Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
J Cell Biol. 2010 May 17;189(4):671-9. doi: 10.1083/jcb.201001039. Epub 2010 May 10.
Mutations in parkin, a ubiquitin ligase, cause early-onset familial Parkinson's disease (AR-JP). How parkin suppresses parkinsonism remains unknown. Parkin was recently shown to promote the clearance of impaired mitochondria by autophagy, termed mitophagy. Here, we show that parkin promotes mitophagy by catalyzing mitochondrial ubiquitination, which in turn recruits ubiquitin-binding autophagic components, HDAC6 and p62, leading to mitochondrial clearance. During the process, juxtanuclear mitochondrial aggregates resembling a protein aggregate-induced aggresome are formed. The formation of these "mito-aggresome" structures requires microtubule motor-dependent transport and is essential for efficient mitophagy. Importantly, we show that AR-JP-causing parkin mutations are defective in supporting mitophagy due to distinct defects at recognition, transportation, or ubiquitination of impaired mitochondria, thereby implicating mitophagy defects in the development of parkinsonism. Our results show that impaired mitochondria and protein aggregates are processed by common ubiquitin-selective autophagy machinery connected to the aggresomal pathway, thus identifying a mechanistic basis for the prevalence of these toxic entities in Parkinson's disease.
Parkin 基因突变导致早发性家族性帕金森病（AR-JP）。Parkin 如何抑制帕金森病仍然未知。最近研究表明，Parkin 通过自噬促进受损线粒体的清除，称为线粒体自噬。在这里，我们表明 Parkin 通过催化线粒体泛素化来促进线粒体自噬，这反过来又招募了泛素结合自噬成分 HDAC6 和 p62，导致线粒体清除。在此过程中，形成类似于蛋白聚集诱导的聚集体的核周线粒体聚集物。这些“线粒体聚集体”结构的形成需要微管动力依赖性运输，并且对于有效的线粒体自噬是必需的。重要的是，我们表明 AR-JP 引起的 Parkin 突变由于识别、运输或受损线粒体的泛素化缺陷而不能支持线粒体自噬，从而表明线粒体自噬缺陷在帕金森病的发展中起作用。我们的结果表明，受损的线粒体和蛋白聚集体通过与聚集途径相连的通用泛素选择性自噬机制进行处理，从而为帕金森病中这些毒性实体的普遍存在确定了机制基础。
