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.

  • Review Article
  • Published:

Human mitochondrial DNA: roles of inherited and somatic mutations

Nature Reviews Genetics volume 13, pages 878–890 (2012)Cite this article

Subjects

Key Points

  • Mitochondrial diseases are among the most common genetic disorders. They can result from mutations in the mitochondrial genome or nuclear genome.

  • The mitochondrial genome needs to be understood in terms of population genetics, rather than Mendelian genetics; this makes it particularly challenging to understand mitochondrial diseases.

  • Mutations in mitochondrial DNA (mtDNA) accumulate over the lifetime of an individual and are now implicated in ageing and neurodegeneration.

  • There is current interest in exploring possible roles of mitochondrial genetic variation in susceptibility to complex diseases, but the evidence remains uncertain at present.

  • The literature documenting the accumulation of mtDNA mutations in tumours needs to be interpreted with caution.

Abstract

Mutations in the human mitochondrial genome are known to cause an array of diverse disorders, most of which are maternally inherited, and all of which are associated with defects in oxidative energy metabolism. It is now emerging that somatic mutations in mitochondrial DNA (mtDNA) are also linked to other complex traits, including neurodegenerative diseases, ageing and cancer. Here we discuss insights into the roles of mtDNA mutations in a wide variety of diseases, highlighting the interesting genetic characteristics of the mitochondrial genome and challenges in studying its contribution to pathogenesis.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Mitochondrial DNA and the human respiratory chain/oxidative phosphorylation system.
Figure 2: Example of the potential to amplify inadvertently a nucleus-embedded mitochondrial sequence.

Similar content being viewed by others

References

  1. Sagan, L. On the origin of mitosing cells. J. Theor. Biol. 14, 255–274 (1967).

    Article  CAS  PubMed  Google Scholar 

  2. Garcia-Rodriguez, L. J. Appendix 1. Basic properties of mitochondria. Methods Cell Biol. 80, 809–812 (2007).

    Article  PubMed  Google Scholar 

  3. Calvo, S. E. et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci. Transl. Med. 4, 118ra10 (2012). This was one of the first applications of sequencing the 'mitochondrial exome' (that is, ∼1,500 nuclear genes encoding mitochondrial-targeted proteins) to identify pathogenic mutations causing mitochondrial disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schaefer, A. M. et al. Prevalence of mitochondrial DNA disease in adults. Ann. Neurol. 63, 35–39 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Greaves, L. C., Reeve, A. K., Taylor, R. W. & Turnbull, D. M. Mitochondrial DNA and disease. J. Pathol. 226, 274–286 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Koopman, W. J., Willems, P. H. & Smeitink, J. A. Monogenic mitochondrial disorders. N. Engl. J. Med. 366, 1132–1141 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Ylikallio, E. & Suomalainen, A. Mechanisms of mitochondrial diseases. Ann. Med. 44, 41–59 (2012). This is a comprehensive overview of mitochondrial respiratory chain disorders.

    Article  CAS  PubMed  Google Scholar 

  8. Anderson, S. et al. Sequence and organization of the human mitochondrial genome. Nature 290, 457–465 (1981).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Sacconi, S. et al. A functionally dominant mitochondrial DNA mutation. Hum. Mol. Genet. 17, 1814–1820 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yoneda, M., Miyatake, T. & Attardi, G. Heteroplasmic mitochondrial tRNALys mutation and its complementation in MERRF patient-derived mitochondrial transformants. Muscle Nerve 3, S95–S101 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. 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).

    Article  CAS  PubMed  Google Scholar 

  13. Santorelli, F. M., Shanske, S., Macaya, A., DeVivo, D. C. & DiMauro, S. The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome. Ann. Neurol. 34, 827–834 (1993).

    Article  CAS  PubMed  Google Scholar 

  14. 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 

  15. Elliott, H. R., Samuels, D. C., Eden, J. A., Relton, C. L. & Chinnery, P. F. Pathogenic mitochondrial DNA mutations are common in the general population. Am. J. Hum. Genet. 83, 254–260 (2008). This was the first large-scale epidemiological survey of the prevalence of common pathological mtDNA mutations in the normal population.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Stewart, J. B. et al. Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol. 6, e10 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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 

  18. Raimundo, N. et al. Mitochondrial stress engages E2F1 apoptotic signaling to cause deafness. Cell 148, 716–726 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gilkerson, R. W. et al. Mitochondrial autophagy in cells with mtDNA mutations results from synergistic loss of transmembrane potential and mTORC1 inhibition. Hum. Mol. Genet. 21, 978–990 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Gilkerson, R. W., Schon, E. A., Hernandez, E. & Davidson, M. M. Mitochondrial nucleoids maintain genetic autonomy but allow for functional complementation. J. Cell Biol. 181, 1117–1128 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sgarbi, G. et al. Inefficient coupling between proton transport and ATP synthesis may be the pathogenic mechanism for NARP and Leigh syndrome resulting from the T8993G mutation in mtDNA. Biochem. J. 395, 493–500 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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).

    Article  CAS  PubMed  Google Scholar 

  23. Lestienne, P. & Ponsot, G. Kearns-Sayre syndrome with muscle mitochondrial DNA deletion. Lancet 331, 885–886 (1988).

    Article  Google Scholar 

  24. Damas, J. et al. Mitochondrial DNA deletions are associated with non-B DNA conformations. Nucleic Acids Res. 40, 7606–7621 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kearns, T. P. & Sayre, G. P. Retinitis pigmentosa, external ophthalmophegia, and complete heart block: unusual syndrome with histologic study in one of two cases. AMA Arch. Ophthalmol. 60, 280–289 (1958).

    Article  CAS  PubMed  Google Scholar 

  26. 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 

  27. Pearson, H. A. et al. A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction. J. Pediatr. 95, 976–984 (1979).

    Article  CAS  PubMed  Google Scholar 

  28. Nakase, H. et al. Transcription and translation of deleted mitochondrial genomes in Kearns–Sayre syndrome: implications for pathogenesis. Am. J. Hum. Genet. 46, 418–427 (1990). This was one of the first studies providing insight into the pathomechanism of mtDNA deletion disorders.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Mita, S., Schmidt, B., Schon, E. A., DiMauro, S. & Bonilla, E. Detection of “deleted” mitochondrial genomes in cytochrome-c oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome. Proc. Natl Acad. Sci. USA 86, 9509–9513 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Moraes, C. T. et al. Molecular analysis of the muscle pathology associated with mitochondrial DNA deletions. Nature Genet. 1, 359–367 (1992).

    Article  CAS  PubMed  Google Scholar 

  31. Ashley, N. et al. Defects in maintenance of mitochondrial DNA are associated with intramitochondrial nucleotide imbalances. Hum. Mol. Genet. 16, 1400–1411 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Moraes, C. T. et al. Mitochondrial DNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases. Am. J. Hum. Genet. 48, 492–501 (1991). This was the first description of a quantitative defect in mtDNA copy number causing disease.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Nishigaki, Y., Marti, R., Copeland, W. C. & Hirano, M. Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency. J. Clin. Invest. 111, 1913–1921 (2003). This was the first description of a secondary mitochondrial disorder causing mtDNA point mutations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nishino, I., Spinazzola, A. & Hirano, M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283, 689–692 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Kaukonen, J. et al. Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science 289, 782–785 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Van Goethem, G., Dermaut, B., Lofgren, A., Martin, J. J. & Van Broeckhoven, C. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nature Genet. 28, 211–212 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. 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 

  38. Naviaux, R. K. & Nguyen, K. V. POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion. Ann. Neurol. 55, 706–712 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Moraes, C. T. et al. Phenotype-genotype correlations in skeletal muscle of patients with mtDNA deletions. Muscle Nerve 3, S150–S153 (1995).

    Article  CAS  PubMed  Google Scholar 

  40. Cortopassi, G. A., Shibata, D., Soong, N. W. & Arnheim, N. A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc. Natl Acad. Sci. USA 89, 7370–7374 (1992). This was among the first reports that called attention to the accumulation of somatic mtDNA deletions in normal ageing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Corral-Debrinski, M. et al. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nature Genet. 2, 324–329 (1992).

    Article  CAS  PubMed  Google Scholar 

  42. Meissner, C. et al. The 4977 bp deletion of mitochondrial DNA in human skeletal muscle, heart and different areas of the brain: a useful biomarker or more? Exp. Gerontol. 43, 645–652 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Pallotti, F., Chen, X., Bonilla, E. & Schon, E. A. Evidence that specific mtDNA point mutations may not accumulate in skeletal muscle during normal human aging. Am. J. Hum. Genet. 59, 591–602 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Simonetti, S., Chen, X., DiMauro, S. & Schon, E. A. Accumulation of deletions in human mitochondrial DNA during normal aging: analysis by quantitative PCR. Biochim. Biophys. Acta 1180, 113–122 (1992).

    Article  CAS  PubMed  Google Scholar 

  45. Oldfors, A. et al. Mitochondrial DNA deletions and cytochrome c oxidase deficiency in muscle fibres. J. Neurol. Sci. 110, 169–177 (1992).

    Article  CAS  PubMed  Google Scholar 

  46. Bodyak, N. D., Nekhaeva, E., Wei, J. Y. & Khrapko, K. Quantification and sequencing of somatic deleted mtDNA in single cells: evidence for partially duplicated mtDNA in aged human tissues. Hum. Mol. Genet. 10, 17–24 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Vu, T. H. et al. Analysis of mtDNA deletions in muscle by in situ hybridization. Muscle Nerve 23, 80–85 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Petruzzella, V. et al. 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 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Bua, E. et al. Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers. Am. J. Hum. Genet. 79, 469–480 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Schon, E. A. & Przedborski, S. Mitochondria: the next (neurode) generation. Neuron 70, 1033–1053 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Vives-Bauza, C. et al. Control of mitochondrial integrity in Parkinson's disease. Prog. Brain Res. 183, 99–113 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Narendra, D. P. & Youle, R. J. Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control. Antioxid. Redox Signal. 14, 1929–1938 (2011).

    CAS  Google Scholar 

  53. Bender, A. et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nature Genet. 38, 515–517 (2006). This was the first report of correlating a neurodegenerative disease with the accumulation of mtDNA mutations in the clinically relevant target tissue.

    Article  CAS  PubMed  Google Scholar 

  54. Kraytsberg, Y. et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nature Genet. 38, 518–520 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Ekstrand, M. I. et al. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc. Natl Acad. Sci. USA 104, 1325–1330 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. De Coo, I. F. et al. A 4-base pair deletion in the mitochondrial cytochrome b gene associated with parkinsonism/MELAS overlap syndrome. Ann. Neurol. 45, 130–133 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. 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).

    Article  CAS  PubMed  Google Scholar 

  58. Tyynismaa, H. et al. Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice. Proc. Natl Acad. Sci. USA 102, 17687–17692 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cann, R. L., Stoneking, M. & Wilson, A. C. Mitochondrial DNA and human evolution. Nature 325, 31–36 (1987).

    Article  CAS  PubMed  Google Scholar 

  60. Ruiz-Pesini, E., Mishmar, D., Brandon, M., Procaccio, V. & Wallace, D. C. Effects of purifying and adaptive selection on regional variation in human mtDNA. Science 303, 223–226 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Amo, T. & Brand, M. D. Were inefficient mitochondrial haplogroups selected during migrations of modern humans? A test using modular kinetic analysis of coupling in mitochondria from cybrid cell lines. Biochem. J. 404, 345–351 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Saxena, R. et al. Comprehensive association testing of common mitochondrial DNA variation in metabolic disease. Am. J. Hum. Genet. 79, 54–61 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kadowaki, T. et al. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N. Engl. J. Med. 330, 962–968 (1994). This was an important survey that demonstrated the importance of a specific mtDNA mutation as a cause of diabetes mellitus.

    Article  CAS  PubMed  Google Scholar 

  64. Bitner-Glindzicz, M. et al. Prevalence of mitochondrial 1555A→G mutation in European children. N. Engl. J. Med. 360, 640–642 (2009).

    Article  PubMed  Google Scholar 

  65. Vandebona, H. et al. Prevalence of mitochondrial 1555A→G mutation in adults of European descent. N. Engl. J. Med. 360, 642–644 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. 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 

  67. Elson, J. L., Majamaa, K., Howell, N. & Chinnery, P. F. Associating mitochondrial DNA variation with complex traits. Am. J. Hum. Genet. 80, 378–382; author reply 382–383 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Carelli, V. et al. Haplogroup effects and recombination of mitochondrial DNA: novel clues from the analysis of Leber hereditary optic neuropathy pedigrees. Am. J. Hum. Genet. 78, 564–574 (2006). This paper provieds a good example of the 'synergistic' relationship between specific mtDNA haplotypes and the severity of pathogenic mtDNA point mutations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hudson, G. et al. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am. J. Hum. Genet. 81, 228–233 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ghelli, A. et al. The background of mitochondrial DNA haplogroup J increases the sensitivity of Leber's hereditary optic neuropathy cells to 2,5-hexanedione toxicity. PLoS ONE 4, e7922 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Anderson, C. D. et al. Common mitochondrial sequence variants in ischemic stroke. Ann. Neurol. 69, 471–480 (2011).

    Article  CAS  PubMed  Google Scholar 

  72. Arning, L. et al. Mitochondrial haplogroup H correlates with ATP levels and age at onset in Huntington disease. J. Mol. Med. 88, 431–436 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Ingram, C. J. et al. Analysis of European case-control studies suggests that common inherited variation in mitochondrial DNA is not involved in susceptibility to amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 13, 341–346 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. Hiona, A. & Leeuwenburgh, C. The role of mitochondrial DNA mutations in aging and sarcopenia: implications for the mitochondrial vicious cycle theory of aging. Exp. Gerontol. 43, 24–33 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Khusnutdinova, E. et al. A mitochondrial etiology of neurodegenerative diseases: evidence from Parkinson's disease. Ann. NY Acad. Sci. 1147, 1–20 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Mancuso, M., Filosto, M., Orsucci, D. & Siciliano, G. Mitochondrial DNA sequence variation and neurodegeneration. Hum. Genom. 3, 71–78 (2008).

    Article  CAS  Google Scholar 

  77. Nishigaki, Y., Fuku, N. & Tanaka, M. Mitochondrial haplogroups associated with lifestyle-related diseases and longevity in the Japanese population. Geriatr. Gerontol. Int. 10, S221–S235 (2010).

    Article  PubMed  Google Scholar 

  78. Rose, G. et al. No evidence of association between frontotemporal dementia and major European mtDNA haplogroups. Eur. J. Neurol. 15, 1006–1008 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. SanGiovanni, J. P. et al. Mitochondrial DNA variants of respiratory complex I that uniquely characterize haplogroup T2 are associated with increased risk of age-related macular degeneration. PLoS ONE 4, e5508 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sanchez-Ferrero, E. et al. Mitochondrial DNA polymorphisms/haplogroups in hereditary spastic paraplegia. J. Neurol. 259, 246–250.

    Article  CAS  PubMed  Google Scholar 

  81. Santoro, A. et al. Evidence for sub-haplogroup h5 of mitochondrial DNA as a risk factor for late onset Alzheimer's disease. PLoS ONE 5, e12037 (2012).

    Article  CAS  Google Scholar 

  82. Sequeira, A. et al. Mitochondrial mutations and polymorphisms in psychiatric disorders. Front. Genet. 3, 103 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Tranah, G. J. Mitochondrial-nuclear epistasis: implications for human aging and longevity. Ageing Res. Rev. 10, 238–252 (2012).

    Article  CAS  Google Scholar 

  84. McRae, A. F., Byrne, E. M., Zhao, Z. Z., Montgomery, G. W. & Visscher, P. M. Power and SNP tagging in whole mitochondrial genome association studies. Genome Res. 18, 911–917 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Battersby, B. J. & Shoubridge, E. A. Selection of a mtDNA sequence variant in hepatocytes of heteroplasmic mice is not due to differences in respiratory chain function or efficiency of replication. Hum. Mol. Genet. 10, 2469–2479 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Warburg, O., Wind, F. & Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol. 8, 519–530 (1927).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Polyak, K. et al. Somatic mutations of the mitochondrial genome in human colorectal tumours. Nature Genet. 20, 291–293 (1998).

    Article  CAS  PubMed  Google Scholar 

  88. Yu, M. Generation, function and diagnostic value of mitochondrial DNA copy number alterations in human cancers. Life Sci. 89, 65–71 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Melnick, P. J. Enzyme patterns of tumors demonstrated histochemically in cryostat sections. Ann. NY Acad. Sci. 125, 689–715 (1965).

    Article  CAS  PubMed  Google Scholar 

  90. Pelicano, H. et al. Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism. J. Cell Biol. 175, 913–923 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Yu, M. et al. Reduced mitochondrial DNA copy number is correlated with tumor progression and prognosis in Chinese breast cancer patients. IUBMB Life 59, 450–457 (2007).

    CAS  PubMed  Google Scholar 

  92. Bai, R. K. et al. Mitochondrial DNA content varies with pathological characteristics of breast cancer. J. Oncol. 2011, 496189 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. King, M. P., Koga, Y., Davidson, M. & Schon, E. A. Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNALeu(UUR) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Mol. Cell. Biol. 12, 480–490 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Miller, R. W. Dihydroorotate-quinone reductase of Neurospora crassa mitochondria. Arch. Biochem. Biophys. 146, 256–270 (1971).

    Article  CAS  PubMed  Google Scholar 

  95. Hayashi, J., Takemitsu, M. & Nonaka, I. Recovery of the missing tumorigenicity in mitochondrial DNA-less HeLa cells by introduction of mitochondrial DNA from normal human cells. Somat. Cell. Mol. Genet. 18, 123–129 (1992).

    Article  CAS  PubMed  Google Scholar 

  96. Morais, R. et al. Tumor-forming ability in athymic nude mice of human cell lines devoid of mitochondrial DNA. Cancer Res. 54, 3889–3896 (1994).

    CAS  PubMed  Google Scholar 

  97. Peters, G. J. et al. In vivo inhibition of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP-785; NSC 368390) in mice and patients. Cancer Res. 50, 4644–4649 (1990).

    CAS  PubMed  Google Scholar 

  98. Mourier, T., Hansen, A. J., Willerslev, E. & Arctander, P. The Human Genome Project reveals a continuous transfer of large mitochondrial fragments to the nucleus. Mol. Biol. Evol. 18, 1833–1837 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Ramos, A. et al. Nuclear insertions of mitochondrial origin: database updating and usefulness in cancer studies. Mitochondrion 11, 946–953 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. Hazkani-Covo, E., Zeller, R. M. & Martin, W. Molecular poltergeists: mitochondrial DNA copies (numts) in sequenced nuclear genomes. PLoS Genet. 6, e1000834 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lang, M. et al. Polymorphic Numts trace human population relationships. Hum. Genet. 131, 757–771 (2012).

    Article  PubMed  Google Scholar 

  102. Wang, D., Lloyd, A. H. & Timmis, J. N. Environmental stress increases the entry of cytoplasmic organellar DNA into the nucleus in plants. Proc. Natl Acad. Sci. USA 109, 2444–2448 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Cheng, X. & Ivessa, A. S. The migration of mitochondrial DNA fragments to the nucleus affects the chronological aging process of Saccharomyces cerevisiae. Aging Cell 9, 919–923 (2010). This is a fascinating example of how mtDNA fragments can be transferred to the nucleus in 'real time' (that is, during the lifetime of an individual).

    Article  CAS  PubMed  Google Scholar 

  104. Caro, P. et al. Mitochondrial DNA sequences are present inside nuclear DNA in rat tissues and increase with age. Mitochondrion 10, 479–486 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Goldin, E. et al. Transfer of a mitochondrial DNA fragment to MCOLN1 causes an inherited case of mucolipidosis IV. Hum. Mutat. 24, 460–465 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Turner, C. et al. Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer. Hum. Genet. 112, 303–309 (2003).

    PubMed  Google Scholar 

  107. Willett-Brozick, J. E., Savul, S. A., Richey, L. E. & Baysal, B. E. Germ line insertion of mtDNA at the breakpoint junction of a reciprocal constitutional translocation. Hum. Genet. 109, 216–223 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Storlazzi, C. T. et al. Gene amplification as double minutes or homogeneously staining regions in solid tumors: origin and structure. Genome Res. 20, 1198–1206 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Valsesia, A. et al. Network-guided analysis of genes with altered somatic copy number and gene expression reveals pathways commonly perturbed in metastatic melanoma. PLoS ONE 6, e18369 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Hirano, T. et al. Co-localization of mitochondrial and double minute DNA in the nuclei of HL-60 cells but not normal cells. Mutat. Res. 425, 195–204 (1999).

    Article  CAS  PubMed  Google Scholar 

  111. Lee, J. H., Ryu, T. Y., Cho, C. H. & Kim, D. K. Different characteristics of mitochondrial microsatellite instability between uterine leiomyomas and leiomyosarcomas. Pathol. Oncol. Res. 17, 201–205 (2011).

    Article  PubMed  Google Scholar 

  112. Ellinger, J. et al. Circulating mitochondrial DNA in serum: A universal diagnostic biomarker for patients with urological malignancies. Urol. Oncol. 30, 509–515 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. Kiebish, M. A. & Seyfried, T. N. Absence of pathogenic mitochondrial DNA mutations in mouse brain tumors. BMC Cancer 5, 102 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ericson, N. G. et al. Decreased mitochondrial DNA mutagenesis in human colorectal cancer. PLoS Genet. 8, e1002689 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Chinnery, P. F., Samuels, D. C., Elson, J. & Turnbull, D. M. Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism? Lancet 360, 1323–1325 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Parr, R. L. et al. The pseudo-mitochondrial genome influences mistakes in heteroplasmy interpretation. BMC Genomics 7, 185 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Maki, J. et al. Mitochondrial genome deletion aids in the identification of false- and true-negative prostate needle core biopsy specimens. Am. J. Clin. Pathol. 129, 57–66 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. Parr, R. L. et al. Somatic mitochondrial DNA mutations in prostate cancer and normal appearing adjacent glands in comparison to age-matched prostate samples without malignant histology. J. Mol. Diagn. 8, 312–319 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. DiMauro, S. & Andreu, A. L. Mutations in mtDNA: are we scraping the bottom of the barrel? Brain Pathol. 10, 431–441 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. Giordano, C. et al. Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy. Brain 134, 220–234 (2011).

    Article  PubMed  Google Scholar 

  121. Kaufmann, P. et al. Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype. Neurology 77, 1965–1971 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Tay, S. H. et al. Aortic rupture in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes. Arch. Neurol. 63, 281–283 (2006).

    Article  PubMed  Google Scholar 

  123. Chong, P. S., Vucic, S., Hedley-Whyte, E. T., Dreyer, M. & Cros, D. Multiple symmetric lipomatosis (Madelung's disease) caused by the MERRF (A8344G) mutation: a report of two cases and review of the literature. J. Clin. Neuromuscul. Dis. 5, 1–7 (2003).

    Article  PubMed  Google Scholar 

  124. Suzuki, T., Nagao, A. & Suzuki, T. Human mitochondrial diseases caused by lack of taurine modification in mitochondrial tRNAs. Wiley Interdiscip. Rev. RNA 2, 376–386 (2011).

    CAS  PubMed  Google Scholar 

  125. Hasegawa, H., Matsuoka, T., Goto, Y. & Nonaka, I. Cytochrome c oxidase activity is deficient in blood vessels of patients with myoclonus epilepsy with ragged-red fibers. Acta Neuropathol. 85, 280–284 (1993).

    Article  CAS  PubMed  Google Scholar 

  126. Naini, A. et al. Hypocitrullinemia in patients with MELAS: an insight into the “MELAS paradox”. J. Neurol. Sci. 229–230, 187–193 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Shiva, S., Brookes, P. S., Patel, R. P., Anderson, P. G. & Darley-Usmar, V. M. Nitric oxide partitioning into mitochondrial membranes and the control of respiration at cytochrome c oxidase. Proc. Natl Acad. Sci. USA 98, 7212–7217 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Torres, J., Darley-Usmar, V. & Wilson, M. T. Inhibition of cytochrome c oxidase in turnover by nitric oxide: mechanism and implications for control of respiration. Biochem. J. 312, 169–173 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Rodriguez-Juarez, F., Aguirre, E. & Cadenas, S. Relative sensitivity of soluble guanylate cyclase and mitochondrial respiration to endogenous nitric oxide at physiological oxygen concentration. Biochem. J. 405, 223–231 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Koga, Y. et al. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology 64, 710–712 (2005).

    Article  CAS  PubMed  Google Scholar 

  131. Horvath, R. et al. Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy. Brain 132, 3165–3174 (2009). An unexpected connection is presented in this paper between an mtDNA mutation and a mitochondrial disorder with an unusual course.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Uusimaa, J. et al. Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease. J. Med. Genet. 48, 660–668 (2011).

    Article  CAS  PubMed  Google Scholar 

  133. Umeda, N. et al. Mitochondria-specific RNA-modifying enzymes responsible for the biosynthesis of the wobble base in mitochondrial tRNAs. Implications for the molecular pathogenesis of human mitochondrial diseases. J. Biol. Chem. 280, 1613–1624 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Yan, Q. et al. Human TRMU encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase is a putative nuclear modifier gene for the phenotypic expression of the deafness-associated 12S rRNA mutations. Biochem. Biophys. Res. Commun. 342, 1130–1136 (2006).

    Article  CAS  PubMed  Google Scholar 

  135. King, M. P. & Attardi, G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246, 500–503 (1989). This was the first description of the use of cybrid technology in mammalian cells.

    Article  CAS  PubMed  Google Scholar 

  136. King, M. P. & Attardi, G. Isolation of human cell lines lacking mitochondrial DNA. Methods Enzymol. 264, 304–313 (1996).

    Article  CAS  PubMed  Google Scholar 

  137. Engel, W. K. & Cunningham, G. G. Rapid examination of muscle tissue. An improved trichrome method for fresh-frozen biopsy sections. Neurology 13, 919–923 (1963).

    Article  CAS  PubMed  Google Scholar 

  138. Bonilla, E. et al. New morphological approaches to the study of mitochondrial encephalomyopathies. Brain Pathol. 2, 113–119 (1992). In this paper, a comprehensive survey is presented of morphological approaches used to diagnose and study mitochondrial diseases.

    Article  CAS  PubMed  Google Scholar 

  139. Quinzii, C. M. et al. Reactive oxygen species, oxidative stress, and cell death correlate with level of CoQ10 deficiency. FASEB J. 24, 3733–3743 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Loveland, B., Wang, C. R., Yonekawa, H., Hermel, E. & Lindahl, K. F. Maternally transmitted histocompatibility antigen of mice: a hydrophobic peptide of a mitochondrially encoded protein. Cell 60, 971–980 (1990).

    Article  CAS  PubMed  Google Scholar 

  141. Gogvadze, V., Orrenius, S. & Zhivotovsky, B. Mitochondria in cancer cells: what is so special about them? Trends Cell Biol. 18, 165–173 (2008).

    Article  CAS  PubMed  Google Scholar 

  142. Madan, E. et al. Regulation of glucose metabolism by p53: emerging new roles for the tumor suppressor. Oncotarget 2, 948–957 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  143. van Nederveen, F. H. et al. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol. 10, 764–771 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Tomlinson, I. P. et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nature Genet. 30, 406–410 (2002).

    Article  CAS  PubMed  Google Scholar 

  145. Selak, M. A. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell 7, 77–85 (2005).

    Article  CAS  PubMed  Google Scholar 

  146. Lemasters, J. J. & Holmuhamedov, E. Voltage-dependent anion channel (VDAC) as mitochondrial governator — thinking outside the box. Biochim. Biophys. Acta 1762, 181–190 (2006).

    Article  CAS  PubMed  Google Scholar 

  147. Majewski, N., Nogueira, V., Robey, R. B. & Hay, N. Akt inhibits apoptosis downstream of BID cleavage via a glucose-dependent mechanism involving mitochondrial hexokinases. Mol. Cell. Biol. 24, 730–740 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Jain, M. et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040–1044 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. DiMauro, S., Hirano, M. & Schon, E. A. Approaches to the treatment of mitochondrial diseases. Muscle Nerve 34, 265–283 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors were supported by grants from the US National Institutes of Health (HD32062), the US Department of Defense (W911NF-12-1-0159), the Muscular Dystrophy Association, the Ellison Medical Foundation, the Alzheimer Drug Discovery Foundation and the Marriott Mitochondrial Disorder Clinical Research Fund.

Author information

Authors and Affiliations

  1. Department of Neurology, Columbia University Medical Center, 630 West 168th Street, New York, 10032, New York, USA

    Eric A. Schon, Salvatore DiMauro & Michio Hirano

  2. Department of Genetics and Development, Columbia University Medical Center, 701 West 168th Street, New York, 10032, New York, USA

    Eric A. Schon

Authors
  1. Eric A. Schon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Salvatore DiMauro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michio Hirano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric A. Schon.

Ethics declarations

Competing interests

Eric A. Schon is a paid consultant to Mitomics, Inc., which is developing tests to diagnose cancer on the basis of the presence of mutations in tumour mitochondrial DNA (mtDNA). Salvatore DiMauro and Michio Hirano declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Eric Schon's homepage 1

Eric Schon's homepage 2

Salvatore DiMauro's homepage

Michio Hirano's homepage

Glossary

Microarray-based sequencing

DNA sequencing based on the ability of the target DNA to hybridize to an ordered set of defined oligonucleotides immobilized on a chip.

Monochromosomal transfer

Typically, the transfer of individual human chromosomes (or parts of chromosomes) to rodent cells in order to identify and map human genes responsible for disease.

Mitodynamics

The morphological properties of mitochondria (for example, fusion, fission, distribution, anchorage, positioning). These properties can change both in space and in time within cells.

Primary pathogenic mtDNA mutations

Mutations that can compromise OXPHOS function and cause disease. They arise in mtDNA through processes such as random errors during normal mtDNA replication.

Nystagmus

An involuntary, quick, rhythmic movement of the eyeball, which can be horizontal, vertical or rotary.

Hemiplegia

Paralysis of the left or right side of the body owing to a brain lesion affecting motor pathways.

Strongly SDH-positive vessels

(SSVs). Abnormal, massive accumulation of mitochondria in blood vessels, as visualized by enzyme histochemistry to detect the activity of succinate dehydrogenase (SDH; complex II of the respiratory chain).

Heteroplasmic

A term that describes the presence of two or more mtDNA genotypes within a cell, tissue or organism.

Lactic acidosis

The abnormal accumulation of lactic acid causing lower pH in blood in a resting individual (that is, not during or immediately after exercise), which is seen in many patients with mitochondrial disease.

Myoclonus

Involuntary jerky movement of an area of the body (usually a limb).

Mitochondrial transmembrane potential

(Δψm). This is the electrical potential generated across the mitochondrial inner membrane due to differences in the distribution of ions (for example, H+, Ca2+, Na+, K+ and ionized ATP species) between the matrix and the intermembrane space.

Secondary mtDNA mutations

Mutations that can compromise OXPHOS function and cause disease and that arise in mtDNA owing to a mutation in the nuclear genome that compromises mtDNA integrity (for example, a mutation in mitochondrial DNA polymerase-γ causing systemic errors in mtDNA replication).

Homoplasmic

A term that describes the presence of a single mtDNA genotype within a cell, tissue, or organism.

Aerobic glycolysis

The conversion of glucose to lactate (and the production of ATP by substrate level phosphorylation) even in the presence of oxygen, especially in tumours.

Double minute DNAs

(dmDNAs). Tiny fragments of extrachromosomal nuclear DNA found in many tumours, derived from the amplification of small regions of chromosomal DNA.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schon, E., DiMauro, S. & Hirano, M. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat Rev Genet 13, 878–890 (2012). https://doi.org/10.1038/nrg3275

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg3275

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer