Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy
Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy
复制标题
DOI：
10.1242/jcs.094110
复制
发表时间：
2012-03-15
影响因子：
4
通讯作者：
Mizushima, Noboru
中科院分区：
文献类型：
--
作者：
Itakura, Eisuke;Kishi-Itakura, Chieko;Mizushima, Noboru
线粒体可以通过自噬降解，这一过程称为线粒体自噬。帕金森病相关的泛素连接酶 Parkin 可以触发去极化线粒体的线粒体自噬。然而，自噬机制如何参与这种特定类型的自噬仍有待确定。据推测，p62 等接头蛋白可能介导自噬体 LC3 家族蛋白与线粒体上泛素化蛋白之间的相互作用。在这里，我们描述了对 Parkin 依赖性线粒体自噬中 Atg 蛋白募集的系统分析。含有上游 Atg 蛋白（包括 ULK1、Atg14、DFCP1、WIPI-1 和 Atg16L1）的结构即使在没有膜结合 LC3 的情况下也可以与去极化线粒体相关。 Atg9A 结构也被招募到这些受损的线粒体以及饥饿诱导的典型自噬过程中的自噬体形成位点。在 Parkin 介导的线粒体自噬的初始步骤中，包含 ULK1 复合物和 Atg9A 的结构被独立地招募到去极化线粒体，并且两者都是进一步招募除 LC3 之外的下游 Atg 蛋白所必需的。自噬体 LC3 对于后期将受损线粒体有效整合到自噬体中非常重要。这些发现表明，隔离膜是在受损的线粒体上从头生成的，而不是预先形成的隔离膜识别线粒体的过程。
Mitochondria can be degraded by autophagy in a process termed mitophagy. The Parkinson-disease-associated ubiquitin ligase Parkin can trigger mitophagy of depolarized mitochondria. However, it remains to be determined how the autophagy machinery is involved in this specific type of autophagy. It has been speculated that adaptor proteins such as p62 might mediate the interaction between the autophagosomal LC3 family of proteins and ubiquitylated proteins on mitochondria. Here, we describe our systematic analysis of the recruitment of Atg proteins in Parkin-dependent mitophagy. Structures containing upstream Atg proteins, including ULK1, Atg14, DFCP1, WIPI-1 and Atg16L1, can associate with depolarized mitochondria even in the absence of membrane-bound LC3. Atg9A structures are also recruited to these damaged mitochondria as well as to the autophagosome formation site during starvation-induced canonical autophagy. In the initial steps of Parkin-mediated mitophagy, the structures containing the ULK1 complex and Atg9A are independently recruited to depolarized mitochondria and both are required for further recruitment of downstream Atg proteins except LC3. Autophagosomal LC3 is important for efficient incorporation of damaged mitochondria into the autophagosome at a later stage. These findings suggest a process whereby the isolation membrane is generated de novo on damaged mitochondria as opposed to one where a preformed isolation membrane recognizes mitochondria.