Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan.
J Biol Chem. 2011 Jun 3;286(22):19630-40. doi: 10.1074/jbc.M110.209338. Epub 2011 Mar 18.
Upon mitochondrial depolarization, Parkin, a Parkinson disease-related E3 ubiquitin ligase, translocates from the cytosol to mitochondria and promotes their degradation by mitophagy, a selective type of autophagy. Here, we report that in addition to mitophagy, Parkin mediates proteasome-dependent degradation of outer membrane proteins such as Tom20, Tom40, Tom70, and Omp25 of depolarized mitochondria. By contrast, degradation of the inner membrane and matrix proteins largely depends on mitophagy. Furthermore, Parkin induces rupture of the outer membrane of depolarized mitochondria, which also depends on proteasomal activity. Upon induction of mitochondrial depolarization, proteasomes are recruited to mitochondria in the perinuclear region. Neither proteasome-dependent degradation of outer membrane proteins nor outer membrane rupture is required for mitophagy. These results suggest that Parkin regulates degradation of outer and inner mitochondrial membrane proteins differently through proteasome- and mitophagy-dependent pathways.
在线粒体去极化时，帕金森病相关的 E3 泛素连接酶 Parkin 从细胞质转位到线粒体，并通过自噬（一种选择性的自噬类型）促进其降解。在这里，我们报告除了自噬外，Parkin 还介导去极化线粒体的外膜蛋白（如 Tom20、Tom40、Tom70 和 Omp25）的蛋白酶体依赖性降解。相比之下，内膜和基质蛋白的降解在很大程度上依赖于自噬。此外，Parkin 诱导去极化线粒体的外膜破裂，这也依赖于蛋白酶体活性。在线粒体去极化诱导时，蛋白酶体被募集到核周区域的线粒体中。外膜蛋白的蛋白酶体依赖性降解和外膜破裂都不是自噬所必需的。这些结果表明，Parkin 通过蛋白酶体和自噬依赖性途径调节线粒体内外膜蛋白的降解方式不同。
