Degradation of defective mitochondria is an essential process to maintain cellular homeostasis and it is strictly regulated by the ubiquitin-proteasome system (UPS) and lysosomal activities. Here, using genome-wide CRISPR and small interference RNA screens, we identified a critical contribution of the lysosomal system in controlling aberrant induction of apoptosis following mitochondrial damage. After treatment with mitochondrial toxins, activation of the PINK1-Parkin axis triggered a BAX- and BAK-independent process of cytochrome c release from mitochondria followed by APAF1 and caspase 9–dependent apoptosis. This phenomenon was mediated by UPS-dependent outer mitochondrial membrane (OMM) degradation and was reversed using proteasome inhibitors. We found that the subsequent recruitment of the autophagy machinery to the OMM protected cells from apoptosis, mediating the lysosomal degradation of dysfunctional mitochondria. Our results underscore a major role of the autophagy machinery in counteracting aberrant noncanonical apoptosis and identified autophagy receptors as key elements in the regulation of this process.

中文翻译：

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线粒体自噬限制 BAX/BAK 独立、Parkin 介导的细胞凋亡


有缺陷的线粒体的降解是维持细胞稳态的重要过程，并受到泛素蛋白酶体系统（UPS）和溶酶体活性的严格调控。在这里，利用全基因组 CRISPR 和小干扰 RNA 筛选，我们确定了溶酶体系统在控制线粒体损伤后异常诱导细胞凋亡方面的关键贡献。用线粒体毒素处理后，PINK1-Parkin 轴的激活触发了不依赖于 BAX 和 BAK 的线粒体释放细胞色素 c 的过程，随后是 APAF1 和 caspase 9 依赖性细胞凋亡。这种现象是由 UPS 依赖性线粒体外膜 (OMM) 降解介导的，并可使用蛋白酶体抑制剂逆转。我们发现，随后将自噬机制募集至 OMM 可以保护细胞免于凋亡，介导功能失调的线粒体的溶酶体降解。我们的结果强调了自噬机制在对抗异常非典型细胞凋亡中的重要作用，并确定自噬受体是调节该过程的关键元件。