Critical role of mitochondrial ubiquitination and the OPTN-ATG9A axis in mitophagy
Critical role of mitochondrial ubiquitination and the OPTN-ATG9A axis in mitophagy
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DOI：
10.1083/jcb.201912144
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发表时间：
2020-09-07
影响因子：
7.8
通讯作者：
Matsuda, Noriyuki
中科院分区：
文献类型：
--
作者：
Yamano, Koji;Kikuchi, Reika;Matsuda, Noriyuki
受损的线粒体在一个称为线粒体自噬的过程中被选择性地清除。Parkin和PINK 1是帕金森氏病中突变的蛋白质，在受损的线粒体上放大泛素信号，随后激活自噬机制。自噬衔接子被认为通过ATG 8蛋白结合将泛素化线粒体和自噬连接起来。在这里，我们建立了方法，诱导线粒体自噬的靶向泛素链和化学诱导的线粒体泛素化。使用这些工具，我们揭示了泛素信号对于线粒体自噬是足够的，而PINK 1和Parkin对于自噬激活本身是不必要的。此外，使用相分离的荧光焦点，我们表明，关键的自噬适配器OPTN与ATG 9A囊泡形成复合物。OPTN-ATG 9A相互作用的破坏不诱导线粒体自噬。因此，除了结合ATG 8蛋白之外，关键的自噬衔接子还结合自噬核心单元，其有助于在泛素化线粒体附近的自噬体膜的从头合成中形成多价相互作用。
Damaged mitochondria are selectively eliminated in a process called mitophagy. Parkin and PINK1, proteins mutated in Parkinson's disease, amplify ubiquitin signals on damaged mitochondria with the subsequent activation of autophagic machinery. Autophagy adaptors are thought to link ubiquitinated mitochondria and autophagy through ATG8 protein binding. Here, we establish methods for inducing mitophagy by mitochondria-targeted ubiquitin chains and chemical-induced mitochondrial ubiquitination. Using these tools, we reveal that the ubiquitin signal is sufficient for mitophagy and that PINK1 and Parkin are unnecessary for autophagy activation per se. Furthermore, using phase-separated fluorescent foci, we show that the critical autophagy adaptor OPTN forms a complex with ATG9A vesicles. Disruption of OPTN-ATG9A interactions does not induce mitophagy. Therefore, in addition to binding ATG8 proteins, the critical autophagy adaptors also bind the autophagy core units that contribute to the formation of multivalent interactions in the de novo synthesis of autophagosomal membranes near ubiquitinated mitochondria.