Copper-Induced DRP1 Activation Disrupts Mitochondrial-Lipid Droplet Contact to Promote Hepatic Steatosis

Copper (Cu) is a vital dietary element for both humans and animals and is widely supplemented in food. However, excessive consumption of this trace element can adversely affect the overall well-being. Previous studies have demonstrated that long-term Cu intake can lead to severe hepatotoxicity. The underlying mechanism by which Cu induces disturbances in hepatic energy metabolism through modulation of mitochondria-lipid droplet (LD) contacts, however, is not known. In this study, we found that Cu exposure significantly disrupted the interaction between mitochondria and LDs, leading to the downregulation of perilipin 2 (PLIN2), perilipin 5 (PLIN5), synaptosomal-associated protein 23 (SNAP23), diacylglycerol acyltransferase 2 (DGAT2), and caveolin-1 (Cav-1) proteins in chicken livers. Mechanistically, we demonstrated that Cu exposure-induced dynamin-related protein 1 (DRP1) protein activation disrupted mitochondria-LD contacts by regulating PLIN2. DRP1 knockdown and PLIN2 overexpression efficiently promoted the mitochondria-LD contacts, alleviating Cu-induced LD accumulation in chicken primary hepatocytes. However, PLIN2 knockdown significantly exacerbated the mitochondria-LD contact disorder induced by Cu exposure. Moreover, PLIN2 knockdown dramatically reversed the ability of DRP1 knockdown to promote mitochondria-LD contacts, while overexpression of PLIN2 had the opposite effect. Overall, our study revealed that the DRP1-PLIN2 axis regulates the connections between mitochondria and LDs under Cu exposure, which may provide a new perspective on Cu exposure-induced lipid metabolism disorders in hepatocytes.