Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations

Eunju Kang, Jun Wu, Nuria Marti Gutierrez, Amy Koski, Rebecca Tippner-Hedges, Karen Agaronyan, Aida Platero-Luengo, Paloma Martinez-Redondo, Hong Ma, Yeonmi Lee, Tomonari Hayama, Crystal Van Dyken, Xinjian Wang, Shiyu Luo, Riffat Ahmed, Ying Li, Dongmei Ji, Refik Kayali, Cengiz Cinnioglu, Susan OlsonJeffrey Jensen, David Battaglia, David Lee, Diana Wu, Taosheng Huang, Don P. Wolf, Dmitry Temiakov, Juan Carlos Izpisua Belmonte, Paula Amato, Shoukhrat Mitalipov

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84 Scopus citations

Abstract

Maternally inherited mitochondrial (mt)DNA mutations can cause fatal or severely debilitating syndromes in children, with disease severity dependent on the specific gene mutation and the ratio of mutant to wild-type mtDNA (heteroplasmy) in each cell and tissue. Pathogenic mtDNA mutations are relatively common, with an estimated 778 affected children born each year in the United States. Mitochondrial replacement therapies or techniques (MRT) circumventing mother-to-child mtDNA disease transmission involve replacement of oocyte maternal mtDNA. Here we report MRT outcomes in several families with common mtDNA syndromes. The mother's oocytes were of normal quality and mutation levels correlated with those in existing children. Efficient replacement of oocyte mutant mtDNA was performed by spindle transfer, resulting in embryos containing >99% donor mtDNA. Donor mtDNA was stably maintained in embryonic stem cells (ES cells) derived from most embryos. However, some ES cell lines demonstrated gradual loss of donor mtDNA and reversal to the maternal haplotype. In evaluating donor-to-maternal mtDNA interactions, it seems that compatibility relates to mtDNA replication efficiency rather than to mismatch or oxidative phosphorylation dysfunction. We identify a polymorphism within the conserved sequence box II region of the D-loop as a plausible cause of preferential replication of specific mtDNA haplotypes. In addition, some haplotypes confer proliferative and growth advantages to cells. Hence, we propose a matching paradigm for selecting compatible donor mtDNA for MRT.

Original languageEnglish (US)
Pages (from-to)270-275
Number of pages6
JournalNature
Volume540
Issue number7632
DOIs
StatePublished - Dec 8 2016

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ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Kang, E., Wu, J., Gutierrez, N. M., Koski, A., Tippner-Hedges, R., Agaronyan, K., Platero-Luengo, A., Martinez-Redondo, P., Ma, H., Lee, Y., Hayama, T., Van Dyken, C., Wang, X., Luo, S., Ahmed, R., Li, Y., Ji, D., Kayali, R., Cinnioglu, C., ... Mitalipov, S. (2016). Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations. Nature, 540(7632), 270-275. https://doi.org/10.1038/nature20592