Abstract
ObjectivesCadmium (Cd) induces mitophagy in neuronal cells, but the underlying mechanisms remain unknown. In this study, we aimed to investigate these mechanisms.Materials and methodsThe 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.ResultsThe 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.ConclusionsThese 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.
Highlights
Cadmium (Cd), an extremely toxic environmental and occupational contaminant, is present primarily in batteries, the food chain, and cigarette smoke.[1,2] Cd can severely damage several organs,[3,4] including the brain.[5]
We suspected that in response to Cd-induced mitochondrial damages, PTEN-inducible kinase 1 (PINK1)/Parkin-mediated mitophagy was induced via AMPK phosphorylation, which could promote the clearance of damaged mitochondria, and inhibit NLPR3-mediated inflammation in neuronal cells
Mitochondrial dysfunction has been implicated in the process of neurodegeneration prominent in diseases, such as Parkinson's disease.[35]
Summary
Cadmium (Cd), an extremely toxic environmental and occupational contaminant, is present primarily in batteries, the food chain, and cigarette smoke.[1,2] Cd can severely damage several organs,[3,4] including the brain.[5]. Mitophagy regulates the mitochondrial number to match metabolic demand and might be a form of quality control to remove damaged mitochondria,[13] and it is central to the maintenance of a healthy population of mitochondria.[14] the impairment of mitophagy causes an increase in damaged mitochondria, generation of mitochondrial ROS, and release of mitochondrial DNA, which leads to overinflammation, tissue injury, and increased mortality in the host.[15,16] The most wellknown and studied mitophagy pathway, to date, has been mediated by PTEN-inducible kinase 1 (PINK1) and Parkin, which represent a crucial amplifying mechanism that renders mitophagy more efficient.[17] Mutations in this pathway contribute to the pathogenesis of neurodegenerative diseases.[18] Many mechanistic studies have been conducted to explore the role of PINK1/ Parkin pathway in vitro by using harsh mitochondrial toxins to activate mitophagy.[19] Activation of PINK1/Parkin pathway promotes ubiquitination of mitochondrial outer membrane proteins and further triggers translocation of the ubiquitin-binding receptor SQSTM1 or NDP52 to mitochondria, completing mitochondrial priming.[20,21,22]. We suspected that in response to Cd-induced mitochondrial damages, PINK1/Parkin-mediated mitophagy was induced via AMPK phosphorylation, which could promote the clearance of damaged mitochondria, and inhibit NLPR3-mediated inflammation in neuronal cells
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