Mitochondrial DNA polymerase gamma is essential for mammalian embryogenesis
Mitochondrial DNA polymerase gamma is essential for mammalian embryogenesis
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DOI：
10.1093/hmg/ddi184
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发表时间：
2005-07-01
影响因子：
3.5
通讯作者：
Trifunovic, A
中科院分区：
文献类型：
--
作者：
Hance, N;Ekstrand, MI;Trifunovic, A
线粒体DNA（mtDNA）聚合酶γ（Polg）是含有Poll I样催化核心（PolgA）和辅助亚基的异二聚体酶。POLGA突变影响mtDNA的稳定性，已在几种人类病理学中被鉴定，如进行性眼外肌麻痹和Alpers综合征。大量文献表明，用于治疗HIV和慢性B型肝炎的核苷类似物逆转录酶抑制剂对Polg具有抑制作用，因此具有线粒体毒性作用。我们之前已经证明，具有容易出错的PolgA版本的小鼠会积累更高水平的体细胞线粒体DNA突变，从而导致过早衰老表型。在本论文中，我们证明PolgA缺乏症在小鼠胚胎中引起早期发育停滞胚胎天7.5和8.5与严重的线粒体DNA耗竭。杂合基因敲除小鼠的PolgA转录水平只有野生型的一半，mtDNA水平略有下降，但发育正常。令人惊讶的是，在杂合基因敲除小鼠中PoIgA转录物的量增加，以响应人为升高的mtDNA拷贝数，揭示了mtDNA维持和PoIgA表达之间可能的调控联系。我们的研究结果表明，Polg确实是唯一的DNA聚合酶能够维持mtDNA在哺乳动物线粒体。此外，Polg的存在对于哺乳动物胚胎发育过程中的器官发生是绝对必要的。
Mitochondrial DNA (mtDNA) polymerase gamma (Polg) is a heterodimeric enzyme containing a Poll I-like catalytic core (PolgA) and an accessory subunit. Mutations in POLGA, affecting the stability of mtDNA, have been identified in several human pathologies such as progressive external ophthalmoplegia and Alpers' syndrome. Extensive literature shows mitochondrial toxicity effects nucleoside analogue reverse transcriptase inhibitors used in the treatment of HIV and chronic hepatitis B as a consequence of an inhibitory effect on Polg. We have previously shown that mice with an error-prone version of PolgA accumulate higher levels of somatic mtDNA mutations resulting in a premature aging phenotype. In the present paper, we demonstrate PolgA deficiency in mouse embryos causes an early developmental arrest between embryonic days 7.5 and 8.5 associated with severe mtDNA depletion. Heterozygous knockout mice have half the wild-type levels of PolgA transcripts and a slight reduction in mtDNA levels but develop normally. Surprisingly, amounts of PoIgA transcripts in heterozygous knockout mice are increased in response to artificially elevated mtDNA copy number, revealing a possible regulatory link between mtDNA maintenance and PoIgA expression. Our results show that Polg indeed is the only DNA polymerase capable of maintaining mtDNA in mammalian mitochondria. In addition, presence of Polg is absolutely essential for the organogenesis during mammalian embryonic development.