近日，美国宾州大学Zoltan Arany及其研究小组发现ADP/ATP转位酶促进线粒体自噬但不依赖于其酶活。相关论文2019年10月16日在线发表在《自然》杂志上。

研究人员设计了一个多维度的CRISPR / Cas9遗传筛选，使用了多个线粒体报告系统和促线粒体自噬触发器，并揭示了Parkin蛋白依赖性线粒体自噬的许多新成分。出乎意料的是，研究人员确定了多种细胞类型线粒体自噬所必需的腺嘌呤核苷酸转运蛋白（ANT）复合体。ANT介导的ADP/ATP交换的药理抑制作用促进了线粒体自噬，而ANT的遗传敲除却自相矛盾地抑制了线粒体吞噬。重要的是，ANT不需要其核苷酸的转位酶催化活性来促进线粒体自噬。取而代之的是，需要ANT复合物来抑制前序列转位酶TIM23，从而响应生物能崩溃，并导致PINK1稳定。ANT通过与TIM44相互作用而间接调节TIM23，已知其调控通过TIM232的多肽导入。

缺少ANT1的小鼠表现出线粒体自噬减少和随之而来的线粒体异常积累。人类ANT1的致病性突变消除了与TIM44和TIM23的结合并抑制线粒体自噬。这些数据一起确定了ANT作为健康和疾病中线粒体自噬的基本介导者的新颖和关键功能。

据了解，线粒体稳态主要取决于线粒体自噬，即线粒体的程序性降解。已知参与线粒体自噬的蛋白质仍然很少。

附：英文原文

Title: The ADP/ATP translocase drives mitophagy independent of nucleotide exchange

Author: Atsushi Hoshino, Wei-jia Wang, Shogo Wada, Chris McDermott-Roe, Chantell S. Evans, Bridget Gosis, Michael P. Morley, Komal S. Rathi, Jian Li, Kristina Li, Steven Yang, Meagen J. McMannus, Caitlyn Bowman, Prasanth Potluri, Michael Levin, Scott Damrauer, Douglas C. Wallace, Erika L. F. Holzbaur, Zoltan Arany

Issue&Volume: 2019-10-16

Abstract: 

Mitochondrial homeostasis vitally depends on mitophagy, the programmed degradation of mitochondria. The roster of proteins known to participate in mitophagy remains small. We devised here a multidimensional CRISPR/Cas9 genetic screen, using multiple mitophagy reporter systems and pro-mitophagy triggers, and uncover numerous new components of Parkin-dependent mitophagy1. Unexpectedly, we identify the adenine nucleotide translocator (ANT) complex as required for mitophagy in multiple cell types. While pharmacological inhibition of ANT-mediated ADP/ATP exchange promotes mitophagy, genetic ablation of ANT paradoxically suppresses mitophagy. Importantly, ANT promotes mitophagy independently of its nucleotide translocase catalytic activity. Instead, the ANT complex is required for inhibition of the presequence translocase TIM23, leading to PINK1 stabilization, in response to bioenergetic collapse. ANT modulates TIM23 indirectly via interaction with TIM44, known to regulate peptide import through TIM232. Mice lacking ANT1 reveal 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, these data identify a novel and essential function for ANT as a fundamental mediator of mitophagy in health and disease.

DOI: 10.1038/s41586-019-1667-4

Source:https://www.nature.com/articles/s41586-019-1667-4