Moore Andrew S, Holzbaur Erika L F
a Department of Physiology , Perelman School of Medicine, University of Pennsylvania , Philadelphia , PA , USA.
Autophagy. 2016 Oct 2;12(10):1956-1957. doi: 10.1080/15548627.2016.1212788. Epub 2016 Aug 2.
Damaged mitochondria are turned over through a process of selective autophagy termed mitophagy. In mitophagy, unhealthy mitochondria are recognized and ubiquitinated by Parkinson disease-linked proteins PINK1 and PARK2. The subsequent recruitment of ubiquitin-binding autophagy receptors leads in turn to the sequestration of the damaged organelles into LC3-positive phagophores, precursors to autophagosomes. The precise identity of these receptors and how they are regulated has been the focus of considerable attention. Our recent work uses live-cell imaging to explore the dynamics and regulation of autophagy receptor recruitment. Utilizing multiple paradigms to induce mitochondrial damage, we identified the rapid, 2-step recruitment of autophagy receptors OPTN, CALCOCO2/NDP52, and TAX1BP1. All 3 receptors are recruited to damaged mitochondria with similar kinetics; however, only OPTN is necessary for efficient formation of a phagophore sequestering damaged mitochondria from the cytosol. OPTN is co-recruited to damaged mitochondria along with its upstream kinase TBK1. Depletion of OPTN or TBK1, or expression of amyotrophic lateral sclerosis (ALS)-linked mutations in either protein, interfere with efficient autophagic engulfment of depolarized mitochondria. These observations suggest that insufficient autophagy of damaged mitochondria may contribute to neurodegenerative disease.
受损的线粒体通过一种称为线粒体自噬的选择性自噬过程被清除。在线粒体自噬中，不健康的线粒体被与帕金森病相关的蛋白质PINK1和PARK2识别并泛素化。随后泛素结合自噬受体的募集进而导致受损细胞器被隔离到LC3阳性吞噬体中，吞噬体是自噬体的前体。这些受体的确切身份以及它们如何被调节一直是备受关注的焦点。我们最近的工作使用活细胞成像来探索自噬受体募集的动态过程和调节机制。利用多种模式诱导线粒体损伤，我们确定了自噬受体OPTN、CALCOCO2/NDP52和TAX1BP1的快速两步募集。所有这三种受体以相似的动力学被募集到受损的线粒体；然而，只有OPTN对于从细胞质中隔离受损线粒体的吞噬体的有效形成是必需的。OPTN与其上游激酶TBK1一起被共同募集到受损的线粒体。OPTN或TBK1的缺失，或这两种蛋白质中任何一种的与肌萎缩侧索硬化症（ALS）相关的突变的表达，都会干扰去极化线粒体的有效自噬吞噬。这些观察结果表明，受损线粒体的自噬不足可能导致神经退行性疾病。
