The ADP/ATP translocase drives mitophagy independent of nucleotide exchange
The ADP/ATP translocase drives mitophagy independent of nucleotide exchange
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DOI：
10.1038/s41586-019-1667-4
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发表时间：
2019-11-14
期刊：
影响因子：
64.8
通讯作者：
Arany, Zoltan
中科院分区：
文献类型：
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作者：
Hoshino, Atsushi;Wang, Wei-jia;Arany, Zoltan
线粒体的稳态依赖于线粒体自噬，即线粒体的程序性降解。已知只有少数蛋白质参与线粒体自噬。在这里，我们使用多种线粒体自噬报告系统和促线粒体自噬触发因子开发了多维CRISPR-Cas9遗传筛查，并鉴定了帕金森依赖性线粒体自噬的许多成分（1）。出乎意料的是，我们发现，腺嘌呤核苷酸转运（ANT）复杂的线粒体自噬所需的几种细胞类型。而药物抑制ANT介导的ADP/ATP交换促进线粒体自噬，基因消融ANT矛盾地抑制线粒体自噬。值得注意的是，ANT促进线粒体自噬独立于其核苷酸移位酶催化活性。相反，ANT复合物是抑制前序列移位酶TIM 23所必需的，这导致PINK 1的稳定，以响应生物能量的崩溃。ANT通过与TIM 44的相互作用间接调节TIM 23，TIM 44通过TIM 23调节肽输入（2）。缺乏ANT 1的小鼠表现出钝化的线粒体自噬和随之而来的异常线粒体的大量积累。ANT 1中的致病人类突变消除与TIM 44和TIM 23的结合并抑制线粒体自噬。总之，我们的研究结果表明，ANT是健康和疾病中线粒体自噬的重要和基本介质。
Mitochondrial homeostasis depends on mitophagy, the programmed degradation of mitochondria. Only a few proteins are known to participate in mitophagy. Here we develop a multidimensional CRISPR-Cas9 genetic screen, using multiple mitophagy reporter systems and pro-mitophagy triggers, and identify numerous components of parkin-dependent mitophagy(1). Unexpectedly, we find that the adenine nucleotide translocator (ANT) complex is required for mitophagy in several cell types. Whereas pharmacological inhibition of ANT-mediated ADP/ATP exchange promotes mitophagy, genetic ablation of ANT paradoxically suppresses mitophagy. Notably, ANT promotes mitophagy independently of its nucleotide translocase catalytic activity. Instead, the ANT complex is required for inhibition of the presequence translocase TIM23, which leads to stabilization of PINK1, in response to bioenergetic collapse. ANT modulates TIM23 indirectly via interaction with TIM44, which regulates peptide import through TIM23(2). Mice that lack ANT1 show blunted mitophagy and consequent profound accumulation of aberrant mitochondria. Disease-causing human mutations in ANT1 abrogate binding to TIM44 and TIM23 and inhibit mitophagy. Together, our findings show that ANT is an essential and fundamental mediator of mitophagy in health and disease.