Lipid droplets promote efficient mitophagy

Mitophagy neutralizes defective mitochondria via lysosomal elimination. Increased levels of mitophagy hallmark metabolic transitions and are induced by iron depletion, yet its metabolic basis has not been studied in-depth. How mitophagy integrates with different homeostatic mechanisms to support metabolic integrity is incompletely understood. We examined metabolic adaptations in cells treated with deferiprone (DFP), a therapeutic iron chelator known to induce PINK1-PRKN-independent mitophagy. We found that iron depletion profoundly rewired the cellular metabolome, remodeling lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurs upstream of mitochondrial turnover, with many LDs bordering mitochondria upon iron chelation. Surprisingly, DGAT1 inhibition restricts mitophagy in vitro by lysosomal dysfunction. Genetic depletion of mdy/DGAT1 in vivo impairs neuronal mitophagy and locomotor function in Drosophila, demonstrating the physiological relevance of our findings.

Automated summary

Mitophagy induced by iron depletion leads to cellular metabolome rewiring and lipid droplet biosynthesis through DGAT1, promoting mitochondrial turnover. Inhibition of DGAT1 restricts mitophagy due to lysosomal dysfunction. Genetic depletion of DGAT1 in Drosophila impairs neuronal mitophagy and locomotor function, highlighting the physiological relevance.