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. 2004 Jun;167(2):897–905. doi: 10.1534/genetics.103.025049

Paternal mitochondrial DNA transmission during nonhuman primate nuclear transfer.

Justin C St John 1, Gerald Schatten 1
PMCID: PMC1470892  PMID: 15238538

Abstract

Offspring produced by nuclear transfer (NT) have identical nuclear DNA (nDNA). However, mitochondrial DNA (mtDNA) inheritance could vary considerably. In sheep, homoplasmy is maintained since mtDNA is transmitted from the oocyte (recipient) only. In contrast, cattle are heteroplasmic, harboring a predominance of recipient mtDNA along with varying levels of donor mtDNA. We show that the two nonhuman primate Macaca mulatta offspring born by NT have mtDNA from three sources: (1) maternal mtDNA from the recipient egg, (2) maternal mtDNA from the egg contributing to the donor blastomere, and (3) paternal mtDNA from the sperm that fertilized the egg from which the donor blastomere was isolated. The introduction of foreign mtDNA into reconstructed recipient eggs has also been demonstrated in mice through pronuclear injection and in humans through cytoplasmic transfer. The mitochondrial triplasmy following M. mulatta NT reported here forces concerns regarding the parental origins of mtDNA in clinically reconstructed eggs. In addition, mtDNA heteroplasmy might result in the embryonic stem cell lines generated for experimental and therapeutic purposes ("therapeutic cloning").

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Selected References

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  1. Ankel-Simons F., Cummins J. M. Misconceptions about mitochondria and mammalian fertilization: implications for theories on human evolution. Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13859–13863. doi: 10.1073/pnas.93.24.13859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baguisi A., Behboodi E., Melican D. T., Pollock J. S., Destrempes M. M., Cammuso C., Williams J. L., Nims S. D., Porter C. A., Midura P. Production of goats by somatic cell nuclear transfer. Nat Biotechnol. 1999 May;17(5):456–461. doi: 10.1038/8632. [DOI] [PubMed] [Google Scholar]
  3. Barritt Jason A., Brenner Carol A., Malter Henry E., Cohen Jacques. Rebuttal: interooplasmic transfers in humans. Reprod Biomed Online. 2001;3(1):47–48. doi: 10.1016/s1472-6483(10)61966-9. [DOI] [PubMed] [Google Scholar]
  4. Birky C. W., Jr The inheritance of genes in mitochondria and chloroplasts: laws, mechanisms, and models. Annu Rev Genet. 2001;35:125–148. doi: 10.1146/annurev.genet.35.102401.090231. [DOI] [PubMed] [Google Scholar]
  5. Birky C. W., Jr Uniparental inheritance of mitochondrial and chloroplast genes: mechanisms and evolution. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11331–11338. doi: 10.1073/pnas.92.25.11331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brenner C. A., Barritt J. A., Willadsen S., Cohen J. Mitochondrial DNA heteroplasmy after human ooplasmic transplantation. Fertil Steril. 2000 Sep;74(3):573–578. doi: 10.1016/s0015-0282(00)00681-6. [DOI] [PubMed] [Google Scholar]
  7. Campbell K. H., McWhir J., Ritchie W. A., Wilmut I. Sheep cloned by nuclear transfer from a cultured cell line. Nature. 1996 Mar 7;380(6569):64–66. doi: 10.1038/380064a0. [DOI] [PubMed] [Google Scholar]
  8. Chesné Patrick, Adenot Pierre G., Viglietta Céline, Baratte Michel, Boulanger Laurent, Renard Jean-Paul. Cloned rabbits produced by nuclear transfer from adult somatic cells. Nat Biotechnol. 2002 Apr;20(4):366–369. doi: 10.1038/nbt0402-366. [DOI] [PubMed] [Google Scholar]
  9. Cummins J. M., Jequier A. M., Martin R., Mehmet D., Goldblatt J. Semen levels of mitochondrial DNA deletions in men attending an infertility clinic do not correlate with phenotype. Int J Androl. 1998 Feb;21(1):47–52. doi: 10.1046/j.1365-2605.1998.00093.x. [DOI] [PubMed] [Google Scholar]
  10. Cummins J. M., Kishikawa H., Mehmet D., Yanagimachi R. Fate of genetically marked mitochondrial DNA from spermatocytes microinjected into mouse zygotes. Zygote. 1999 May;7(2):151–156. doi: 10.1017/s0967199499000519. [DOI] [PubMed] [Google Scholar]
  11. Cummins J. M., Wakayama T., Yanagimachi R. Fate of microinjected sperm components in the mouse oocyte and embryo. Zygote. 1997 Nov;5(4):301–308. doi: 10.1017/s0967199400003889. [DOI] [PubMed] [Google Scholar]
  12. Cummins J. M., Wakayama T., Yanagimachi R. Fate of microinjected spermatid mitochondria in the mouse oocyte and embryo. Zygote. 1998 Aug;6(3):213–222. doi: 10.1017/s0967199498000148. [DOI] [PubMed] [Google Scholar]
  13. Dey R., Barrientos A., Moraes C. T. Functional constraints of nuclear-mitochondrial DNA interactions in xenomitochondrial rodent cell lines. J Biol Chem. 2000 Oct 6;275(40):31520–31527. doi: 10.1074/jbc.M004053200. [DOI] [PubMed] [Google Scholar]
  14. Evans M. J., Gurer C., Loike J. D., Wilmut I., Schnieke A. E., Schon E. A. Mitochondrial DNA genotypes in nuclear transfer-derived cloned sheep. Nat Genet. 1999 Sep;23(1):90–93. doi: 10.1038/12696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gabriel Sánchez-Partida L., Maginnis G., Dominko T., Martinovich C., McVay B., Fanton J., Schatten G. Live rhesus offspring by artificial insemination using fresh sperm and cryopreserved sperm. Biol Reprod. 2000 Oct;63(4):1092–1097. doi: 10.1095/biolreprod63.4.1092. [DOI] [PubMed] [Google Scholar]
  16. Giles R. E., Blanc H., Cann H. M., Wallace D. C. Maternal inheritance of human mitochondrial DNA. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6715–6719. doi: 10.1073/pnas.77.11.6715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gyllensten U., Wharton D., Josefsson A., Wilson A. C. Paternal inheritance of mitochondrial DNA in mice. Nature. 1991 Jul 18;352(6332):255–257. doi: 10.1038/352255a0. [DOI] [PubMed] [Google Scholar]
  18. Hewitson L., Dominko T., Takahashi D., Martinovich C., Ramalho-Santos J., Sutovsky P., Fanton J., Jacob D., Monteith D., Neuringer M. Unique checkpoints during the first cell cycle of fertilization after intracytoplasmic sperm injection in rhesus monkeys. Nat Med. 1999 Apr;5(4):431–433. doi: 10.1038/7430. [DOI] [PubMed] [Google Scholar]
  19. Hiendleder S., Schmutz S. M., Erhardt G., Green R. D., Plante Y. Transmitochondrial differences and varying levels of heteroplasmy in nuclear transfer cloned cattle. Mol Reprod Dev. 1999 Sep;54(1):24–31. doi: 10.1002/(SICI)1098-2795(199909)54:1<24::AID-MRD4>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
  20. Hoeh W. R., Blakley K. H., Brown W. M. Heteroplasmy suggests limited biparental inheritance of Mytilus mitochondrial DNA. Science. 1991 Mar 22;251(5000):1488–1490. doi: 10.1126/science.1672472. [DOI] [PubMed] [Google Scholar]
  21. Holyoake A. J., McHugh P., Wu M., O'Carroll S., Benny P., Sin I. L., Sin F. Y. High incidence of single nucleotide substitutions in the mitochondrial genome is associated with poor semen parameters in men. Int J Androl. 2001 Jun;24(3):175–182. doi: 10.1046/j.1365-2605.2001.00292.x. [DOI] [PubMed] [Google Scholar]
  22. Holyoake A. J., Sin I. L., Benny P. S., Sin F. Y. Association of a novel human mtDNA ATPase6 mutation with immature sperm cells. Andrologia. 1999 Dec;31(6):339–345. doi: 10.1046/j.1439-0272.1999.00150.x. [DOI] [PubMed] [Google Scholar]
  23. Hopgood R., Sullivan K. M., Gill P. Strategies for automated sequencing of human mitochondrial DNA directly from PCR products. Biotechniques. 1992 Jul;13(1):82–92. [PubMed] [Google Scholar]
  24. Ivanov P. L., Wadhams M. J., Roby R. K., Holland M. M., Weedn V. W., Parsons T. J. Mitochondrial DNA sequence heteroplasmy in the Grand Duke of Russia Georgij Romanov establishes the authenticity of the remains of Tsar Nicholas II. Nat Genet. 1996 Apr;12(4):417–420. doi: 10.1038/ng0496-417. [DOI] [PubMed] [Google Scholar]
  25. Jansen R. P., de Boer K. The bottleneck: mitochondrial imperatives in oogenesis and ovarian follicular fate. Mol Cell Endocrinol. 1998 Oct 25;145(1-2):81–88. doi: 10.1016/s0303-7207(98)00173-7. [DOI] [PubMed] [Google Scholar]
  26. Jenuth J. P., Peterson A. C., Fu K., Shoubridge E. A. Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA. Nat Genet. 1996 Oct;14(2):146–151. doi: 10.1038/ng1096-146. [DOI] [PubMed] [Google Scholar]
  27. Kaneda H., Hayashi J., Takahama S., Taya C., Lindahl K. F., Yonekawa H. Elimination of paternal mitochondrial DNA in intraspecific crosses during early mouse embryogenesis. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4542–4546. doi: 10.1073/pnas.92.10.4542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kao S. H., Chao H. T., Wei Y. H. Multiple deletions of mitochondrial DNA are associated with the decline of motility and fertility of human spermatozoa. Mol Hum Reprod. 1998 Jul;4(7):657–666. doi: 10.1093/molehr/4.7.657. [DOI] [PubMed] [Google Scholar]
  29. Kao S., Chao H. T., Wei Y. H. Mitochondrial deoxyribonucleic acid 4977-bp deletion is associated with diminished fertility and motility of human sperm. Biol Reprod. 1995 Apr;52(4):729–736. doi: 10.1095/biolreprod52.4.729. [DOI] [PubMed] [Google Scholar]
  30. Kitiyanant Yindee, Saikhun Jumnian, Pavasuthipaisit Kanok. Somatic cell nuclear transfer in domestic cat oocytes treated with IGF-I for in vitro maturation. Theriogenology. 2003 Apr 15;59(8):1775–1786. doi: 10.1016/s0093-691x(02)01235-9. [DOI] [PubMed] [Google Scholar]
  31. Kondo R., Matsuura E. T., Chigusa S. I. Further observation of paternal transmission of Drosophila mitochondrial DNA by PCR selective amplification method. Genet Res. 1992 Apr;59(2):81–84. doi: 10.1017/s0016672300030287. [DOI] [PubMed] [Google Scholar]
  32. Laipis P. J. Construction of heteroplasmic mice containing two mitochondrial DNA genotypes by micromanipulation of single-cell embryos. Methods Enzymol. 1996;264:345–357. doi: 10.1016/s0076-6879(96)64033-6. [DOI] [PubMed] [Google Scholar]
  33. Larsson N. G., Oldfors A., Holme E., Clayton D. A. Low levels of mitochondrial transcription factor A in mitochondrial DNA depletion. Biochem Biophys Res Commun. 1994 May 16;200(3):1374–1381. doi: 10.1006/bbrc.1994.1603. [DOI] [PubMed] [Google Scholar]
  34. Lestienne P., Reynier P., Chrétien M. F., Penisson-Besnier I., Malthièry Y., Rohmer V. Oligoasthenospermia associated with multiple mitochondrial DNA rearrangements. Mol Hum Reprod. 1997 Sep;3(9):811–814. doi: 10.1093/molehr/3.9.811. [DOI] [PubMed] [Google Scholar]
  35. McKenzie M., Trounce I. Expression of Rattus norvegicus mtDNA in Mus musculus cells results in multiple respiratory chain defects. J Biol Chem. 2000 Oct 6;275(40):31514–31519. doi: 10.1074/jbc.M004070200. [DOI] [PubMed] [Google Scholar]
  36. Meirelles F. V., Smith L. C. Mitochondrial genotype segregation in a mouse heteroplasmic lineage produced by embryonic karyoplast transplantation. Genetics. 1997 Feb;145(2):445–451. doi: 10.1093/genetics/145.2.445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Petri B., von Haeseler A., Päbo S. Extreme sequence heteroplasmy in bat mitochondrial DNA. Biol Chem. 1996 Oct;377(10):661–667. doi: 10.1515/bchm3.1996.377.10.661. [DOI] [PubMed] [Google Scholar]
  38. Polejaeva I. A., Chen S. H., Vaught T. D., Page R. L., Mullins J., Ball S., Dai Y., Boone J., Walker S., Ayares D. L. Cloned pigs produced by nuclear transfer from adult somatic cells. Nature. 2000 Sep 7;407(6800):86–90. doi: 10.1038/35024082. [DOI] [PubMed] [Google Scholar]
  39. Poulton J., Morten K., Freeman-Emmerson C., Potter C., Sewry C., Dubowitz V., Kidd H., Stephenson J., Whitehouse W., Hansen F. J. Deficiency of the human mitochondrial transcription factor h-mtTFA in infantile mitochondrial myopathy is associated with mtDNA depletion. Hum Mol Genet. 1994 Oct;3(10):1763–1769. doi: 10.1093/hmg/3.10.1763. [DOI] [PubMed] [Google Scholar]
  40. Reynier P., Chrétien M. F., Savagner F., Larcher G., Rohmer V., Barrière P., Malthièry Y. Long PCR analysis of human gamete mtDNA suggests defective mitochondrial maintenance in spermatozoa and supports the bottleneck theory for oocytes. Biochem Biophys Res Commun. 1998 Nov 18;252(2):373–377. doi: 10.1006/bbrc.1998.9651. [DOI] [PubMed] [Google Scholar]
  41. Seibel P., Flierl A., Kottlors M., Reichmann H. A rapid and sensitive PCR screening method for point mutations associated with mitochondrial encephalomyopathies. Biochem Biophys Res Commun. 1994 Apr 29;200(2):938–942. doi: 10.1006/bbrc.1994.1540. [DOI] [PubMed] [Google Scholar]
  42. Shitara H., Hayashi J. I., Takahama S., Kaneda H., Yonekawa H. Maternal inheritance of mouse mtDNA in interspecific hybrids: segregation of the leaked paternal mtDNA followed by the prevention of subsequent paternal leakage. Genetics. 1998 Feb;148(2):851–857. doi: 10.1093/genetics/148.2.851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Spiropoulos John, Turnbull Douglass M., Chinnery Patrick F. Can mitochondrial DNA mutations cause sperm dysfunction? Mol Hum Reprod. 2002 Aug;8(8):719–721. doi: 10.1093/molehr/8.8.719. [DOI] [PubMed] [Google Scholar]
  44. St John J. C., Jokhi R. P., Barratt C. L. Men with oligoasthenoteratozoospermia harbour higher numbers of multiple mitochondrial DNA deletions in their spermatozoa, but individual deletions are not indicative of overall aetiology. Mol Hum Reprod. 2001 Jan;7(1):103–111. doi: 10.1093/molehr/7.1.103. [DOI] [PubMed] [Google Scholar]
  45. St John J., Sakkas D., Dimitriadi K., Barnes A., Maclin V., Ramey J., Barratt C., De Jonge C. Failure of elimination of paternal mitochondrial DNA in abnormal embryos. Lancet. 2000 Jan 15;355(9199):200–200. doi: 10.1016/s0140-6736(99)03842-8. [DOI] [PubMed] [Google Scholar]
  46. St John Justin C., Lloyd Rhiannon, El Shourbagy Shahinaz. The potential risks of abnormal transmission of mtDNA through assisted reproductive technologies. Reprod Biomed Online. 2004 Jan;8(1):34–44. doi: 10.1016/s1472-6483(10)60496-8. [DOI] [PubMed] [Google Scholar]
  47. St John Justin C. Ooplasm donation in humans: the need to investigate the transmission of mitochondrial DNA following cytoplasmic transfer. Hum Reprod. 2002 Aug;17(8):1954–1958. doi: 10.1093/humrep/17.8.1954. [DOI] [PubMed] [Google Scholar]
  48. Steinborn R., Schinogl P., Zakhartchenko V., Achmann R., Schernthaner W., Stojkovic M., Wolf E., Müller M., Brem G. Mitochondrial DNA heteroplasmy in cloned cattle produced by fetal and adult cell cloning. Nat Genet. 2000 Jul;25(3):255–257. doi: 10.1038/77000. [DOI] [PubMed] [Google Scholar]
  49. Steinborn R., Zakhartchenko V., Jelyazkov J., Klein D., Wolf E., Müller M., Brem G. Composition of parental mitochondrial DNA in cloned bovine embryos. FEBS Lett. 1998 Apr 24;426(3):352–356. doi: 10.1016/s0014-5793(98)00350-0. [DOI] [PubMed] [Google Scholar]
  50. Steinborn R., Zakhartchenko V., Wolf E., Müller M., Brem G. Non-balanced mix of mitochondrial DNA in cloned cattle produced by cytoplast-blastomere fusion. FEBS Lett. 1998 Apr 24;426(3):357–361. doi: 10.1016/s0014-5793(98)00351-2. [DOI] [PubMed] [Google Scholar]
  51. Sutovsky P., Moreno R. D., Ramalho-Santos J., Dominko T., Simerly C., Schatten G. Ubiquitin tag for sperm mitochondria. Nature. 1999 Nov 25;402(6760):371–372. doi: 10.1038/46466. [DOI] [PubMed] [Google Scholar]
  52. Sutovsky P., Navara C. S., Schatten G. Fate of the sperm mitochondria, and the incorporation, conversion, and disassembly of the sperm tail structures during bovine fertilization. Biol Reprod. 1996 Dec;55(6):1195–1205. doi: 10.1095/biolreprod55.6.1195. [DOI] [PubMed] [Google Scholar]
  53. Takeda K., Takahashi S., Onishi A., Goto Y., Miyazawa A., Imai H. Dominant distribution of mitochondrial DNA from recipient oocytes in bovine embryos and offspring after nuclear transfer. J Reprod Fertil. 1999 Jul;116(2):253–259. doi: 10.1530/jrf.0.1160253. [DOI] [PubMed] [Google Scholar]
  54. Wakayama T., Rodriguez I., Perry A. C., Yanagimachi R., Mombaerts P. Mice cloned from embryonic stem cells. Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14984–14989. doi: 10.1073/pnas.96.26.14984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Wakayama T., Yanagimachi R. Mouse cloning with nucleus donor cells of different age and type. Mol Reprod Dev. 2001 Apr;58(4):376–383. doi: 10.1002/1098-2795(20010401)58:4<376::AID-MRD4>3.0.CO;2-L. [DOI] [PubMed] [Google Scholar]
  56. Wilmut I., Schnieke A. E., McWhir J., Kind A. J., Campbell K. H. Viable offspring derived from fetal and adult mammalian cells. Nature. 1997 Feb 27;385(6619):810–813. doi: 10.1038/385810a0. [DOI] [PubMed] [Google Scholar]

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