60, 373–380 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. White, S. L. et al. Two cases of prenatal analysis for the pathogenic T to G substitution at nucleotide 8993 in mitochondrial DNA. Prenat. Diagn. 19, 1165–1168 (1999).

    Article  CAS  PubMed  Google Scholar 

  124. Lin, D. P. et al. Comparison of mitochondrial DNA contents in human embryos with good or poor morphology at the 8-cell stage. Fertil. Steril. 81, 73–79 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Dean, N. L. et al. Prospect of preimplantation genetic diagnosis for heritable mitochondrial DNA diseases. Mol. Hum. Reprod. 9, 631–638 (2003).

    Article  CAS  PubMed  Google Scholar 

  126. Kagawa, Y. & Hayashi, J. I. Gene therapy of mitochondrial diseases using human cytoplasts. Gene Ther. 4, 6–10 (1997).

    Article  CAS  PubMed  Google Scholar 

  127. Cohen, J., Scott, R., Schimmel, T., Levron, J. & Willadsen, S. Birth of infant after transfer of anucleate donor oocyte cytoplasm into recipient eggs. Lancet 350, 186–187 (1997).

    Article  CAS  PubMed  Google Scholar 

  128. Hawes, S. M., Sapienza, C. & Latham, K. E. Ooplasmic donation in humans: the potential for epigenic modifications. Hum. Reprod. 17, 850–852 (2002).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  130. Thorburn, D. R. & Dahl, H. H. M. Mitochondrial disorders: genetics, counseling, prenatal diagnosis and reproductive options. Am. J. Med. Genet. 106, 102–114 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Roberts, R. M. Prevention of human mitochondrial (mtDNA) disease by nucleus transplantation into an enucleated donor oocyte. Am. J. Med. Genet. 87, 265–266 (1999). This paper describes the possibility of preventing transmission of mitochondrial DNA disease.

    Article  CAS  PubMed  Google Scholar 

  132. Liu, H., Wang, C. W., Grifo, J. A., Krey, L. C. & Zhang, J. Reconstruction of mouse oocytes by germinal vesicle transfer: maturity of host oocyte cytoplasm determines meiosis. Hum. Reprod. 14, 2357–2361 (1999).

    Article  CAS  PubMed  Google Scholar 

  133. Liu, H., Zhang, J., Krey, L. C. & Grifo, J. A. In-vitro development of mouse zygotes following reconstruction by sequential transfer of germinal vesicles and haploid pronuclei. Hum. Reprod. 15, 1997–2002 (2000).

    Article  CAS  PubMed  Google Scholar 

  134. Takeuchi, T., Ergun, B., Huang, T. H., Rosenwaks, Z. & Palermo, G. D. A reliable technique of nuclear transplantation for immature mammalian oocytes. Hum. Reprod. 14, 1312–1317 (1999).

    Article  CAS  PubMed  Google Scholar 

  135. Barnes, F. L. et al. Blastocyst development and birth after in-vitro maturation of human primary oocytes, intracytoplasmic sperm injection and assisted hatching. Hum. Reprod. 10, 3243–3247 (1995).

    Article  CAS  PubMed  Google Scholar 

  136. Goud, P. T. et al. In-vitro maturation of human germinal vesicle stage oocytes: role of cumulus cells and epidermal growth factor in the culture medium. Hum. Reprod. 13, 1638–1644 (1998).

    Article  CAS  PubMed  Google Scholar 

  137. Kattera, S. & Chen, C. Normal birth after microsurgical enucleation of tripronuclear human zygotes: case report. Hum. Reprod. 18, 1319–1322 (2003).

    Article  PubMed  Google Scholar 

  138. Meirelles, F. & Smith, L. C. Mitochondrial genotype segregation in a mouse heteroplasmic lineage produced by embyonic karyoplast transplantation. Genetics 145, 445–451 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Meirelles, F. & Smith, L. C. Mitochondrial genotype segregation during preimplantation development in mouse heteroplasmic embryos. Genetics 148, 877–883 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Harman, D. Free radical theory of aging. Mutat. Res. 275, 257–266 (1992). This is a description of the theory of ageing in which mitochondria have a key role.

    Article  CAS  PubMed  Google Scholar 

  141. Geromel, V. et al. 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 (2001).

    Article  CAS  PubMed  Google Scholar 

  142. Mattiazzi, M. et al. The mtDNA T8993G (NARP) mutation results in an impairment of oxidative phosphorylation that can be improved by antioxidants. Hum. Mol. Genet. 13, 869–879 (2004).

    Article  CAS  PubMed  Google Scholar 

  143. Muller-Hocker, J. Cytochrome-c-oxidase deficient cardiomyocytes in the human heart —an age-related phenomenon. A histochemical ultracytochemical study. Am. J. Pathol. 134, 1167–1173 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Muller-Hocker, J., Seibel, P., Schneiderbanger, K. & Kadenbach, B. Different in situ hybridization patterns of mitochondrial DNA in cytochrome c oxidase-deficient extraocular muscle fibres in the elderly. Virchows Arch. A Pathol. Anat. Histopathol. 422, 7–15 (1993).

    Article  CAS  PubMed  Google Scholar 

  145. Brierley, E. J., Johnson, M. A., Lightowlers, R. N., James, O. F. & Turnbull, D. M. Role of mitochondrial DNA mutations in human aging: implications for the central nervous system and muscle. Ann. Neurol. 43, 217–223 (1998).

    Article  CAS  PubMed  Google Scholar 

  146. Nekhaeva, E. et al. Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues. Proc. Natl Acad. Sci. USA 99, 5521–5526 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Wallace, D. C. Diseases of the mitochondrial DNA. Annu. Rev. Biochem. 61, 1175–1212 (1992).

    Article  CAS  PubMed  Google Scholar 

  148. de Grey, A. D. A proposed refinement of the mitochondrial free radical theory of aging. Bioessays 19, 161–166 (1997).

    Article  CAS  PubMed  Google Scholar 

  149. Yoneda, M., Chomyn, A., Martinuzzi, A., Hurko, O. & Attardi, G. Marked replicative advantage of human mtDNA carrying a point mutation that causes the MELAS encephalomyopathy. Proc. Natl Acad. Sci. USA 89, 11164–11168 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Elson, J. L., Samuels, D. C., Turnbull, D. M. & Chinnery, P. F. Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age. Am. J. Hum. Genet. 68, 802–806 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Polyak, K. et al. Somatic mutations of the mitochondrial genome in human colorectal tumours. Nature Genet. 20, 291–293 (1998). The first paper to describe the presence of somatic mtDNA mutations in solid human tumours, in this case colon cancer. In many cases, the mtDNA mutations had accumulated to homoplasmic levels and were not evident in the matched (normal) tissue from the same patient. A causal relationship between mtDNA mutations and tumorigenesis is yet to be established.

    Article  CAS  PubMed  Google Scholar 

  152. Fliss, M. S. et al. Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science 287, 2017–2019 (2000).

    Article  CAS  PubMed  Google Scholar 

  153. Jeronimo, C. et al. Mitochondrial mutations in early stage prostate cancer and bodily fluids. Oncogene 20, 5195–5198 (2001).

    Article  CAS  PubMed  Google Scholar 

  154. Jones, J. B. et al. Detection of mitochondrial DNA mutations in pancreatic cancer offers a 'mass'-ive advantage over detection of nuclear DNA mutations. Cancer Res. 61, 1299–1304 (2001).

    CAS  PubMed  Google Scholar 

  155. Kirches, E. et al. High frequency of mitochondrial DNA mutations in glioblastoma multiforme identified by direct sequence comparison to blood samples. Int. J. Cancer 93, 534–538 (2001).

    Article  CAS  PubMed  Google Scholar 

  156. He, L. et al. Somatic mitochondrial DNA mutations in adult-onset leukaemia. Leukemia 17, 2487–2491 (2003).

    Article  CAS  PubMed  Google Scholar 

  157. Wardell, T. M. et al. Changes in the human mitochondrial genome after treatment of malignant disease. Mutat. Res. 525, 19–27 (2003).

    Article  CAS  PubMed  Google Scholar 

  158. Zeviani, M. et al. Deletions of mitochondrial DNA in Kearns–Sayre syndrome. Neurology 38, 1339–1346 (1988).

    Article  CAS  PubMed  Google Scholar 

  159. Goto, Y., Nonaka, I. & Horai, S. A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348, 651–653 (1990).

    Article  CAS  PubMed  Google Scholar 

  160. Santorelli, F. M. et al. Identification of a novel mutation in the mtDNA ND5 gene associated with MELAS. Biochem. Biophys. Res. Commun. 238, 326–328 (1997).

    Article  CAS  PubMed  Google Scholar 

  161. Kirby, D. M. et al. Mutations of the mitochondrial ND1 gene as a cause of MELAS. J. Med. Genet. 41, 784–789 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Shoffner, J. M. et al. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation. Cell 61, 931–937 (1990).

    Article  CAS  PubMed  Google Scholar 

  163. Holt, I. J., Harding, A. E., Petty, R. K. & Morgan-Hughes, J. A. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am. J. Hum. Genet. 46, 428–433 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. van den Ouweland, J. W. M., Lemkes, H. H. P. J. & Ruitenbeek, K. Mutation in mitochondrial tRNALeu(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nature Genet. 1, 368–371 (1992).

    Article  CAS  PubMed  Google Scholar 

  165. Howell, N. et al. Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. Am. J. Hum. Genet. 49, 939–950 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Johns, D. R., Neufeld, M. J. & Park, R. D. An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem. Biophys. Res. Commun. 187, 1551–1557 (1992).

    Article  CAS  PubMed  Google Scholar 

  167. Hao, H., Bonilla, E., Manfredi, G., DiMauro, S. & Moraes, C. T. Segregation patterns of a novel mutation in the mitochondrial tRNA glutamic acid gene associated with myopathy and diabetes mellitus. Am. J. Hum. Genet. 56, 1017–1025 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. McFarland, R. et al. Familial myopathy: New insights into the T14709C mitochondrial tRNA mutation. Ann. Neurol. 55, 478–484 (2004).

    Article  CAS  PubMed  Google Scholar 

  169. Reid, F. M., Vernham, G. A. & Jacobs, H. T. A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness. Hum. Mutat. 3, 243–247 (1994).

    Article  CAS  PubMed  Google Scholar 

  170. Sue, C. M. et al. Maternally inherited hearing loss in a large kindred with a novel T7511C mutation in the mitochondrial DNA tRNASer(UCN) gene. Neurology 52, 1905–1908 (1999).

    Article  CAS  PubMed  Google Scholar 

  171. Strachan, T. & Read, A. P. Human Molecular Genetics 2nd edn (John Wiley and Sons, New York, 1999).

    Google Scholar 

Download references

Acknowledgements

The authors work is supported by the Wellcome Trust, Medical Research Centre, Alzheimer's Research Trust, Muscular Dystrophy Campaign, Newcastle upon Tyne Hospitals NHS Trust and the European Union (FP6, EUmitocombat). We thank R.N. Lightowlers, N. Howell, R. McFarland and M. Herbert for valuable input, and L. Craven and M. Barron for help with the figures.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Doug M. Turnbull.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez

GFM1

MRPS16

ND2

ND4

POLRMT

RNR1

TFAM

TFB1M

TFB2M

TRNK

TRNL1

OMIM

Alzheimer disease

diabetes

Kearns–Sayre syndrome

Leber hereditary optic neuropathy

Leigh syndrome

progressive external ophthalmoplegia

Parkinson disease

rhabdomyolysis

FURTHER INFORMATION

EUmitocombat web site

MITOMAP — a Human Mitochondrial Genome Database

mtDB — Human Mitochondrial Genome Database

Glossary

NUCLEOID

A dynamic complex that consists of several copies of mitochondrial DNA and key maintenance proteins within the organelle.

POLYCISTRONIC

A form of gene organization that results in transcription of an mRNA that codes for multiple gene products, each of which is independently translated from the mRNA.

TRANSMITOCHONDRIAL CYBRID

Derived from the term 'cytoplasmic hybrid'. A cell line that is used to study the pathophysiological consequences of any given mitochondrial DNA mutation in a control nuclear background. Cybrids are generated by fusing patient cytoplasts (enucleated cells that contain mitochondria) with a cell line that lacks mitochondrial DNA.

LEBER HEREDITARY OPTIC NEUROPATHY

A mitochondrial disease that is characterized by optic nerve dysfunction, which leads to bilateral visual failure in young adults.

GENETIC BOTTLENECK

A temporary reduction in population size that causes the loss of genetic variation.

DIPLOPIA

Double vision; derived from the Greek diplous, meaning double, and ops, meaning eye.

ATAXIA

The loss of the ability to coordinate muscular movement.

DYSPHAGIA

A difficulty in swallowing.

PTOSIS

The abnormal lowering or drooping of the upper eyelid that is caused by muscle weakness.

DYSTONIA

A neurological movement disorder that is characterized by involuntary muscle contractions that might cause twisting or jerking movements of the body.

PANCYTOPAENIA

A deficiency of all blood cells including red cells, white cells and platelets.

OPHTHALMOPLEGIA

Weakness of one or more of the muscles that control eye movement.

PEARSON SYNDROME

A severe disease during infancy that affects bone marrow and pancreas function owing to large-scale rearrangements of the mitochondrial genome.

LEIGH SYNDROME

A disease that affects the brainstem and basal ganglia and is characterised by defects in mitochondrial oxidative phosphorylation.

RHABDOMYOLYSIS

The breakdown of muscle fibres owing to injury, toxins or metabolic disease, which leads to high concentrations of myoglobin in both plasma and urine

RAGGED-RED FIBRES

The pathological hallmark of mtDNA disease that is characterized by the subsarcolemmal accumulation of abnormal mitochondria in the muscle fibre, which stains red with a Gomori trichrome stain.

CYTOPLAST

An enucleated donor cell that contains patient mitochondria and that is used to generate cybrid fusions.

SATELLITE CELLS

Quiescent cells that are located between the basal lamina and the plasmalemma of the muscle fibre, and are a main contributor to postnatal muscle growth.

ALLOTOPIC EXPRESSION

The expression of a gene in a different cellular compartment to its target location. In the context described here, it is the recoding of a mitochondrial gene to allow it to be expressed in the nucleus. The subsequent conjugation of a mitochondrial-targeting sequence promotes import and localization of the gene product to the organelle.

AMNIOCENTESIS

An aspiration of cells from the amniotic sac, using a needle, for biochemical and genetic analysis.

CHORIONIC VILLUS BIOPSY

A placental biopsy that is carried out in early pregnancy to collect fetal tissue for genetic and biochemical analysis.

POLAR BODY

A small haploid cell that is produced during oogenesis and that does not develop into a functional ovum.

GERMINAL VESICLE

A stage during oocyte maturation in which the oocyte nucleus is located close to the surface of the egg cell and is clearly visible.

GENETIC DRIFT

Changes in the frequency of a genetic variant in a population owing to chance alone.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Taylor, R., Turnbull, D. Mitochondrial DNA mutations in human disease. Nat Rev Genet 6, 389–402 (2005). https://doi.org/10.1038/nrg1606

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg1606

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing