Department of Experimental Neurology, Katholieke Universiteit Leuven, Leuven, Belgium.
Autophagy. 2011 Dec;7(12):1555-6. doi: 10.4161/auto.7.12.17893.
Mutations in the gene for the E3 ubiquitin ligase Parkin are the most prevalent cause of autosomal recessive Parkinson disease (PD), an incurable neurodegenerative disorder. Parkin surveys mitochondrial quality by translocating to depolarized mitochondria and inducing their selective macroautophagic removal (mitophagy). We recently reported that Parkin interacts with Ambra1 (activating molecule in Beclin 1-regulated autophagy), a protein that promotes autophagy in the vertebrate central nervous system. We discovered that prolonged mitochondrial depolarization strongly increases the interaction of Parkin with Ambra1. Ambra1 is recruited in a Parkin-dependent manner to perinuclear clusters of depolarized mitochondria, activates the class III phosphatidylinositol 3-kinase (PtdIns3K) complex around these mitochondria and contributes to their selective autophagic clearance. Here, we discuss these findings and suggest a model where translocated Parkin efficiently triggers mitophagy through combined recruitment of Ambra1 and ubiquitination of outer mitochondrial membrane proteins.
基因突变在 E3 泛素连接酶 Parkin 是最常见的原因常染色体隐性帕金森病 (PD)，一种不可治愈的神经退行性疾病。Parkin 通过易位到去极化的线粒体并诱导其选择性的巨自噬去除 (mitophagy) 来检测线粒体的质量。我们最近报道 Parkin 与 Ambra1（Beclin 1 调节的自噬中的激活分子）相互作用，这是一种在脊椎动物中枢神经系统中促进自噬的蛋白质。我们发现，线粒体去极化的延长强烈增加了 Parkin 与 Ambra1 的相互作用。Ambra1 以 Parkin 依赖性方式被募集到去极化线粒体的核周簇中，在这些线粒体周围激活 III 类磷酸肌醇 3-激酶 (PtdIns3K) 复合物，并有助于它们的选择性自噬清除。在这里，我们讨论了这些发现，并提出了一个模型，其中易位的 Parkin 通过结合募集 Ambra1 和泛素化外线粒体膜蛋白来有效地触发 mitophagy。
