Data Availability StatementThe data that support the results of this study are available from your corresponding author upon reasonable request. 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. strong class=”kwd-title” Keywords: AMPK, cadmium (Cd), mitophagy, PC12 cells, PINK1/Parkin 1.?INTRODUCTION 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 It has been reported that Cd can cause neuronal degenerative disease, in which Levalbuterol tartrate mitochondrial dysfunction plays a large role. 6 The molecular mechanisms underlying Cd toxicity are multiple and complex. We have previously identified that Cd\triggered autophagy plays an important anti\apoptotic and anti\senescent role in both primary Rabbit Polyclonal to JAK2 (phospho-Tyr570) rat neurons and PC12 cells. 7 , 8 , 9 Furthermore, it has been demonstrated that Cd\induced cytotoxicity in Levalbuterol tartrate primary rat proximal tubular cells can be attributed to the inhibition of the cytosolic Ca2+\dependent autophagosome\lysosome fusion. 10 , 11 Accumulating evidence indicates that Compact disc exposure qualified prospects to mitochondrial reduction in cells; nevertheless, the mechanisms root Compact disc induces mitochondrial reduction during Compact disc\induced neurotoxicity aren’t fully realized. Mitochondria are crucial for maintaining adequate cellular ATP amounts to sustain the experience of the mind. 12 Under demanding conditions, mitochondria are recruited into isolation membranes selectively, which seal and fuse with lysosomes to remove the stuck mitochondria after that, a process referred to as mitophagy. Mitophagy regulates the mitochondrial quantity to complement metabolic demand and may also be considered a type of quality control to eliminate broken mitochondria, 13 which is central towards the maintenance of a wholesome inhabitants of mitochondria. 14 Furthermore, the impairment of mitophagy causes a rise in broken mitochondria, era of mitochondrial ROS, and launch of mitochondrial DNA, that leads to overinflammation, cells injury, and improved mortality Levalbuterol tartrate in the sponsor. 15 , 16 Probably the most researched and well\known mitophagy pathway, to day, continues to be mediated by PTEN\inducible kinase 1 (Red1) and Parkin, which represent an essential amplifying mechanism that renders better mitophagy. 17 Mutations with this pathway donate 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, thus completing mitochondrial priming. 20 , 21 , 22 It was recently reported that Cd induced mitochondrial loss via the overactivation of mitophagy in several different types of cells and organs. 23 , 24 , 25 , 26 However, the causative role of PINK1/Parkin\mediated mitophagy in neurodegeneration is still under investigation. 5\AMP\activated protein kinase (AMPK) has been extensively studied and highly implicated in neurons. 27 It has been reported that AMPK and unc\51\like autophagy activating kinase 1 (Ulk1) play critical roles in mitophagy in primary hepatocytes and erythrocytes. 28 Levalbuterol tartrate , 29 , 30 The association of AMPK with Ulk1 regulates autophagy and phosphorylation at multiple sites. 31 Moreover, it has been identified that AMPK could activate mitophagy to prevent heart failure via PINK1 phosphorylation. 32 Above all, 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.