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Regulation of Mother-to-Offspring Transmission of mtDNA Heteroplasmy

机译：调节MTDNA异质的母致谐波

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SUMMARY mtDNA is present in multiple copies in each cell derived from the expansions of those in the oocyte. Heteroplasmy, more than one mtDNA variant, may be generated by mutagenesis, paternal mtDNA leakage, and novel medical technologies aiming to prevent inheritance of mtDNA-linked diseases. Heteroplasmy phenotypic impact remains poorly understood. Mouse studies led to contradictory models of random drift or haplotype selection for mother-to-offspring transmission of mtDNA heteroplasmy. Here, we show that mtDNA heteroplasmy affects embryo metabolism, cell fitness, and induced pluripotent stem cell (iPSC) generation. Thus, genetic and pharmacological interventions affecting oxidative phosphorylation (OXPHOS) modify competition among mtDNA haplotypes during oocyte development and/or at early embryonic stages. We show that heteroplasmy behavior can fall on a spectrum from random drift to strong selection, depending on mito-nuclear interactions and metabolic factors. Understanding heteroplasmy dynamics and its mechanisms provide novel knowledge of a fundamental biological process and enhance our ability to mitigate risks in clinical applications affecting mtDNA transmission.
机译：摘要：线粒体DNA在每个细胞中都有多个拷贝，这些细胞来源于卵母细胞中的线粒体DNA的扩增。异质性，即一种以上的线粒体DNA变体，可能由突变、父系线粒体DNA泄漏和旨在防止线粒体DNA相关疾病遗传的新医学技术产生。异质性对表型的影响仍知之甚少。小鼠研究导致了随机漂移或单倍型选择的相互矛盾的模型，用于线粒体DNA异质性的母子传播。在这里，我们发现线粒体DNA异质性影响胚胎代谢、细胞适应性和诱导多能干细胞（iPSC）的产生。因此，影响氧化磷酸化（OXPHOS）的遗传和药理学干预改变了卵母细胞发育和/或早期胚胎阶段线粒体DNA单倍型之间的竞争。我们表明，异质性行为可以从随机漂移到强选择，这取决于有丝分裂-核相互作用和代谢因素。了解异质性动力学及其机制可以提供基本生物学过程的新知识，并增强我们在临床应用中降低影响线粒体DNA传输的风险的能力。

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