Single point mutations in ATP synthase compensate for mitochondrial genome loss in trypanosomes
Single point mutations in ATP synthase compensate for mitochondrial genome loss in trypanosomes
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DOI：
10.1073/pnas.1305404110
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发表时间：
2013-09-03
影响因子：
11.1
通讯作者：
Schnaufer, Achim C.
中科院分区：
文献类型：
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作者：
Dean, Samuel;Gould, Matthew K.;Schnaufer, Achim C.
采采蝇传播的非洲锥虫布鲁氏锥虫的生存能力取决于其动质体（kDNA）的维持和表达，这种寄生虫的线粒体基因组是兽医和人类抗锥虫药物的假定靶点。然而，密切相关的动物病原体伊万氏绦虫和装备绦虫是独立于采采蝇传播的，并且在没有功能着丝体的情况下存活，原因尚不清楚。在这里，我们提供了明确的证据，证明核编码的f1fo - atp酶亚基γ的单个氨基酸变化可以补偿这些寄生虫中kDNA的完全物理损失。我们的研究结果通过显示不依赖于f - o的线粒体膜电位的产生，增加了对ADP/ATP载体的依赖，为kDNA损失补偿的分子机制提供了深入的见解。我们的研究结果还表明，在布鲁氏体的致病性血流阶段，kDNA维持和表达所需的巨大而能量消耗的装置服务于单个f1fo - atp酶亚基的产生。这些结果对药物发现和我们对这些寄生虫进化的理解具有重要意义。
Viability of the tsetse fly-transmitted African trypanosome Trypanosoma brucei depends on maintenance and expression of its kinetoplast (kDNA), the mitochondrial genome of this parasite and a putative target for veterinary and human antitrypanosomatid drugs. However, the closely related animal pathogens T. evansi and T. equiperdum are transmitted independently of tsetse flies and survive without a functional kinetoplast for reasons that have remained unclear. Here, we provide definitive evidence that single amino acid changes in the nuclearly encoded F1FO-ATPase subunit gamma can compensate for complete physical loss of kDNA in these parasites. Our results provide insight into the molecular mechanism of compensation for kDNA loss by showing F-O-independent generation of the mitochondrial membrane potential with increased dependence on the ADP/ATP carrier. Our findings also suggest that, in the pathogenic bloodstream stage of T. brucei, the huge and energetically demanding apparatus required for kDNA maintenance and expression serves the production of a single F1FO-ATPase subunit. These results have important implications for drug discovery and our understanding of the evolution of these parasites.