McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
EMBO Rep. 2012 Apr;13(4):378-85. doi: 10.1038/embor.2012.14.
Mutations in phosphatase and tensin homologue-induced kinase 1 (PINK1) cause recessively inherited Parkinson's disease (PD), a neurodegenerative disorder linked to mitochondrial dysfunction. In healthy mitochondria, PINK1 is rapidly degraded in a process involving both mitochondrial proteases and the proteasome. However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy. These results highlight a new role for MPP in PINK1 import and mitochondrial quality control via the PINK1–Parkin pathway.
磷酸酶和张力蛋白同源物诱导激酶 1（PINK1）突变导致常染色体隐性遗传帕金森病（PD），这是一种与线粒体功能障碍相关的神经退行性疾病。在健康的线粒体中，PINK1 会迅速降解，这一过程既涉及线粒体蛋白酶，也涉及蛋白酶体。然而，当线粒体的摄取因去极化而受损时，PINK1 会在其表面积累，从而从细胞质中招募与 PD 相关的 E3 泛素连接酶 Parkin，后者反过来介导功能失调细胞器的自噬性破坏。通过使用无偏见的 RNA 介导的干扰（RNAi）为基础的筛选，我们鉴定了四种参与 PINK1 降解的线粒体蛋白酶，即线粒体加工肽酶（MPP）、早老素相关的类 Rhomboid 蛋白酶（PARL）、m-AAA 和 ClpXP。我们发现，PINK1 的周转对 MPP 水平的适度降低特别敏感。此外，MPP 对 PINK1 的切割与摄取偶联，因此降低 MPP 活性会导致 PINK1 在线粒体表面积累，从而导致 Parkin 的募集和线粒体自噬。这些结果突出了 MPP 在 PINK1 导入和通过 PINK1-Parkin 通路的线粒体质量控制中的新作用。
