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  • Review Article
  • Published:

The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease

Nature Reviews Genetics volume 16, pages 530–542 (2015)Cite this article

Subjects

Key Points

  • Mitochondria contain their own genome, which is maternally inherited and codes for polypeptides forming the mitochondrial respiratory chain. Mitochondrial DNA (mtDNA) has a structure and code different from those of the nuclear genome.

  • mtDNA mutations contribute to human disease across a range of severity, from rare, highly penetrant mutations causal for monogenic disorders that often affect the nervous system, muscles, heart and endocrine organs, to mutations that have a milder contribution to common complex traits and late-onset disorders.

  • Many healthy humans harbour low levels (<1%) of mtDNA point mutations, including both inherited and acquired mutations. An increased burden of acquired mutations can contribute to late-onset diseases.

  • Studies in model organisms are beginning to provide insights into the mechanisms by which the acquisition of new mtDNA mutations is suppressed, particularly in the germ line.

Abstract

Common genetic variants of mitochondrial DNA (mtDNA) increase the risk of developing several of the major health issues facing the western world, including neurodegenerative diseases. In this Review, we consider how these mtDNA variants arose and how they spread from their origin on one single molecule in a single cell to be present at high levels throughout a specific organ and, ultimately, to contribute to the population risk of common age-related disorders. mtDNA persists in all aerobic eukaryotes, despite a high substitution rate, clonal propagation and little evidence of recombination. Recent studies have found that de novo mtDNA mutations are suppressed in the female germ line; despite this, mtDNA heteroplasmy is remarkably common. The demonstration of a mammalian mtDNA genetic bottleneck explains how new germline variants can increase to high levels within a generation, and the ultimate fixation of less-severe mutations that escape germline selection explains how they can contribute to the risk of late-onset disorders.

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Figure 1: mtDNA heteroplasmy and the threshold effect.
Figure 2: New technologies to analyse mtDNA.
Figure 3: mtDNA heteroplasmy can change throughout the lifetime of an individual.
Figure 4: Models for the mtDNA genetic bottleneck.
Figure 5: Human population migrations and major mtDNA haplogroups.

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References

  1. Wallace, D. C. et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242, 1427–1430 (1988). Describes the first-identified human pathogenic mtDNA mutation, which was a homoplasmic point mutation in MTND4 . It transpires that this mutation (m.11778A>G) is actually the most common pathogenic mtDNA mutation encountered in clinical practice.

    CAS  PubMed  Google Scholar 

  2. Holt, I., Harding, A. E. & Morgan-Hughes, J. A. Deletion of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331, 717–719 (1988).

    CAS  PubMed  Google Scholar 

  3. Gorman, G. S. et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann. Neurol. 77, 753–759 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Chinnery, P. F. et al. Epidemiology of pathogenic mitochondrial DNA mutations. Ann. Neurol. 48, 188–193 (2000). The first epidemiological study of pathogenic mtDNA mutations, which shows that mtDNA diseases are not exceptionally rare, as previously thought.

    CAS  PubMed  Google Scholar 

  5. Di Mauro, S., Schon, E. A., Carelli, V. & Hirano, M. The clinical maze of mitochondrial neurology. Nat. Rev. Neurol. 9, 429–444 (2013).

    CAS  Google Scholar 

  6. Vafai, S. B. & Mootha, V. K. Mitochondrial disorders as windows into an ancient organelle. Nature 491, 374–383 (2012).

    CAS  PubMed  Google Scholar 

  7. Wallace, D. C. Colloquium paper: bioenergetics, the origins of complexity, and the ascent of man. Proc. Natl Acad. Sci. USA 107 (Suppl. 2), 8947–8953 (2011).

    Google Scholar 

  8. Pinto, M. & Moraes, C. T. Mechanisms linking mtDNA damage and aging. Free Radic. Biol. Med. 85, 250–258 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Pinto, M. & Moraes, C. T. Mitochondrial genome changes and neurodegenerative diseases. Biochim. Biophys. Acta 1842, 1198–1207 (2014).

    CAS  PubMed  Google Scholar 

  10. Ross, J. M. et al. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501, 412–415 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Keogh, M. & Chinnery, P. F. Hereditary mtDNA heteroplasmy: a baseline for aging? Cell Metab. 18, 463–464 (2013).

    CAS  PubMed  Google Scholar 

  12. Hudson, G., Gomez-Duran, A., Wilson, I. J. & Chinnery, P. F. Recent mitochondrial DNA mutations increase the risk of developing common late-onset human diseases. PLoS Genet. 10, e1004369 (2014).

    PubMed  PubMed Central  Google Scholar 

  13. Wallace, D. C. & Chalkia, D. Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harb. Perspect. Med. 3, a021220 (2013).

    Google Scholar 

  14. Gomez-Duran, A. et al. Unmasking the causes of multifactorial disorders: OXPHOS differences between mitochondrial haplogroups. Hum. Mol. Genet. 19, 3343–3353 (2010).

    CAS  PubMed  Google Scholar 

  15. Mereschkowsky, K. Theorie der zwei Plasmaarten als Grundlage der Symbiogenesis, einer neuen Lehre von der Ent-stehung der Organismen. Biol. Centralbl. 30, 353–367 (1910) (in German).

    Google Scholar 

  16. Pagliarini, D. J. et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112–123 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Vafai, S. B. & Mootha, V. K. Medicine. A common pathway for a rare disease? Science 342, 1453–1454 (2013).

    CAS  PubMed  Google Scholar 

  18. Anderson, S. et al. Sequence and organization of the human mitochondrial genome. Nature 290, 457–465 (1981). Provides the first human mitochondrial DNA sequence, subsequently referred to as the Cambridge reference sequence (CRS). The published sequence was derived predominantly from a human placenta from a person belonging to haplogroup H, but difficult regions were derived from other sources, including the bovine sequence.

    CAS  PubMed  Google Scholar 

  19. Andrews, R. M. et al. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat. Genet. 23, 147 (1999). Sequence errors in the original CRS (reference 18) were corrected in this publication, resulting in a new sequence referred to as the revised CRS (rCRS).

    CAS  PubMed  Google Scholar 

  20. Calvo, S. E. & Mootha, V. K. The mitochondrial proteome and human disease. Annu. Rev. Genom. Hum. Genet. 11, 25–44 (2010).

    CAS  Google Scholar 

  21. Kukat, C. et al. Super-resolution microscopy reveals that mammalian mitochondrial nucleoids have a uniform size and frequently contain a single copy of mtDNA. Proc. Natl Acad. Sci. USA 108, 13534–13539 (2011).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  23. Schon, E. A., DiMauro, S. & Hirano, M. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat. Rev. Genet. 13, 878–890 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. McFarland, R. et al. Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation. Nat. Genet. 30, 145–146 (2002).

    CAS  PubMed  Google Scholar 

  26. Tiranti, V. et al. A novel frameshift mutation of the mtDNA COIII gene leads to impaired assembly of cytochrome c oxidase in a patient affected by Leigh-like syndrome. Hum. Mol. Genet. 9, 2733–2742 (2000).

    CAS  PubMed  Google Scholar 

  27. Limongelli, A. et al. Variable penetrance of a familial progressive necrotising encephalopathy due to a novel tRNAIle homoplasmic mutation in the mitochondrial genome. J. Med. Genet. 41, 342–349 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. King, M. P. & Attardi, G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246, 500–503 (1989).

    CAS  PubMed  Google Scholar 

  29. Boulet, L., Karpati, G. & Shoubridge, E. A. Distribution and threshold expression of the tRNALys mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF). Am. J. Hum. Genet. 51, 1187–1200 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Carelli, V., Giordano, C. & d'Amati, G. Pathogenic expression of homoplasmic mtDNA mutations needs a complex nuclear–mitochondrial interaction. Trends Genet. 19, 257–262 (2003).

    CAS  PubMed  Google Scholar 

  31. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Cortopassi, G. A. & Arnheim, N. Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res. 18, 6927–6933 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 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).

    CAS  PubMed  Google Scholar 

  34. Corral-Debrinski, M., Shoffner, J. M., Lott, M. T. & Wallace, D. C. Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease. Mutat. Res. 275, 169–180 (1992). One of the early papers describing the presence of somatic mtDNA mutations in aged individuals and the association of these mutations with age-related diseases.

    CAS  PubMed  Google Scholar 

  35. Corral-Debrinski, M. et al. Marked changes in mitochondrial DNA deletion levels in Alzheimer brains. Genomics 23, 471–476 (1994).

    CAS  PubMed  Google Scholar 

  36. Bender, A. et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat. Genet. 38, 515–517 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  38. Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004).

    CAS  PubMed  Google Scholar 

  39. Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005). References 38 and 39 provides the first descriptions of a mouse with a defective mtDNA polymerase. They show that mtDNA mutations accumulated in somatic tissues over time and were accompanied by a premature ageing phenotype.

    CAS  PubMed  Google Scholar 

  40. Polyak, K. et al. Somatic mutations of the mitochondrial genome in human colorectal tumours. Nat. Genet. 20, 291–293 (1998). A key paper describing clonally expanded mtDNA mutations in human tumours.

    CAS  PubMed  Google Scholar 

  41. He, Y. et al. Heteroplasmic mitochondrial DNA mutations in normal and tumour cells. Nature 464, 610–614 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Ju, Y. S. et al. Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. eLife 3, e02935 (2014).

    PubMed Central  Google Scholar 

  43. Payne, B. A. et al. Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nat. Genet. 43, 806–810 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Payne, B. A., Gardner, K., Coxhead, J. & Chinnery, P. F. Deep resequencing of mitochondrial DNA. Methods Mol. Biol. 1264, 59–66 (2015).

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  46. Dayama, G., Emery, S. B., Kidd, J. M. & Mills, R. E. The genomic landscape of polymorphic human nuclear mitochondrial insertions. Nucleic Acids Res. 42, 12640–12649 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Li, M. et al. Detecting heteroplasmy from high-throughput sequencing of complete human mitochondrial DNA genomes. Am. J. Hum. Genet. 87, 237–249 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ameur, A. et al. Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins. PLoS Genet. 7, e1002028 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Payne, B. A. et al. Universal heteroplasmy of human mitochondrial DNA. Hum. Mol. Genet. 22, 384–390 (2013).

    CAS  PubMed  Google Scholar 

  50. Rajasimha, H. K., Chinnery, P. F. & Samuels, D. C. Selection against pathogenic mtDNA mutations in a stem cell population leads to the loss of the 3243A→G mutation in blood. Am. J. Hum. Genet. 82, 333–343 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Lehtinen, S. K. et al. Genotypic stability, segregation and selection in heteroplasmic human cell lines containing np 3243 mutant mtDNA. Genetics 154, 363–380 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Raap, A. K. et al. Non-random mtDNA segregation patterns indicate a metastable heteroplasmic segregation unit in m.3243A&gt;G cybrid cells. PLoS ONE 7, e52080 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Chinnery, P. F. & Samuels, D. C. Relaxed replication of mtDNA: a model with implications for the expression of disease. Am. J. Hum. Genet. 64, 1158–1165 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Diaz, F. et al. Human mitochondrial DNA with large deletions repopulates organelles faster than full-length genomes under relaxed copy number control. Nucleic Acids Res. 30, 4626–4633 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Clark, K. A. et al. Selfish little circles: transmission bias and evolution of large deletion-bearing mitochondrial DNA in Caenorhabditis briggsae nematodes. PLoS ONE 7, e41433 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Samuels, D. C. et al. Recurrent tissue-specific mtDNA mutations are common in humans. PLoS Genet. 9, e1003929 (2013).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  59. Takeda, K., Takahashi, S., Onishi, A., Hanada, H. & Imai, H. Replicative advantage and tissue-specific segregation of RR mitochondrial DNA between C57BL/6 and RR heteroplasmic mice. Genetics 155, 777–783 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Burgstaller, J. P. et al. mtDNA segregation in heteroplasmic tissues is common in vivo and modulated by haplotype differences and developmental stage. Cell Rep. 7, 2031–2041 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Wanrooij, S. et al. In vivo mutagenesis reveals that OriL is essential for mitochondrial DNA replication. EMBO Rep. 13, 1130–1137 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Trifunovic, A. et al. Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc. Natl Acad. Sci. USA 102, 17993–17998 (2005).

    CAS  PubMed  Google Scholar 

  63. Durham, S. E., Brown, D. T., Turnbull, D. M. & Chinnery, P. F. Progressive depletion of mtDNA in mitochondrial myopathy. Neurology 67, 502–504 (2006).

    CAS  PubMed  Google Scholar 

  64. Durham, S. E., Samuels, D. C., Cree, L. M. & Chinnery, P. F. Normal levels of wild-type mitochondrial DNA maintain cytochrome c oxidase activity for two pathogenic mitochondrial DNA mutations but not for m.3243A→G. Am. J. Hum. Genet. 81, 189–195 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 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).

    CAS  PubMed  Google Scholar 

  66. Cree, L. M. et al. A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nat. Genet. 40, 249–254 (2008).

    CAS  PubMed  Google Scholar 

  67. Battersby, B. J., Redpath, M. E. & Shoubridge, E. A. Mitochondrial DNA segregation in hematopoietic lineages does not depend on MHC presentation of mitochondrially encoded peptides. Hum. Mol. Genet. 14, 2587–2594 (2005).

    CAS  PubMed  Google Scholar 

  68. Jokinen, R. et al. Gimap3 regulates tissue-specific mitochondrial DNA segregation. PLoS Genet. 6, e1001161 (2010).

    PubMed  PubMed Central  Google Scholar 

  69. Upholt, W. B. & Dawid, I. B. Mapping of mitochondrial DNA of individual sheep and goats: rapid evolution in the D loop region. Cell 11, 571–583 (1977).

    CAS  PubMed  Google Scholar 

  70. Olivo, P. D., Van de Walle, M. J., Laipis, P. J. & Hauswirth, W. W. Nucleotide sequence evidence for rapid genotypic shifts in the bovine mitochondrial DNA D-loop. Nature 306, 400–402 (1983). References 69 and 70 describe rapid shifts in mtDNA heteroplasmy in cows. These observations laid the foundations for the mtDNA bottleneck hypothesis, which explains differences in the level of heteroplasmy observed within human pedigrees transmitting pathogenic mtDNA mutations.

    CAS  PubMed  Google Scholar 

  71. Solignac, M., Génermont, J., Monnerot, M. & Mounolou, J.-C. Genetics of mitochondria in Drosophila: mtDNA inheritance in heteroplasmic strains of D.mauritania. Mol. Genet. Genomics 197, 183–188 (1984).

    CAS  Google Scholar 

  72. Rand, D. M. & Harrison, R. G. Mitochondrial DNA transmission genetics in crickets. Genetics 114, 955–970 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Birky, C. W. Relaxed and stringent genomes: why cytoplasmic genes don't obey Mendel's laws. J. Hered. 85, 355–365 (1994).

    Google Scholar 

  74. Wright, S. Evolution and the Genetics of Populations (University of Chicago Press, 1969).

    Google Scholar 

  75. Howell, N. et al. Mitochondrial gene segregation in mammals: is the bottleneck always narrow? Hum. Genet. 90, 117–120 (1992).

    CAS  PubMed  Google Scholar 

  76. Chinnery, P. F., Howell, N., Lightowlers, R. N. & Turnbull, D. M. MELAS and MERRF: the relationship between maternal mutation load and the frequency of clinically affected offspring. Brain 121, 1889–1894 (1998).

    PubMed  Google Scholar 

  77. White, S. L. et al. Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am. J. Hum. Genet. 65, 474–482 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Wai, T., Teoli, D. & Shoubridge, E. A. The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes. Nat. Genet. 40, 1484–1488 (2008).

    CAS  PubMed  Google Scholar 

  79. Cao, L. et al. The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells. Nat. Genet. 39, 386–390 (2007). References 66, 78 and 79 describe a reduction in the amount of mtDNA present within the germ line of mice, thus providing the first direct evidence of the existence of a mammalian mtDNA genetic bottleneck.

    CAS  PubMed  Google Scholar 

  80. Freyer, C. et al. Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission. Nat. Genet. 44, 1282–1285 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Cree, L. M., Samuels, D. C. & Chinnery, P. F. The inheritance of pathogenic mitochondrial DNA mutations. Biochim. Biophys. Acta 1792, 1097–1102 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Chinnery, P. F. et al. The inheritance of mitochondrial DNA heteroplasmy: random drift, selection or both? Trends Genet. 16, 500–505 (2000).

    CAS  PubMed  Google Scholar 

  83. 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. Nat. Genet. 14, 146–151 (1996).

    CAS  PubMed  Google Scholar 

  84. 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 (2001).

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  86. Fan, W. et al. A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science 319, 958–962 (2008). References 85 and 86 provide evidence of selection against mtDNA variants during maternal transmission in different mouse models.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Greaves, L. C. et al. Comparison of mitochondrial mutation spectra in ageing human colonic epithelium and disease: absence of evidence for purifying selection in somatic mitochondrial DNA point mutations. PLoS Genet. 8, e1003082 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Ma, H., Xu, H. & O'Farrell, P. H. Transmission of mitochondrial mutations and action of purifying selection in Drosophila melanogaster. Nat. Genet. 46, 393–397 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Hill, J. H., Chen, Z. & Xu, H. Selective propagation of functional mitochondrial DNA during oogenesis restricts the transmission of a deleterious mitochondrial variant. Nat. Genet. 46, 389–392 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Chacinska, A., Koehler, C. M., Milenkovic, D., Lithgow, T. & Pfanner, N. Importing mitochondrial proteins: machineries and mechanisms. Cell 138, 628–644 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Piko, L. & Taylor, K. D. Amounts of mitochondrial DNA and abundance of some mitochondrial gene transcripts in early mouse embryos. Dev. Biol. 123, 364–374 (1987).

    CAS  PubMed  Google Scholar 

  92. Stewart, J. B. & Larsson, N. G. Keeping mtDNA in shape between generations. PLoS Genet. 10, e1004670 (2014).

    PubMed  PubMed Central  Google Scholar 

  93. Krakauer, D. C. & Mira, A. Mitochondria and germ-cell death. Nature 400, 125–126 (1999).

    CAS  PubMed  Google Scholar 

  94. Kaare, M. et al. Do mitochondrial mutations cause recurrent miscarriage? Mol. Hum. Reprod. 15, 295–300 (2009).

    CAS  PubMed  Google Scholar 

  95. Behar, D. M. et al. The Genographic Project public participation mitochondrial DNA database. PLoS Genet. 3, e104 (2007).

    PubMed  PubMed Central  Google Scholar 

  96. Soares, P. et al. Correcting for purifying selection: an improved human mitochondrial molecular clock. Am. J. Hum. Genet. 84, 740–759 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Salas, A., Carracedo, A., Macaulay, V., Richards, M. & Bandelt, H. J. A practical guide to mitochondrial DNA error prevention in clinical, forensic, and population genetics. Biochem. Biophys. Res. Commun. 335, 891–899 (2005).

    CAS  PubMed  Google Scholar 

  98. Bandelt, H. J., Yao, Y. G., Salas, A., Kivisild, T. & Bravi, C. M. High penetrance of sequencing errors and interpretative shortcomings in mtDNA sequence analysis of LHON patients. Biochem. Biophys. Res. Commun. 352, 283–291 (2007).

    CAS  PubMed  Google Scholar 

  99. Blier, P. U., Dufresne, F. & Burton, R. S. Natural selection and the evolution of mtDNA-encoded peptides: evidence for intergenomic co-adaptation. Trends Genet. 17, 400–406 (2001).

    CAS  PubMed  Google Scholar 

  100. 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).

    CAS  PubMed  Google Scholar 

  101. Mishmar, D. et al. Natural selection shaped regional mtDNA variation in humans. Proc. Natl Acad. Sci. USA 100, 171–176 (2003).

    CAS  PubMed  Google Scholar 

  102. Samuels, D. C., Carothers, A. D., Horton, R. & Chinnery, P. F. The power to detect disease associations with mitochondrial DNA haplogroups. Am. J. Hum. Genet. 78, 713–720 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Moreno-Loshuertos, R. et al. Differences in reactive oxygen species production explain the phenotypes associated with common mouse mitochondrial DNA variants. Nat. Genet. 38, 1261–1268 (2006).

    CAS  PubMed  Google Scholar 

  104. Baudouin, S. V. et al. Mitochondrial DNA and survival after sepsis: a prospective study. Lancet 366, 2118–2121 (2005).

    PubMed  Google Scholar 

  105. Jimenez-Sousa, M. A. et al. Mitochondrial DNA haplogroups are associated with severe sepsis and mortality in patients who underwent major surgery. J. Infect. 70, 20–29 (2015).

    PubMed  Google Scholar 

  106. Hudson, G. et al. Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease. Neurology 80, 2042–2048 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Ghezzi, D. et al. Mitochondrial DNA haplogroup K is associated with a lower risk of Parkinson's disease in Italians. Eur. J. Hum. Genet. 13, 748–752 (2005).

    CAS  PubMed  Google Scholar 

  108. Reinhardt, K., Dowling, D. K. & Morrow, E. H. Medicine. Mitochondrial replacement, evolution, and the clinic. Science 341, 1345–1346 (2013).

    PubMed  Google Scholar 

  109. Chinnery, P. F. et al. The challenges of mitochondrial replacement. PLoS Genet. 10, e1004315 (2014).

    PubMed  PubMed Central  Google Scholar 

  110. Kmietowicz, Z. UK becomes first country to allow mitochondrial donation. BMJ 350, h1103 (2015).

    PubMed  Google Scholar 

  111. Shadel, G. S. & Clayton, D. A. Mitochondrial DNA maintenance in vertebrates. Annu. Rev. Biochem. 66, 409–435 (1997).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  113. 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).

    CAS  PubMed  Google Scholar 

  114. Yasukawa, T., Yang, M. Y., Jacobs, H. T. & Holt, I. J. A bidirectional origin of replication maps to the major noncoding region of human mitochondrial DNA. Mol. Cell 18, 651–662 (2005).

    CAS  PubMed  Google Scholar 

  115. Terzioglu, M. et al. MTERF1 binds mtDNA to prevent transcriptional interference at the light-strand promoter but is dispensable for rRNA gene transcription regulation. Cell Metab. 17, 618–626 (2013).

    CAS  PubMed  Google Scholar 

  116. Kuhl, I. et al. POLRMT does not transcribe nuclear genes. Nature 514, E7–E11 (2014).

    PubMed  Google Scholar 

  117. Kirkman, M. A. et al. Gene–environment interactions in Leber hereditary optic neuropathy. Brain 132, 2317–2326 (2009).

    PubMed  PubMed Central  Google Scholar 

  118. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Chinnery, P. F., Andrews, R. M., Turnbull, D. M. & Howell, N. Leber's hereditary optic neuropathy: does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation? Am. J. Med. Genet. 98, 235–243 (2001).

    CAS  PubMed  Google Scholar 

  120. Kennedy, S. R., Salk, J. J., Schmitt, M. W. & Loeb, L. A. Ultra-sensitive sequencing reveals an age-related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage. PLoS Genet. 9, e1003794 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Boore, J. L., Macey, J. R. & Medina, M. Sequencing and comparing whole mitochondrial genomes of animals. Methods Enzymol. 395, 311–348 (2005).

    CAS  PubMed  Google Scholar 

  122. Lou, D. I. et al. High-throughput DNA sequencing errors are reduced by orders of magnitude using circle sequencing. Proc. Natl Acad. Sci. USA 110, 19872–19877 (2013).

    CAS  PubMed  Google Scholar 

  123. Cao, L. et al. New evidence confirms that the mitochondrial bottleneck is generated without reduction of mitochondrial DNA content in early primordial germ cells of mice. PLoS Genet. 5, e1000756 (2009).

    PubMed  PubMed Central  Google Scholar 

  124. Carling, P. J., Cree, L. M. & Chinnery, P. F. The implications of mitochondrial DNA copy number regulation during embryogenesis. Mitochondrion 11, 686–692 (2011).

    CAS  PubMed  Google Scholar 

  125. Wallace, D. C., Brown, M. D. & Lott, M. T. Mitochondrial DNA variation in human evolution and disease. Gene 238, 211–230 (1999).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  127. van Oven, M. & Kayser, M. Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation. Hum. Mutat. 30, E386–E394 (2009).

    PubMed  Google Scholar 

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Acknowledgements

J.B.S. is supported by the Max Planck Society and a project grant from the United Mitochondrial Disease Foundation. P.F.C. is an honorary consultant neurologist at Newcastle upon Tyne Foundation Hospitals UK National Health Service (NHS) Foundation Trust, a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z) and a UK National Institute for Health Research (NIHR) senior investigator. P.F.C. receives additional support from the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z), the UK Medical Research Council Centre for Translational Muscle Disease research (G0601943), the European Union FP7 (Seventh Framework Programme for Research and Technological Development) TIRCON (Treat Iron-Related Childhood-Onset Neurodegeneration) consortium, and the NIHR Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the UK Department of Health.

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  1. Max Planck Institute for Biology of Ageing, Cologne, 50931, Germany

    James B. Stewart

  2. Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 1BZ, UK

    Patrick F. Chinnery

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Correspondence to Patrick F. Chinnery.

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FURTHER INFORMATION

MITOMAP

PowerPoint slides

Glossary

Proteobacterium

A major phylum of Gram-negative bacteria.

Iron–sulfur clusters

Associated iron and sulfur molecules forming part of an iron–sulfur protein.

Homoplasmy

A situation in which all the mitochondrial DNA molecules within a cell or organism are identical.

Heteroplasmy

A mixture of wild-type and mutant mitochondrial DNA within the cell. The percentage of mtDNA containing mutations can vary from 1% to 99%.

Cybrid

A cytoplasmic hybrid cell line made by fusing a whole cell with a cytoplast and usually used as a cellular model system to study the effects of mitochondrial DNA variants or mutations on the same nuclear genetic background.

Warburg effect

The shift from aerobic to anaerobic (glycolytic) metabolism that characterizes rapidly dividing cancer cell lineages.

Nuclear mitochondrial DNA sequences

(NUMTs). Pseudogene sequences in nuclear DNA that are derived from mitochondrial DNA.

Vegetative segregation

Changes in heteroplasmy that occur owing to the unequal partitioning of different mitochondrial genotypes during cell division.

Relaxed replication

DNA replication that occurs continuously throughout the cell cycle and is independent of nuclear division, as with mitochondrial DNA.

Replicative advantage

A situation in which one molecule is preferentially copied over another.

Haplogroups

Groups of similar haplotypes (groups of genes) that share several polymorphisms. Single-nucleotide variants acquired during human history have subdivided the mitochondrial DNA phylogeny into several major haplogroups, typically present at >5% in the population.

Bottleneck

A restriction in the number of molecules (for example, mitochondrial DNA) or groups of molecules arranged in segregating units.

Homoplasies

Mutations of the same nucleotide at the same genomic position arising by two (or more) independent mutations.

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Stewart, J., Chinnery, P. The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat Rev Genet 16, 530–542 (2015). https://doi.org/10.1038/nrg3966

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