Identification of molecular mechanism of mitochondrial quality control by PINK1-Parkin pathway

果蝇遗传学和细胞生物学研究表明，两个帕金森氏病相关基因PINK1和Parkin参与了线粒体的维持。Parkin被激活，并以PINK1活性不依赖的方式移位到受损的线粒体。然而，尚不清楚PINK1是如何将帕金招募到受损的线粒体中的。在这项研究中发现，PINK1在线粒体膜电位降低时使Parkin磷酸化，这是有效的Parkin线粒体易位所必需的。我们的研究还揭示了在表达野生型或突变型Parkin(SA，SE)的果蝇中Parkin磷酸化的生物学意义。在体内，我们认为PINK1介导的Parkin的磷酸化增强了其泛素连接酶的活性，而Parkin的结构性激活可能会损伤线粒体，降解线粒体蛋白Mitofusin、Miro和线粒体呼吸复合体蛋白。

Drosophila genetics and cell biological studies have revealed that two Parkinson's disease-associated genes PINK1 and parkin are involved in the mitochondrial maintenance. Parkin is activated and translocated to damaged mitochondria in a PINK1 activity depenednt manner. However, it was unclear how PINK1 recruits Parkin to the damaged mitochondria. In this study found that Parkin is phosphorylated by PINK1 upon reduction of mitochondrial membrane potential, which is required for effective Parkin mitochondrial translocation. Our study also revealed that the biological significance of Parkin phosphorylation using Drosophila expressing wild-type or mutant forms of Parkin (SA, SE). In vivo, we suggested that PINK1 mediated phosphorylation of Parkin boosts its ubiquitin-ligase activity and that constitutive activation of Parkin could damage mitochondria, degrading mitochondrial proteins Mitofusin, Miro and the mitochondrial respiratory complex proteins.