NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy.
NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy.
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DOI：
10.15252/embj.2022111372
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发表时间：
2023-03-01
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线粒体自噬，即通过自噬-溶酶体途径消除线粒体，对维持细胞稳态至关重要。最典型的线粒体自噬途径是通过稳定蛋白激酶PINK1和向受损线粒体募集泛素连接酶Parkin介导的。泛素化的线粒体表面蛋白被自噬受体识别，包括NDP52，它启动线粒体周围自噬囊泡的形成。受损的线粒体也会产生活性氧（ROS），这被认为是线粒体自噬的信号，但ROS的感知机制尚不清楚。在这里，我们发现NDP52的氧化对于有效的PINK1/Parkin依赖性有丝分裂是必不可少的。我们发现氧化还原敏感的半胱氨酸残基参与了受损线粒体上NDP52的二硫键形成和寡聚化。NDP52的寡聚化促进了自噬机制的招募，以实现线粒体的快速降解。我们提出NDP52的氧化还原感应允许线粒体自噬作为氧化应激反应的一种机制。人类自噬受体NDP52感知活性氧来标记受损的线粒体以进行清除。
Mitophagy, the elimination of mitochondria via the autophagy‐lysosome pathway, is essential for the maintenance of cellular homeostasis. The best characterised mitophagy pathway is mediated by stabilisation of the protein kinase PINK1 and recruitment of the ubiquitin ligase Parkin to damaged mitochondria. Ubiquitinated mitochondrial surface proteins are recognised by autophagy receptors including NDP52 which initiate the formation of an autophagic vesicle around the mitochondria. Damaged mitochondria also generate reactive oxygen species (ROS) which have been proposed to act as a signal for mitophagy, however the mechanism of ROS sensing is unknown. Here we found that oxidation of NDP52 is essential for the efficient PINK1/Parkin‐dependent mitophagy. We identified redox‐sensitive cysteine residues involved in disulphide bond formation and oligomerisation of NDP52 on damaged mitochondria. Oligomerisation of NDP52 facilitates the recruitment of autophagy machinery for rapid mitochondrial degradation. We propose that redox sensing by NDP52 allows mitophagy to function as a mechanism of oxidative stress response. Human autophagy receptor NDP52 senses reactive oxygen species to mark damaged mitochondria for removal.