Selective Autophagy of Mitochondria on a Ubiquitin-Endoplasmic-Reticulum Platform
Selective Autophagy of Mitochondria on a Ubiquitin-Endoplasmic-Reticulum Platform
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基于泛素 - 内质网平台的线粒体选择性自噬
DOI：
10.1016/j.devcel.2019.06.016
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发表时间：
2019-09-09
影响因子：
11.8
通讯作者：
Ktistakis, Nicholas T.
中科院分区：
文献类型：
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作者：
Zachari, Maria;Gudmundsson, Sigurdur R.;Ktistakis, Nicholas T.
线粒体自噬过程中自噬机制和选择性受体之间的动力学和协调尚不清楚。同样未知的是，线粒体自噬是否依赖于预先存在的膜或在受损线粒体的表面上触发。使用泛素依赖的线粒体自噬诱导剂，伊维菌素内酯，我们结合遗传和成像实验来解决这些问题。最早需要线粒体片段的泛素化，然后是TBK1的自磷酸化。接下来，早期必需的自噬蛋白FIP200和ATG13在不同的步骤起作用，而ULK1和ULK2则是互补的。受体在时间上和机制上作用于ATG 13的上游，但在FIP 200的下游。VPS34复合物在omegasome步骤起作用。ATG13和视神经磷酸酶以不连续的振荡方式靶向线粒体，表明多个起始事件。靶向的泛素化线粒体由内质网（ER）链支撑，即使没有功能性自噬机制和线粒体自噬适配器。我们认为受损的线粒体被遍在化并动态包裹在ER链中，为线粒体吞噬体的形成提供平台。
The dynamics and coordination between autophagy machinery and selective receptors during mitophagy are unknown. Also unknown is whether mitophagy depends on pre-existing membranes or is triggered on the surface of damaged mitochondria. Using a ubiquitin-dependent mitophagy inducer, the lactone ivermectin, we have combined genetic and imaging experiments to address these questions. Ubiquitination of mitochondrial fragments is required the earliest, followed by auto-phosphorylation of TBK1. Next, early essential autophagy proteins FIP200 and ATG13 act at different steps, whereas ULK1 and ULK2 are dispensable. Receptors act temporally and mechanistically upstream of ATG13 but downstream of FIP200. The VPS34 complex functions at the omegasome step. ATG13 and optineurin target mitochondria in a discontinuous oscillatory way, suggesting multiple initiation events. Targeted ubiquitinated mitochondria are cradled by endoplasmic reticulum (ER) strands even without functional autophagy machinery and mitophagy adaptors. We propose that damaged mitochondria are ubiquitinated and dynamically encased in ER strands, providing platforms for formation of the mitophagosomes.