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Regulation of Mother-to-Offspring Transmission of mtDNA Heteroplasmy.
Cell Metabolism ( IF 27.7 ) Pub Date : 2019-10-03 , DOI: 10.1016/j.cmet.2019.09.007 Ana Latorre-Pellicer 1 , Ana Victoria Lechuga-Vieco 2 , Iain G Johnston 3 , Riikka H Hämäläinen 4 , Juan Pellico 2 , Raquel Justo-Méndez 5 , Jose María Fernández-Toro 5 , Cristina Clavería 5 , Adela Guaras 5 , Rocío Sierra 5 , Jordi Llop 6 , Miguel Torres 5 , Luis Miguel Criado 5 , Anu Suomalainen 7 , Nick S Jones 8 , Jesús Ruíz-Cabello 9 , José Antonio Enríquez 10
Cell Metabolism ( IF 27.7 ) Pub Date : 2019-10-03 , DOI: 10.1016/j.cmet.2019.09.007 Ana Latorre-Pellicer 1 , Ana Victoria Lechuga-Vieco 2 , Iain G Johnston 3 , Riikka H Hämäläinen 4 , Juan Pellico 2 , Raquel Justo-Méndez 5 , Jose María Fernández-Toro 5 , Cristina Clavería 5 , Adela Guaras 5 , Rocío Sierra 5 , Jordi Llop 6 , Miguel Torres 5 , Luis Miguel Criado 5 , Anu Suomalainen 7 , Nick S Jones 8 , Jesús Ruíz-Cabello 9 , José Antonio Enríquez 10
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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.
中文翻译：
调节mtDNA杂种母婴传播。
mtDNA存在于每个细胞中的多个副本中，这些副本源自卵母细胞中的mtDNA的扩增。诱变，父系mtDNA泄漏和旨在防止与mtDNA连锁的疾病遗传的新型医学技术可能会产生多于一种mtDNA变体的异质性。异质表型的影响仍然知之甚少。小鼠研究导致了mtDNA异质性母婴传播的随机漂移或单倍型选择的矛盾模型。在这里，我们显示mtDNA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会改变卵母细胞发育过程中和/或早期胚胎阶段mtDNA单倍型之间的竞争。我们表明，异质行为可以落在从随机漂移到强选择的频谱上，具体取决于微核相互作用和代谢因子。了解异质动力学及其机理为基础生物学过程提供了新颖的知识，并增强了我们减轻影响mtDNA传播的临床应用中的风险的能力。
更新日期：2019-11-09
中文翻译：
调节mtDNA杂种母婴传播。
mtDNA存在于每个细胞中的多个副本中，这些副本源自卵母细胞中的mtDNA的扩增。诱变，父系mtDNA泄漏和旨在防止与mtDNA连锁的疾病遗传的新型医学技术可能会产生多于一种mtDNA变体的异质性。异质表型的影响仍然知之甚少。小鼠研究导致了mtDNA异质性母婴传播的随机漂移或单倍型选择的矛盾模型。在这里，我们显示mtDNA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会改变卵母细胞发育过程中和/或早期胚胎阶段mtDNA单倍型之间的竞争。我们表明，异质行为可以落在从随机漂移到强选择的频谱上，具体取决于微核相互作用和代谢因子。了解异质动力学及其机理为基础生物学过程提供了新颖的知识，并增强了我们减轻影响mtDNA传播的临床应用中的风险的能力。
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