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.

Assisted reproductive technologies to prevent human mitochondrial disease transmission

A Corrigendum to this article was published on 06 July 2018

A Corrigendum to this article was published on 06 February 2018

This article has been updated

Abstract

Mitochondria are essential cytoplasmic organelles that generate energy (ATP) by oxidative phosphorylation and mediate key cellular processes such as apoptosis. They are maternally inherited and in humans contain a 16,569-base-pair circular genome (mtDNA) encoding 37 genes required for oxidative phosphorylation. Mutations in mtDNA cause a range of pathologies, commonly affecting energy-demanding tissues such as muscle and brain. Because mitochondrial diseases are incurable, attention has focused on limiting the inheritance of pathogenic mtDNA by mitochondrial replacement therapy (MRT). MRT aims to avoid pathogenic mtDNA transmission between generations by maternal spindle transfer, pronuclear transfer or polar body transfer: all involve the transfer of nuclear DNA from an egg or zygote containing defective mitochondria to a corresponding egg or zygote with normal mitochondria. Here we review recent developments in animal and human models of MRT and the underlying biology. These have led to potential clinical applications; we identify challenges to their technical refinement.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Genetic map of mtDNA showing positions and nomenclature of mutations and population haplogroups.
Figure 2: Migration patterns of mitochondrial haplogroups.
Figure 3: Distribution patterns of mutated mtDNA in oocytes in three families with pathogenic mutations.
Figure 4: Protocols for mitochondrial replacement therapy.

Change history

  • 14 December 2017

    In the version of this article initially published, in Table 2, first column, “m.13095T > C” should have been “m.130bT > C,” where “b” refers to the footnote “Characters hidden to respect confidentiality,” as with the other three from the Newcastle Group. In addition, the footnote “a” for Table 2 should have read “http://hfeaarchive.uksouth.cloudapp.azure.com/www.hfea.gov.uk/docs/Fourth_scientific_review_mitochondria_2016.pdf” rather than “Personal communication.” The following acknowledgment was omitted: “The authors thank Rob Taylor, Charlotte Alston, Emma Watson, Sam Byerley, Jane Stewart and Robert McFarland (Wellcome Centre for Mitochondrial Research Newcastle University and Newcastle upon Tyne Hospitals NHS Foundation Trust) for unpublished data included in Table 2.” The errors have been corrected in the HTML and PDF versions of the article.

References

  1. 1

    Chinnery, P.F. & Hudson, G. Mitochondrial genetics. Br. Med. Bull. 106, 135–159 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    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).

    Article  CAS  Google Scholar 

  3. 3

    Otten, A.B. & Smeets, H.J. Evolutionary defined role of the mitochondrial DNA in fertility, disease and ageing. Hum. Reprod. Update 21, 671–689 (2015).

    Article  CAS  Google Scholar 

  4. 4

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

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

    Article  CAS  Google Scholar 

  6. 6

    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).

    Article  CAS  Google Scholar 

  7. 7

    Song, W.H., Ballard, J.W., Yi, Y.J. & Sutovsky, P. Regulation of mitochondrial genome inheritance by autophagy and ubiquitin-proteasome system: implications for health, fitness, and fertility. BioMed Res. Int. 2014, 981867 (2014).

    PubMed  PubMed Central  Google Scholar 

  8. 8

    Kaneda, H. et al. Elimination of paternal mitochondrial DNA in intraspecific crosses during early mouse embryogenesis. Proc. Natl. Acad. Sci. USA 92, 4542–4546 (1995).

    Article  CAS  Google Scholar 

  9. 9

    Shitara, H. et al. Selective and continuous elimination of mitochondria microinjected into mouse eggs from spermatids, but not from liver cells, occurs throughout embryogenesis. Genetics 156, 1277–1284 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Song, W.H., Yi, Y.J., Sutovsky, M., Meyers, S. & Sutovsky, P. Autophagy and ubiquitin-proteasome system contribute to sperm mitophagy after mammalian fertilization. Proc. Natl. Acad. Sci. USA 113, E5261–E5270 (2016).

    Article  CAS  Google Scholar 

  11. 11

    Luo, S.M. et al. Unique insights into maternal mitochondrial inheritance in mice. Proc. Natl. Acad. Sci. USA 110, 13038–13043 (2013).

    Article  Google Scholar 

  12. 12

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

    Article  CAS  Google Scholar 

  13. 13

    Caporali, L. et al. Incomplete penetrance in mitochondrial optic neuropathies. Mitochondrion 36, 130–137 (2017).

    Article  CAS  Google Scholar 

  14. 14

    Poulton, J., Finsterer, J. & Yu Wai Man, P. Genetic counselling for maternally inherited mitochondrial disorders. Mol. Diagn. Ther. 21, 419–429 (2017).

    Article  Google Scholar 

  15. 15

    Steffann, J. et al. Analysis of mtDNA variant segregation during early human embryonic development: a tool for successful NARP preimplantation diagnosis. J. Med. Genet. 43, 244–247 (2006).

    Article  CAS  Google Scholar 

  16. 16

    Mitalipov, S., Amato, P., Parry, S. & Falk, M.J. Limitations of preimplantation genetic diagnosis for mitochondrial DNA diseases. Cell Reports 7, 935–937 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Mann, J.R. & Lovell-Badge, R.H. Inviability of parthenogenones is determined by pronuclei, not egg cytoplasm. Nature 310, 66–67 (1984).

    Article  CAS  Google Scholar 

  18. 18

    Kimura, Y. & Yanagimachi, R. Development of normal mice from oocytes injected with secondary spermatocyte nuclei. Biol. Reprod. 53, 855–862 (1995).

    Article  CAS  Google Scholar 

  19. 19

    Wang, M.K., Chen, D.Y., Liu, J.L., Li, G.P. & Sun, Q.Y. In vitro fertilisation of mouse oocytes reconstructed by transfer of metaphase II chromosomes results in live births. Zygote 9, 9–14 (2001).

    Article  Google Scholar 

  20. 20

    Wakayama, T. & Yanagimachi, R. The first polar body can be used for the production of normal offspring in mice. Biol. Reprod. 59, 100–104 (1998).

    Article  CAS  Google Scholar 

  21. 21

    Wakayama, T., Hayashi, Y. & Ogura, A. Participation of the female pronucleus derived from the second polar body in full embryonic development of mice. J. Reprod. Fertil. 110, 263–266 (1997).

    Article  CAS  Google Scholar 

  22. 22

    Wakayama, T., Perry, A.C., Zuccotti, M., Johnson, K.R. & Yanagimachi, R. Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei. Nature 394, 369–374 (1998).

    Article  CAS  Google Scholar 

  23. 23

    Inoue, K. et al. Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes. Nat. Genet. 26, 176–181 (2000).

    Article  CAS  Google Scholar 

  24. 24

    Nakada, K., Inoue, K. & Hayashi, J.I. Mito-mice: animal models for mitochondrial DNA-based diseases. Semin. Cell Dev. Biol. 12, 459–465 (2001).

    Article  CAS  Google Scholar 

  25. 25

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

    Article  CAS  Google Scholar 

  26. 26

    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).

    Article  CAS  Google Scholar 

  27. 27

    Kauppila, T.E.S., Kauppila, J.H.K. & Larsson, N.G. Mammalian mitochondria and aging: an update. Cell Metab. 25, 57–71 (2017).

    Article  CAS  Google Scholar 

  28. 28

    Hayashi, J.I., Hashizume, O., Ishikawa, K. & Shimizu, A. Mutations in mitochondrial DNA regulate mitochondrial diseases and metastasis but do not regulate aging. Curr. Opin. Genet. Dev. 38, 63–67 (2016).

    Article  CAS  Google Scholar 

  29. 29

    Latorre-Pellicer, A. et al. Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing. Nature 535, 561–565 (2016).

    Article  CAS  Google Scholar 

  30. 30

    Saben, J.L. et al. Maternal metabolic syndrome programs mitochondrial dysfunction via germline changes across three generations. Cell Rep. 16, 1–8 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Boudoures, A.L. et al. Obesity-exposed oocytes accumulate and transmit damaged mitochondria due to an inability to activate mitophagy. Dev. Biol. 426, 126–138 (2017).

    Article  CAS  Google Scholar 

  32. 32

    Ma, H. et al. Incompatibility between nuclear and mitochondrial genomes contributes to an interspecies reproductive barrier. Cell Metab. 24, 283–294 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Lee, H.S. et al. Rapid mitochondrial DNA segregation in primate preimplantation embryos precedes somatic and germline bottleneck. Cell Rep. 1, 506–515 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Wang, T. et al. Polar body genome transfer for preventing the transmission of inherited mitochondrial diseases. Cell 157, 1591–1604 (2014).

    Article  CAS  Google Scholar 

  35. 35

    Tachibana, M. et al. Towards germline gene therapy of inherited mitochondrial diseases. Nature 493, 627–631 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Paull, D. et al. Nuclear genome transfer in human oocytes eliminates mitochondrial DNA variants. Nature 493, 632–637 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Craven, L. et al. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature 465, 82–85 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Kang, E. et al. Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations. Nature 540, 270–275 (2016).

    Article  CAS  Google Scholar 

  39. 39

    Yamada, M. et al. Genetic drift can compromise mitochondrial replacement by nuclear transfer in human oocytes. Cell Stem Cell 18, 749–754 (2016).

    Article  CAS  Google Scholar 

  40. 40

    Hyslop, L.A. et al. Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease. Nature 534, 383–386 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Ma, H. et al. Functional Human Oocytes Generated by Transfer of Polar Body Genomes. Cell Stem Cell 20, 112–119 (2017).

    Article  CAS  Google Scholar 

  42. 42

    Yamada, M. et al. Human oocytes reprogram adult somatic nuclei of a type 1 diabetic to diploid pluripotent stem cells. Nature 510, 533–536 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Palacios-González, C. & Medina-Arellano, M.J. Mitochondrial replacement techniques and Mexico's rule of law: on the legality of the first maternal spindle transfer case. J. Law Biosci. 4, 50–69 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Ishii, T. Potential impact of human mitochondrial replacement on global policy regarding germline gene modification. Reprod. Biomed. Online 29, 150–155 (2014).

    Article  Google Scholar 

  45. 45

    Zhang, J. et al. Pregnancy derived from human zygote pronuclear transfer in a patient who had arrested embryos after IVF. Reprod. Biomed. Online 33, 529–533 (2016).

    Article  Google Scholar 

  46. 46

    Zhang, J. et al. Live birth derived from oocyte spindle transfer to prevent mitochondrial disease. Reprod. Biomed. Online 34, 361–368 (2017).

    Article  Google Scholar 

  47. 47

    Alikani, M., Fauser, B.C.J., García-Valesco, J.A., Simpson, J.L. & Johnson, M.H. First birth following spindle transfer for mitochondrial replacement therapy: hope and trepidation. Reprod. Biomed. Online 34, 333–336 (2017).

    Article  Google Scholar 

  48. 48

    Quirós, P.M., Mottis, A. & Auwerx, J. Mitonuclear communication in homeostasis and stress. Nat. Rev. Mol. Cell Biol. 17, 213–226 (2016).

    Article  CAS  Google Scholar 

  49. 49

    Akman, G. et al. Pathological ribonuclease H1 causes R-loop depletion and aberrant DNA segregation in mitochondria. Proc. Natl. Acad. Sci. USA 113, E4276–E4285 (2016).

    Article  CAS  Google Scholar 

  50. 50

    Wolf, D.P., Hayama, T. & Mitalipov, S. Mitochondrial genome inheritance and replacement in the human germline. EMBO J. 36, 2659 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Reddy, P. et al. Selective elimination of mitochondrial mutations in the germline by genome editing. Cell 161, 459–469 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

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

    Article  Google Scholar 

  53. 53

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Li, M., Schröder, R., Ni, S., Madea, B. & Stoneking, M. Extensive tissue-related and allele-related mtDNA heteroplasmy suggests positive selection for somatic mutations. Proc. Natl. Acad. Sci. USA 112, 2491–2496 (2015).

    Article  CAS  Google Scholar 

  55. 55

    Eyre-Walker, A. Mitochondrial replacement therapy: are mito-nuclear interactions likely to be a problem? Genetics 205, 1365–1372 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  56. 56

    Rishishwar, L. & Jordan, I.K. Implications of human evolution and admixture for mitochondrial replacement therapy. BMC Genomics 18, 140 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Ledford, H. AstraZeneca launches project to sequence 2 million genomes. Nature 532, 427 (2016).

    Article  Google Scholar 

  58. 58

    Sallevelt, S.C. et al. De novo mtDNA point mutations are common and have a low recurrence risk. J. Med. Genet. 54, 73–83 (2017).

    Article  Google Scholar 

  59. 59

    Dalton, C.M. & Carroll, J. Biased inheritance of mitochondria during asymmetric cell division in the mouse oocyte. J. Cell Sci. 126, 2955–2964 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Steuerwald, N. et al. Quantification of mtDNA in single oocytes, polar bodies and subcellular components by real-time rapid cycle fluorescence monitored PCR. Zygote 8, 209–215 (2000).

    Article  CAS  Google Scholar 

  61. 61

    Gammage, P.A. et al. Near-complete elimination of mutant mtDNA by iterative or dynamic dose-controlled treatment with mtZFNs. Nucleic Acids Res. 44, 7804–7816 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Jo, A. et al. Efficient mitochondrial genome editing by CRISPR/Cas9. BioMed Res. Int. 2015, 305716 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Katayama, M. et al. Mitochondrial distribution and microtubule organization in fertilized and cloned porcine embryos: implications for developmental potential. Dev. Biol. 299, 206–220 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Shoji, S. et al. Mammalian Emi2 mediates cytostatic arrest and transduces the signal for meiotic exit via Cdc20. EMBO J. 25, 834–845 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Koutsopoulos, O.S. et al. Human Miltons associate with mitochondria and induce microtubule-dependent remodeling of mitochondrial networks. Biochim. Biophys. Acta 1803, 564–574 (2010).

    Article  CAS  Google Scholar 

  66. 66

    Azoury, J. et al. Spindle positioning in mouse oocytes relies on a dynamic meshwork of actin filaments. Curr. Biol. 18, 1514–1519 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Chaigne, A. et al. F-actin mechanics control spindle centring in the mouse zygote. Nat. Commun. 7, 10253 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Hikabe, O. et al. Reconstitution in vitro of the entire cycle of the mouse female germ line. Nature 539, 299–303 (2016).

    Article  CAS  Google Scholar 

  69. 69

    Ma, H. et al. Metabolic rescue in pluripotent cells from patients with mtDNA disease. Nature 524, 234–238 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Cross, P.C. & Brinster, R.L. In vitro development of mouse oocytes. Biol. Reprod. 3, 298–307 (1970).

    Article  CAS  Google Scholar 

  71. 71

    Cha, K.Y. et al. Pregnancy after in vitro fertilization of human follicular oocytes collected from nonstimulated cycles, their culture in vitro and their transfer in a donor oocyte program. Fertil. Steril. 55, 109–113 (1991).

    Article  CAS  Google Scholar 

  72. 72

    Bredenoord, A.L. & Hyun, I. Ethics of stem cell-derived gametes made in a dish: fertility for everyone? EMBO Mol. Med. 9, 396–398 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Cohen, I.G., Daley, G.Q. & Adashi, E.Y. Disruptive reproductive technologies. Sci. Transl. Med. 9, eaag2959 (2017).

    Article  Google Scholar 

  74. 74

    Palacios-González, C. Mitochondrial replacement techniques: egg donation, genealogy and eugenics. Monash Bioeth. Rev. 34, 37–51 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Appleby, J.B., Scott, R. & Wilkinson, S. The ethics of mitochondrial replacement. Bioethics 31, 2–6 (2017).

    Article  Google Scholar 

  76. 76

    Nuffield Council on Bioethics. Novel techniques for the prevention of mitochondrial DNA disorders: an ethical review http://nuffieldbioethics.org/project/mitochondrial-dna-disorders (2012).

  77. 77

    Gleicher, N., Kushnir, V., Albertini, D. & Barad, D. First birth following spindle cell transfer. Reprod. Biomed. Online https://dx.doi.org/10.1016/j.rbmo.2017.07.006 (2017).

  78. 78

    Liao, S.M. Do mitochondrial replacement techniques affect qualitative or numerical identity? Bioethics 31, 20–26 (2017).

    Article  Google Scholar 

  79. 79

    Newson, A.J. & Wrigley, A. Is mitochondrial donation germ-line gene therapy? classifications and ethical implications. Bioethics 31, 55–67 (2017).

    Article  Google Scholar 

  80. 80

    Bredenoord, A.L. & Appleby, J.B. Mitochondrial replacement techniques: remaining ethical challenges. Cell Stem Cell 21, 301–304 (2017).

    Article  CAS  Google Scholar 

  81. 81

    Wallace, D.C. & Chalkia, D. Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harb. Perspect. Biol. 5, a021220 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Thorburn, D., Wilton, L. & Stock-Myers, S. Healthy baby girl born following pre-implantation genetic diagnosis for mitochondrial DNA m.8993t>g mutation. Mol. Genet. Metab. 98, 5–6 (2009).

    Google Scholar 

  83. 83

    Monnot, S. et al. Segregation of mtDNA throughout human embryofetal development: m.3243A>G as a model system. Hum. Mutat. 32, 116–125 (2011).

    Article  CAS  Google Scholar 

  84. 84

    Treff, N.R. et al. Blastocyst preimplantation genetic diagnosis (PGD) of a mitochondrial DNA disorder. Fertil. Steril. 98, 1236–1240 (2012).

    Article  CAS  Google Scholar 

  85. 85

    Sallevelt, S.C. et al. Preimplantation genetic diagnosis in mitochondrial DNA disorders: challenge and success. J. Med. Genet. 50, 125–132 (2013).

    Article  CAS  Google Scholar 

  86. 86

    Steffann, J. et al. Data from artificial models of mitochondrial DNA disorders are not always applicable to humans. Cell Rep. 7, 933–934 (2014).

    Article  CAS  Google Scholar 

  87. 87

    Heindryckx, B. et al. Mutation-free baby born from a mitochondrial encephalopathy, lactic acidosis and stroke-like syndrome carrier after blastocyst trophectoderm preimplantation genetic diagnosis. Mitochondrion 18, 12–17 (2014).

    Article  CAS  Google Scholar 

  88. 88

    Kondoh, H., Lleonart, M.E., Bernard, D. & Gil, J. Protection from oxidative stress by enhanced glycolysis; a possible mechanism of cellular immortalization. Histol. Histopathol. 22, 85–90 (2007).

    CAS  PubMed  Google Scholar 

  89. 89

    Bernstein, B.E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

    Article  CAS  Google Scholar 

  90. 90

    Tucker, K.L., Talbot, D., Lee, M.A., Leonhardt, H. & Jaenisch, R. Complementation of methylation deficiency in embryonic stem cells by a DNA methyltransferase minigene. Proc. Natl. Acad. Sci. USA 93, 12920–12925 (1996).

    Article  CAS  Google Scholar 

  91. 91

    Eggan, K. et al. Hybrid vigor, fetal overgrowth, and viability of mice derived by nuclear cloning and tetraploid embryo complementation. Proc. Natl. Acad. Sci. USA 98, 6209–6214 (2001).

    Article  CAS  Google Scholar 

  92. 92

    Matilainen, O., Quirós, P.M. & Auwerx, J. Mitochondria and epigenetics - crosstalk in homeostasis and stress. Trends Cell Biol. 27, 453–463 (2017).

    Article  CAS  Google Scholar 

  93. 93

    Yang, V.S. et al. Geminin escapes degradation in G1 of mouse pluripotent cells and mediates the expression of Oct4, Sox2, and Nanog. Curr. Biol. 21, 692–699 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Mishra, P. & Chan, D.C. Mitochondrial dynamics and inheritance during cell division, development and disease. Nat. Rev. Mol. Cell Biol. 15, 634–646 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Lonergan, T., Bavister, B. & Brenner, C. Mitochondria in stem cells. Mitochondrion 7, 289–296 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Prigione, A. & Adjaye, J. Modulation of mitochondrial biogenesis and bioenergetic metabolism upon in vitro and in vivo differentiation of human ES and iPS cells. Int. J. Dev. Biol. 54, 1729–1741 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Deglincerti, A., Etoc, F., Ozair, M.Z. & Brivanlou, A.H. Self-organization of spatial patterning in human embryonic stem cells. Curr. Top. Dev. Biol. 116, 99–113 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Shahbazi, M.N. et al. Self-organization of the human embryo in the absence of maternal tissues. Nat. Cell Biol. 18, 700–708 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

A.C.F.P. is grateful for support from the Medical Research Council, UK (grants MR/N000080/1 and MR/N020294/1). The authors thank Rob Taylor, Charlotte Alston, Emma Watson, Sam Byerley, Jane Stewart and Robert McFarland (Wellcome Centre for Mitochondrial Research Newcastle University and Newcastle upon Tyne Hospitals NHS Foundation Trust) for unpublished data included in Table 2.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Andy Greenfield.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Greenfield, A., Braude, P., Flinter, F. et al. Assisted reproductive technologies to prevent human mitochondrial disease transmission. Nat Biotechnol 35, 1059–1068 (2017). https://doi.org/10.1038/nbt.3997

Download citation

Further reading

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