Intracellular lipid metabolism, encompassing the synthesis, storage, mobilization, and utilization of lipids, is essential for cellular homeostasis, energy provision, and regulation of physiological processes. Disruptions in lipid metabolism are linked to metabolic disorders such as obesity, diabetes, and cardiovascular diseases. Lipid droplets (LDs) and mitochondria are key organelles in managing cellular lipid metabolism to maintain energy homeostasis and overall health.
During starvation, cells employ two main LD utilization pathways: transferring fatty acids (FAs) to mitochondria for β-oxidation and degrading LDs through lipophagy. Our research has uncovered a pivotal role for PISD-LD, a lipid droplet-localized enzyme, as a metabolic switch that orchestrates these pathways. PISD-LD promotes LD-mitochondria contacts, facilitating efficient FA transfer while simultaneously inhibiting lipophagy. This dynamic regulation ensures cells remain metabolically adaptable during nutrient stress, positioning PISD-LD as a crucial regulator of energy homeostasis and metabolic flexibility.