Lack of mitochondrial MutS homolog 1 in Toxoplasma gondii disrupts maintenance and fidelity of mitochondrial DNA and reveals metabolic plasticity.
Lack of mitochondrial MutS homolog 1 in Toxoplasma gondii disrupts maintenance and fidelity of mitochondrial DNA and reveals metabolic plasticity.
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DOI：
10.1371/journal.pone.0188040
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Arrizabalaga G
中科院分区：
文献类型：
--
作者：
Garbuz T;Arrizabalaga G
线粒体基因组中各种修复途径的存在，突显了维持线粒体基因组保真度的重要性。据推测，线粒体DNA的修复在只有一个线粒体的生物体中尤其重要，比如人类病原体恶性疟原虫和弓形虫。了解这些寄生虫中维持线粒体DNA的机制具有特别重要的意义，因为线粒体功能是抗寄生虫药物有效的有效靶点。我们先前确定弓形虫MutS同源基因TgMSH1定位于线粒体。MutS同源物是哺乳动物细胞核错配修复系统的关键组成部分，酵母和植物都含有MutS同源物，定位于线粒体，在那里调节DNA的稳定性。在这里，我们表明，缺乏TgMSH1导致线粒体DNA中单核苷酸变异的积累和线粒体DNA含量的减少。此外，缺乏TgMSH1功能的寄生虫可以在细胞色素b抑制剂阿托瓦酮的治疗下存活。虽然Tgmsh1基因敲除菌株在细胞色素b上有几个错义突变，但没有影响已知的阿托瓦酮敏感性决定因素的氨基酸，阿托瓦酮仍然能够抑制Tgmsh1突变体中的电子传递。此外，在阿托瓦酮存在的情况下培养Tgmsh1突变体会导致寄生虫对阿托瓦酮的抵抗力增强，呼吸完全停止。因此，缺乏TgMSH1的寄生虫通过调整自己的生理能力来克服线粒体DNA的破坏，从而放弃氧化磷酸化的需要。与这一想法一致，Tgmsh1突变体对具有不同靶点的线粒体抑制剂具有抗性，并显示出在没有葡萄糖的情况下生长能力降低。这项工作表明TgMSH1对弓形虫线粒体DNA的维持和保真度至关重要，揭示了阿托瓦酮抵抗的新机制，并揭示了这种重要的人类病原体的生理可塑性。
The importance of maintaining the fidelity of the mitochondrial genome is underscored by the presence of various repair pathways within this organelle. Presumably, the repair of mitochondrial DNA would be of particular importance in organisms that possess only a single mitochondrion, like the human pathogens Plasmodium falciparum and Toxoplasma gondii. Understanding the machinery that maintains mitochondrial DNA in these parasites is of particular relevance, as mitochondrial function is a validated and effective target for anti-parasitic drugs. We previously determined that the Toxoplasma MutS homolog TgMSH1 localizes to the mitochondrion. MutS homologs are key components of the nuclear mismatch repair system in mammalian cells, and both yeast and plants possess MutS homologs that localize to the mitochondria where they regulate DNA stability. Here we show that the lack of TgMSH1 results in accumulation of single nucleotide variations in mitochondrial DNA and a reduction in mitochondrial DNA content. Additionally, parasites lacking TgMSH1 function can survive treatment with the cytochrome b inhibitor atovaquone. While the Tgmsh1 knockout strain has several missense mutations in cytochrome b, none affect amino acids known to be determinants of atovaquone sensitivity and atovaquone is still able to inhibit electron transport in the Tgmsh1 mutants. Furthermore, culture of Tgmsh1 mutant in the presence atovaquone leads to parasites with enhanced atovaquone resistance and complete shutdown of respiration. Thus, parasites lacking TgMSH1 overcome the disruption of mitochondrial DNA by adapting their physiology allowing them to forgo the need for oxidative phosphorylation. Consistent with this idea, the Tgmsh1 mutant is resistant to mitochondrial inhibitors with diverse targets and exhibits reduced ability to grow in the absence of glucose. This work shows TgMSH1 as critical for the maintenance and fidelity of the mitochondrial DNA in Toxoplasma, reveals a novel mechanism for atovaquone resistance, and exposes the physiological plasticity of this important human pathogen.
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