Letter | Published:

Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease

Nature volume 465, pages 8285 (06 May 2010) | Download Citation


Mutations in mitochondrial DNA (mtDNA) are a common cause of genetic disease. Pathogenic mutations in mtDNA are detected in approximately 1 in 250 live births1,2,3 and at least 1 in 10,000 adults in the UK are affected by mtDNA disease4. Treatment options for patients with mtDNA disease are extremely limited and are predominantly supportive in nature. Mitochondrial DNA is transmitted maternally and it has been proposed that nuclear transfer techniques may be an approach for the prevention of transmission of human mtDNA disease5,6. Here we show that transfer of pronuclei between abnormally fertilized human zygotes results in minimal carry-over of donor zygote mtDNA and is compatible with onward development to the blastocyst stage in vitro. By optimizing the procedure we found the average level of carry-over after transfer of two pronuclei is less than 2.0%, with many of the embryos containing no detectable donor mtDNA. We believe that pronuclear transfer between zygotes, as well as the recently described metaphase II spindle transfer, has the potential to prevent the transmission of mtDNA disease in humans.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    , , , & Pathogenic mitochondrial DNA mutations are common in the general population. Am. J. Hum. Genet. 83, 254–260 (2008)

  2. 2.

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

  3. 3.

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

  4. 4.

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

  5. 5.

    et al. Gene therapy for progeny of mito-mice carrying pathogenic mtDNA by nuclear transplantation. Proc. Natl Acad. Sci. USA 102, 16765–16770 (2005)

  6. 6.

    et al. Transmission of mitochondrial DNA disorders: possibilities for the future. Lancet 368, 87–89 (2006)

  7. 7.

    Why do we still have a maternally inherited mitochondrial DNA? Insights from evolutionary medicine. Annu. Rev. Biochem. 76, 781–821 (2007)

  8. 8.

    & Mitochondrial disorders in the nervous system. Annu. Rev. Neurosci. 31, 91–123 (2008)

  9. 9.

    et al. The epidemiology of Leber hereditary optic neuropathy in the north east of England. Am. J. Hum. Genet. 72, 333–339 (2003)

  10. 10.

    & Mitochondrial DNA mutations in human disease. Nature Rev. Genet. 6, 389–402 (2005)

  11. 11.

    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)

  12. 12.

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

  13. 13.

    , , , & Quantification of human ooplasmic mitochondria. Reprod. Biomed. Online 4, 243–247 (2002)

  14. 14.

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

  15. 15.

    et al. The development of novel quantification assay for mitochondrial DNA heteroplasmy aimed at preimplantation genetic diagnosis of Leigh encephalopathy. J. Assist. Reprod. Genet. 24, 227–232 (2007)

  16. 16.

    et al. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 461, 367–372 (2009)

  17. 17.

    , , & Fertilization and early embryology: influence of maternal age on meiotic spindle assembly oocytes from naturally cycling women. Hum. Reprod. 11, 2217–2222 (1996)

  18. 18.

    & The effect of temperature fluctuations on the cytoskeletal organisation and chromosomal constitution of the human oocyte. Zygote 3, 357–365 (1995)

  19. 19.

    & Mitochondrial genotype segregation in a mouse heteroplasmic lineage produced by embryonic karyoplast transplantation. Genetics 145, 445–451 (1997)

  20. 20.

    & Can ‘abnormally’ fertilized zygotes give rise to viable embryos? Hum. Fertil. (Camb.) 9, 157–169 (2006)

  21. 21.

    , , & Treatment for mitochondrial disorders. Cochrane Database Syst. Rev. CD004426 (2006)

  22. 22.

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

  23. 23.

    , , & Decrease of 3243 A→G mtDNA mutation from blood in MELAS syndrome: a longitudinal study. Am. J. Hum. Genet. 68, 238–240 (2001)

  24. 24.

    et al. Adult phenotype in the mouse can be affected by epigenetic events in the early embryo. Development 119, 933–942 (1993)

  25. 25.

    , , & The determination of complete human mitochondrial DNA sequences in single cells: implications for the study of somatic mitochondrial DNA point mutations. Nucleic Acids Res. 29, e74 (2001)

  26. 26.

    et al. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nature Genet. 23, 147 (1999)

  27. 27.

    et al. A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 41, 1786–1796 (2003)

  28. 28.

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

  29. 29.

    et al. Detection and quantification of mitochondrial DNA deletions in individual cells by real-time PCR. Nucleic Acids Res. 30, e68 (2002)

  30. 30.

    , , & A multiplex real-time PCR method to detect and quantify mitochondrial DNA deletions in individual cells. Anal. Biochem. 370, 127–129 (2007)

Download references


We thank M. Nesbitt, L. Burgess and S. Byerley for help with embryo donation and collection, and V. Wilson and S. Abbs for help with the nuclear genotyping. We thank the patients and staff at Newcastle Fertility Centre, and J. Lawford-Davies, K. Stern, Sir John Burn and Lord Walton of Detchant for helping us to obtain a Human Fertilisation and Embryology Authority research licence and guidance with the legislation. This work was funded by the Muscular Dystrophy Campaign, the Wellcome Trust (074454/Z/04/Z), the Medical Research Council (G0601157, G0601943), One North East, the UK National Institute for Health Research Biomedical Research Centre for Ageing and Age-related Disease and the Newcastle University Centre for Brain Ageing and Vitality supported by the Biotechnology and Biological Sciences Research Council, the Engineering and Physical Sciences Research Council, the Economic and Social Research Council and the Medical Research Council (G0700718). P.F.C. is a Wellcome Trust Senior Fellow in Clinical Science.

Author information


  1. Mitochondrial Research Group, Institute for Ageing and Health,

    • Lyndsey Craven
    • , Helen A. Tuppen
    • , Julie L. Murphy
    • , Lynsey M. Cree
    • , Patrick F. Chinnery
    • , Robert W. Taylor
    • , Robert N. Lightowlers
    •  & Douglass M. Turnbull
  2. Newcastle University Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE2 4HH, UK

    • Douglass M. Turnbull
  3. Newcastle Fertility Centre, International Centre for Life,

    • Gareth D. Greggains
    • , Stephen J. Harbottle
    • , Alison P. Murdoch
    •  & Mary Herbert
  4. Institute for Ageing and Health, International Centre for Life,

    • Gareth D. Greggains
    •  & Mary Herbert
  5. North East England Stem Cell Institute (NESCI), Bioscience Centre, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 4EP, UK

    • Alison P. Murdoch
    • , Mary Herbert
    •  & Douglass M. Turnbull


  1. Search for Lyndsey Craven in:

  2. Search for Helen A. Tuppen in:

  3. Search for Gareth D. Greggains in:

  4. Search for Stephen J. Harbottle in:

  5. Search for Julie L. Murphy in:

  6. Search for Lynsey M. Cree in:

  7. Search for Alison P. Murdoch in:

  8. Search for Patrick F. Chinnery in:

  9. Search for Robert W. Taylor in:

  10. Search for Robert N. Lightowlers in:

  11. Search for Mary Herbert in:

  12. Search for Douglass M. Turnbull in:


M.H., A.P.M., R.N.L. and D.M.T. conceived the project and designed the experiments. L.C., H.A.T., S.J.H., G.D.G., J.L.M., L.M.C., P.F.C. and R.W.T. performed experiments and analysed data. L.C., M.H., H.A.T. and D.M.T. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Mary Herbert or Douglass M. Turnbull.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figure 1 with legend and Supplementary Tables 1-2.

About this article

Publication history






Further reading Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.