Cadmium induces mitophagy via AMP‐activated protein kinases activation in a PINK1/Parkin‐dependent manner in PC12 cells

OBJECTIVES: Cadmium (Cd) induces mitophagy in neuronal cells, but the underlying mechanisms remain unknown. In this study, we aimed to investigate these mechanisms. MATERIALS AND METHODS: The effects of Cd on the mitophagy in rat pheochromocytoma PC12 cells were detected, and the role of PINK1/Parkin pathway in Cd‐induced mitophagy was also analysed by using PINK1 siRNA. In order to explore the relationship between AMPK and PINK1/Parkin in Cd‐induced mitophagy in PC12 cells, the CRISPR‐Cas9 system was used to knock down AMPK expression. RESULTS: The results showed that Cd treatment triggered a significant increase in mitophagosome formation and the colocalization of mitochondria and lysosomes, which was further proved by the colocalization of LC3 puncta and its receptors NDP52 or P62 with mitochondria in PC12 cells. Moreover, an accumulation of PINK1 and Parkin was found in mitochondria. Additionally, upon PINK1 knock‐down using PINK1 siRNA, Cd‐induced mitophagy was efficiently suppressed. Interestingly, chemical or genetic reversal of AMPK activation: (a) significantly inhibited the activation of mitophagy and (b) promoted NLRP3 activation by inhibiting PINK/Parkin translocation. CONCLUSIONS: These results suggest that Cd induces mitophagy via the PINK/Parkin pathway following AMPK activation in PC12 cells. Targeting the balanced activity of AMPK/PINK1/Parkin‐mediated mitophagy signalling may be a potential therapeutic approach to treat Cd‐induced neurotoxicity.