Department of Neurology, National Neuroscience Institute, Singapore; Department of Neurology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China.
Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore.
Biochim Biophys Acta Mol Cell Res. 2017 Jul;1864(7):1308-1317. doi: 10.1016/j.bbamcr.2017.04.009. Epub 2017 Apr 19.
Parkin/PINK1-mediated mitophagy is implicated in the pathogenesis of Parkinson's disease (PD). Prior to elimination of damaged mitochondria, Parkin translocates to mitochondria and induces mitochondrial clustering. While the mechanism of PINK1-dependent Parkin redistribution to mitochondria is now becoming clear, the role of mitochondrial clustering has been less well understood. In our study, we found that loss of p62 disrupted mitochondrial aggregation and specifically sensitized Parkin-expressing cells to apoptosis induced by mitochondrial depolarization. Notably, altering mitochondrial aggregation through regulating p62 or other methods was sufficient to affect such apoptosis. Moreover, disruption of mitochondrial aggregation promoted proteasome-dependent degradation of outer mitochondrial membrane (OMM) proteins. The accelerated degradation in turn facilitated cytochrome c release from mitochondria, leading to apoptosis. Together, our study demonstrates a protective role of mitochondrial clustering in mitophagy and helps in understanding how aggregation defends cells against stress.
Parkin/PINK1 介导的线粒体自噬与帕金森病（PD）的发病机制有关。在清除受损线粒体之前，Parkin 会转移到线粒体并诱导线粒体聚集。虽然 PINK1 依赖性 Parkin 再分布到线粒体的机制现在已经清楚，但线粒体聚集的作用还不太清楚。在我们的研究中，我们发现 p62 的缺失破坏了线粒体的聚集，并特异性地使表达 Parkin 的细胞对线粒体去极化诱导的细胞凋亡敏感。值得注意的是，通过调节 p62 或其他方法改变线粒体聚集足以影响这种细胞凋亡。此外，破坏线粒体聚集促进了蛋白酶体依赖的外膜（OMM）蛋白的降解。这种加速的降解反过来促进了细胞色素 c 从线粒体中的释放，导致细胞凋亡。总之，我们的研究表明线粒体聚集在线粒体自噬中具有保护作用，并有助于理解聚集如何保护细胞免受应激。
