p62-Mediated mitochondrial clustering attenuates apoptosis induced by mitochondrial depolarization

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.