ROS Impair Mitophagy via PARylation of PINK1

Abstract

Mitophagy is the process of selective autophagic clearance of damaged mitochondria and is closely implicated in neurodegenerative disease. PTEN-induced kinase 1 (PINK1) and a RBR E3 ubiquitin-protein ligase (Parkin) constitute a positive feedback loop in mitophagy initiation. It is known that reactive oxygen species (ROS) modulate mitophagy, while the exact regulatory mechanism remains largely elusive. Here, we found that exogenously applied ROS effectively block mitophagy induced by acute mitochondrial damage agents, which could be reversed by antioxidants. Mechanistically, ROS activate poly(ADP-ribose) polymerase 1 (PARP1), and suppression of PARP1 eliminates the inhibitory effect of ROS on mitophagy. Notably, PARP1 directly interacts with PINK1 and mediates its PARylation at residue E417, thereby negatively regulating PINK1 function. Collectively, our study identifies PARylation as a new form of post-translational modification of PINK1 and reveals a novel mechanism underlying the regulatory role of ROS in mitophagy by PARP1 activation and PARylation of PINK1. In briefGao et al. demonstrate that exogenous ROS inhibit mitophagy. Mechanistically, ROS activate PARP1, which mediates PARylation of PINK1, a central regulator of mitophagy, leading to its functional impairment. This study reveals a novel regulatory mechanism of ROS on mitophagy through PARP1 activation and identifies PARylation as a novel form of post-translational modification of PINK1. HighlightsO_LIROS block PINK1-Parkin-mediated mitophagy. C_LIO_LIROS activate PARP1. C_LIO_LIPARP1 suppression eliminates the inhibitory effect of ROS on mitophagy. C_LIO_LIPARylation of PINK1 by PARP1 impairs its activity and mitophagy. C_LI