PISD acts as a switch between lipophagy and fatty acid transfer to mitochondria

Fatty acids (FAs) are transported from lipid droplets (LDs) to mitochondria for β-oxidation during cell starvation. Starvation also triggers engulfment of LDs by autophagosomes and their subsequent degradation by lysosomes (lipophagy). The mechanisms coordinating these pathways remain unclear. Here, we demonstrate that PISD-LD, an LD-localized isoform of phosphatidylserine decarboxylase, facilitates FA transfer while inhibiting lipophagy. PISD-LD mediates LD–mitochondrion (LD-mito) contacts via interaction with mitochondrial PISD. In PISD-LD KD cells, LDs are larger, and FA trafficking and mitochondrial FA β-oxidation are suppressed. The lipid transfer proteins ATG2A/B are recruited by PISDs to mediate FA transfer from LDs to mitochondria. Disruption of PISD-LD–mediated LD-mito contacts activates lipophagy, aiding LD degradation. PISD-LD binds the lipophagy receptor Spartin and inhibits lipophagy by impeding Spartin-LC3 interaction. PISD-LD also regulates LD-mito contacts and lipid metabolism in mouse liver. Thus, PISD-LD serves as a switch between LD-to-mitochondrion FA transfer and lipophagy, ensuring efficient energy production.