Loss of Lipid Droplet-Mitochondria contacts confers protection against Ethanol-induced cardiotoxicity.

Abstract

EtOH (Ethanol)-induced cardiotoxicity (EIC) is intimately associated with perturbed lipid metabolism. Lipid droplet-Mitochondria contacts (LD-Mito contacts) are important nodes in lipid metabolism. However, the roles of LD-Mito contacts in EIC have yet to be clarified. In the present study, EtOH exposure induced a significant build-up of LD in cardiomyocytes accompanied by the disturbances in lipogenesis and lipolysis. Upon EtOH treatment, we also observed a substantial decrease in LD-Mito contacts, downregulation of the tethering protein PLIN5 (Perilipin 5), and reduced fatty acid (FA) flux from LD to mitochondria. Overexpression of full-length PLIN5, but not its truncated form (PLIN5Δ), reversed the reduction in LD-Mito contacts and restored FA flux. A synthetic LD-Mito-Linker was generated to exclude the influence of PLIN5's versatile functions and investigate the specific role of LD-Mito contacts in EIC. Tethering LD to mitochondria by the synthetic linker restored the LD-Mito contacts and FA flux in EtOH-treated cardiomyocytes. Inflammation and cardiomyocyte death were measured to indicate lipotoxicity in EIC. Our results demonstrated that overexpression of PLIN5Δ ameliorated EtOH-induced cardiomyocytes death and inflammation whereas restoration of LD-Mito contacts by the synthetic linker aggravated apoptosis, inflammatory response, oxidative stress and Mitochondrial membrane potential depolarization . These findings indicated that loss of LD-Mito contacts and the blocked FA flux may act as a cellular adaptive response to EtOH exposure, thus targeting LD-Mito contacts may serve as a potential therapeutic strategy to combat EIC.