Journal Article

Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations

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

2016

Overview

Analysis of mitochondrial replacement therapy shows, even with efficient mutant mitochondrial DNA replacement and maintenance in embryonic stem cells, a gradual loss of donor mitochondrial DNA in some lines owing to a polymorphism in the D-loop, potentially causing preferential replication of specific mitochondrial DNA haplotypes. A new mitochondrial replacement technique Mitochondrial replacement techniques (MRT) could potentially be used to avoid mother-to-child transmission of mitochondria carrying disease-causing mutations. Shoukhrat Mitalipov and colleagues have investigated the outcome of MRT using oocytes from women from families with common mtDNA-associated syndromes and by transferring meiotic spindle from patient oocytes to healthy donor oocytes. Although donor mtDNA replaced the patient mtDNA efficiently and was stably maintained in embryonic stem cells (ES cells) derived from most embryos, some ES cell lines lost donor mtDNA. The authors' analysis suggests that polymorphisms in mtDNA could be associated with preferential replication and could be cause the amplification of specific maternal haplotype. Maternally inherited mitochondrial (mt)DNA mutations can cause fatal or severely debilitating syndromes in children 1 , 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 tissue 4 . Pathogenic mtDNA mutations are relatively common, with an estimated 778 affected children born each year in the United States 5 . Mitochondrial replacement therapies or techniques (MRT) circumventing mother–to–child mtDNA disease transmission involve replacement of oocyte maternal mtDNA 6 , 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 transfer 8 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/136 / 631/208 / Blastocyst - cytology / Blastocyst - metabolism / Cell growth / Cell Line / Cloning / Conserved Sequence - genetics / Disease / Disease transmission / DNA, Mitochondrial - biosynthesis / DNA, Mitochondrial - genetics / DNA, Mitochondrial - therapeutic use / Embryonic Stem Cells - cytology / Embryonic Stem Cells - metabolism / Embryos / Female / Fibroblasts / Gene mutation / Genetic aspects / Growth / Haplotypes / Haplotypes - genetics / Humanities and Social Sciences / Humans / letter / Male / Maternal Inheritance - genetics / Meiosis / Mitochondria / Mitochondrial Diseases - genetics / Mitochondrial Diseases - metabolism / Mitochondrial Diseases - pathology / Mitochondrial Diseases - prevention & control / Mitochondrial DNA / Mitochondrial Replacement Therapy - methods / multidisciplinary / Mutation / Oocyte Donation / Oocytes / Oocytes - cytology / Oocytes - metabolism / Oocytes - pathology / Oxidative Phosphorylation / Pedigree / Polymorphism, Genetic / Properties / Science / Stem cells / Womens health