Reply to: Reversion after replacement of mitochondrial DNA.
Reply to: Reversion after replacement of mitochondrial DNA.
复制标题
回复：替换线粒体DNA后的回复。
DOI：
10.1038/s41586-019-1624-2
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发表时间：
2019
期刊：
影响因子：
64.8
通讯作者：
Mitalipov,Shoukhrat
中科院分区：
文献类型：
--
作者：
Kang,Eunju;Koski,Amy;Amato,Paula;Temiakov,Dmitry;Mitalipov,Shoukhrat
The risk of transmitting deleterious mutations in mitochondrial DNA (mtDNA) from mother to child may be reduced by mitochondrial replacement, which involves transplanting the nuclear DNA from the egg of a woman containing such a mutation into an enucleated egg from an unaffected donor 1. Although embryonic stem cell lines derived from mitochondrial replacement embryos can revert to the mitochondrial genome of the nuclear donor 1, a study that involved eggs from women who carry pathogenic mutations reported that mutant mtDNA was efficiently eliminated and did not re-emerge in embryonic stem cell lines 2. Contrary to this, we find that two embryonic stem cell lines derived by Kang et al. 2 exhibited reversion to a pathogenic variant, which was present in the mitochondrial genome of a nuclear donor assigned to the control group. Although the clinical relevance is unclear, reversion in embryonic stem cell lines remains a consideration for therapeutic applications of mitochondrial replacement, and accurate reporting of the research that underpins these applications is therefore essential. The mitochondrial replacement procedure involves transplanting the nuclear genome in a karyoplast containing a small amount of cytoplasm. The small amount of mtDNA contained in the karyoplast generally accounts for less than 2% of the mtDNA content of mitochondrial replacement embryos 2–4. Despite this, around 15% of embryonic stem (ES) cell lines derived from such embryos show complete reversion to the mitochondrial genome of the nuclear donor during proliferation in vitro 2–4. Because the majority of mitochondrial replacement studies are based on mtDNA sequence variants that are not pathogenic, evidence for the fate of pathogenic variants in ES cell lines derived from mitochondrial replacement embryos is limited. The study published by Kang et al. 2 was therefore of considerable interest. These authors reported that three of the women who donated eggs for their study were heteroplasmic for pathogenic mutations in their mtDNA. The study also included eggs from 11 women who were screened to confirm the absence of mtDNA mutations. Mitochondrial replacement was performed by transplanting the metaphase II spindle from eggs that carried pathogenic mtDNA mutations into enucleated eggs from unaffected donors, as well as between eggs that were donated by women who were deemed to be free of pathogenic mutations. Consistent with others 3, 4, Kang et al. 2 found that reversion to the mitochondrial genome of the nuclear donor occurred in a minority of ES cell lines (n= 3 out of 18). This included two lines (ST-ES7 and ST-ES8) that were reported to originate from mitochondrial replacement procedures involving eggs donated by women who did not carry inherited pathogenic mtDNA mutations. The remaining reverted ES cell line (3243ST-ES1) was derived from a mitochondrial replacement procedure in which the nuclear donor was a carrier of the m. 3243A> G mtDNA mutation. However, the authors reported that reversion in this ES cell line involved the wild type, rather than the mutated mtDNA.They therefore concluded that mitochondrial genomes that carry pathogenic mutations were efficiently eliminated by spindle transfer 2. Analysis of the mtDNA sequence data published in Kang et al. 2 indicates that one of the egg donors (ED5, of haplogroup U5a) included in the control group is homoplasmic for a pathogenic mtDNA mutation. The mutation (m. 14484T> C) is in the MT-ND6 gene (Fig. 1) and causes Leber’s hereditary optic neuropathy (LHON) 5, 6. The authors derived three ES cell lines from mitochondrial replacement embryos, in …
