Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK.
Commun Biol. 2021 May 14;4(1):584. doi: 10.1038/s42003-021-02069-2.
Most humans carry a mixed population of mitochondrial DNA (mtDNA heteroplasmy) affecting ~1-2% of molecules, but rapid percentage shifts occur over one generation leading to severe mitochondrial diseases. A decrease in the amount of mtDNA within the developing female germ line appears to play a role, but other sub-cellular mechanisms have been implicated. Establishing an in vitro model of early mammalian germ cell development from embryonic stem cells, here we show that the reduction of mtDNA content is modulated by oxygen and reaches a nadir immediately before germ cell specification. The observed genetic bottleneck was accompanied by a decrease in mtDNA replicating foci and the segregation of heteroplasmy, which were both abolished at higher oxygen levels. Thus, differences in oxygen tension occurring during early development likely modulate the amount of mtDNA, facilitating mtDNA segregation and contributing to tissue-specific mutation loads.
大多数人携带混合的线粒体 DNA（mtDNA 异质性），影响约 1-2%的分子，但在一代人中会迅速发生百分比变化，导致严重的线粒体疾病。发育中的雌性生殖细胞中线粒体 DNA 数量的减少似乎起作用，但其他亚细胞机制也被牵连进来。在这里，我们从胚胎干细胞建立了早期哺乳动物生殖细胞发育的体外模型，结果表明 mtDNA 含量的减少受氧的调节，并在生殖细胞特化之前达到最低点。观察到的遗传瓶颈伴随着 mtDNA 复制焦点的减少和异质性的分离，这两者在较高的氧水平下都被消除。因此，早期发育过程中氧张力的差异可能调节 mtDNA 的数量，促进 mtDNA 的分离，并有助于组织特异性突变负荷。
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