A Novel and Evolutionarily Conserved Metabolic Axis for Efficient Hepatic Lipid Catabolism Governed by Mfn2-Hsl-Mediated Mitochondria-Lipid Droplet Coupling

Inter-organelle contact between mitochondria and lipid droplets (LDs) is crucial for hepatic lipid homeostasis, but the tethering complex underlying this interaction remains unclear. To address this, we aimed to characterize the molecular machinery governing mitochondria-LD coupling and evaluate the evolutionary conservation of its metabolic functions. Using hepatocyte models from multiple species and in vivo experiments in yellow catfish with differential lipid and creatine diets, we explored the mechanism and evolutionary conservation of mitochondria-LD coupling. The key findings were: (1) A novel complex formed by mitofusin 2 on mitochondria and hormone-sensitive lipase on lipid droplets via specific residues orchestrates efficient hepatic lipid catabolism by mediating mitochondria-LD coupling; (2) Creatine enhances this coupling by transcriptionally upregulating mfn2 via hnf4, thereby promoting peridroplet mitochondria formation and alleviating hepatic lipid accumulation; (3) The Mfn2-phosphorylated HSL axis is evolutionarily conserved across fish and mammals, representing a potential therapeutic target for hepatic steatosis.