Maternally inherited mitochondrial (mt)DNA mutations can cause fatal or severely debilitating syndromes in children1,2,3, with disease severity dependent on the specific gene mutation and the ratio of mutant to wild-type mtDNA (heteroplasmy) in each cell and tissue4. Pathogenic mtDNA mutations are relatively common, with an estimated 778 affected children born each year in the United States5. Mitochondrial replacement therapies or techniques (MRT) circumventing mother–to–child mtDNA disease transmission involve replacement of oocyte maternal mtDNA6,7,8. 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 transfer8, 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.
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The authors acknowledge the OHSU Embryonic Stem Cell Research Oversight Committee and the Institutional Review Board for oversight and guidance. We thank all study participants for tissue donations and the Women’s Health Research Unit staff, University Fertility Consultants and the Reproductive Endocrinology and Infertility Division in the Department of Obstetrics and Gynecology, Oregon Health and Science University for support and procurement of human gametes. Studies were supported by the Leducq Foundation, OHSU institutional funds and Cincinnati Children’s Hospital Research Foundation. Work in the laboratory of J.C.I.B. was supported by the G. Harold and Leila Y. Mathers Charitable Foundation, the Leona M. and Harry B. Helmsley Charitable Trust and the Moxie Foundation. A.P.L. was partially supported by a fellowship from the Hewitt Foundation. P.M.R. was partially supported by a fellowship from Fundación Alfonso Martín Escudero.
Extended data figures
Sequence differences between egg donor haplotypes understudy by whole mtDNA sequencing (syn, synonymous; non-syn, nonsynonymous; frmshft, frameshift).
mtDNA variants in oocytes and somatic tissues from mutant carriers and children and healthy oocyte donors (syn, synonymous; non-syn,non- synonymous; frmshft, frameshift).
Maternal mtDNA analysis in ESCs derived from ST blastocysts (syn, synonymous; non-syn, non- synonymous; frmshft, frameshift).
Analysis of maternal mtDNA heteroplasmy in ESCs derived from somatic cell nuclear transfer (SCNT) blastocysts (syn, synonymous; nonsyn, non- synonymous; frmshft, frameshift).
Maternal mtDNA heteroplasmy changes in 18 ST-ES and 8NT-ES cell lines. Filtered reads were aligned to the human mitochondrial sequence reference NC_012920.1 followed by variant calling. Presented nucleotide positions indicate difference from the reference or between different human haplotypes.
About this article
Nature Biotechnology (2017)