Abstract
Reactive oxygen species (ROS) and mitophagy are profoundly implicated in the pathogenesis of neurodegenerative diseases, such as Parkinson’s disease (PD). Several studies have suggested that ROS are not involved in mitochondrial translocation of Parkin which primes mitochondria for autophagic elimination. However, whether ROS play a role in the execution of mitophagy is unknown. In the present study, we show that carbonyl cyanide m-chlorophenylhydrazone (CCCP) treatment induced both mitochondrial depolarization and generation of ROS that were needed for the mitophagy process. Cells failed to proceed to complete mitophagy if CCCP treatment was discontinued even after recruitment of Parkin and autophagy machinery to mitochondria. Notably, treatment of pro-oxidant was able to replace CCCP treatment to take mitophagy forward, while it alone was insufficient to induce translocation of Parkin to mitochondria or autophagic clearance of mitochondria. In addition, an SOD mimetic that attenuated the superoxide level suppressed mitophagy, while an SOD inhibitor accumulated cellular superoxide and promoted mitophagy. Furthermore, blockage of the p38 signaling pathway inhibited mitophagy induced by ROS, suggesting that it may contribute to the activation of ROS-mediated mitophagy. Together, our study sheds light on the link between ROS and mitophagy at a molecular level, and suggests the therapeutic potential of regulating mitophagy through the superoxide–p38–mitophagy axis.
Highlights
Reactive oxygen species (ROS )are closely related to human health and diseases through their impact on the signaling transduction pathways and diverse physiological processes
Current research on the mechanism of Parkin/PINK1dependent mitophagy is largely focused on the translocation of Parkin to the damaged mitochondria, with the view that mitophagy will proceed towards completion upon the fulfillment of this prerequisite step
Translocation of p62 to the mitochondria was detected in Parkin-expressing cells as early as 0.5 h post-carbonyl cyanide m-chlorophenylhydrazone (CCCP) treatment, p62 was absent in a proportion of Parkin-positive mitochondria (Figure 1a), indicating that p62 translocation to the mitochondria likely lies downstream of Parkin recruitment to mitochondria
Summary
Reactive oxygen species (ROS )are closely related to human health and diseases through their impact on the signaling transduction pathways and diverse physiological processes. ROS cause damage to proteins, lipids and DNA in neurons.[1,2] Gain or loss of function in PD-related genes has been found to increase intracellular ROS levels, thereby promoting ROS-induced cell death.[3,4]. An important cellular process of quality control, maintains cellular homeostasis by eliminating deleterious damaged proteins or organelles, which would otherwise be accumulated, leading to neurodegenerative diseases.[5,6]. It has been widely considered as a culprit for neurodegenerative diseases, ROS may confer protection to cells by regulating autophagy. Dysfunction of Parkin/PINK1-dependent mitophagy contributes to the pathogenesis of PD.[9,10] In mitophagy, PINK1 phosphorylates and activates Parkin[11,12] and ubiquitin.[13,14,15]
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