Regulation of Mother-to-Offspring Transmission of mtDNA Heteroplasmy
Regulation of Mother-to-Offspring Transmission of mtDNA Heteroplasmy
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DOI：
10.1016/j.cmet.2019.09.007
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发表时间：
2019-12-03
期刊：
影响因子：
29
通讯作者：
Antonio Enriquez, Jose
中科院分区：
文献类型：
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作者：
Latorre-Pellicer, Ana;Victoria Lechuga-Vieco, Ana;Antonio Enriquez, Jose
线粒体DNA在每个细胞中以多个副本的形式存在，这些副本来自卵母细胞中的那些副本的扩张。异质性，不止一个线粒体DNA变体，可能是由突变、父亲的线粒体DNA泄漏和旨在防止线粒体DNA连锁疾病遗传的新医学技术产生的。异质性对表型的影响仍然知之甚少。小鼠的研究导致了线粒体DNA异质性母子传播的随机漂移或单倍型选择的相互矛盾的模型。在这里，我们表明线粒体DNA异质性影响胚胎新陈代谢、细胞适合性和诱导多能干细胞(IPSC)的产生。因此，影响氧化磷酸化(OXPHOS)的遗传和药物干预改变了卵母细胞发育和/或早期胚胎阶段mtDNA单倍型之间的竞争。我们表明，异质性行为可以落在从随机漂移到强烈选择的光谱上，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提供了基本生物学过程的新知识，并增强了我们在临床应用中降低影响线粒体DNA传递的风险的能力。
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-tooffspring 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.