DGAT1 activity synchronises with mitophagy to protect cells from metabolic rewiring by iron  depletion

Abstract

Mitophagy removes defective mitochondria via lysosomal elimination. Increased mitophagy coincides with metabolic reprogramming, yet it remains unknown whether mitophagy is a cause or consequence of such state changes. The signalling pathways that integrate with mitophagy to sustain cell and tissue integrity also remain poorly defined. We performed temporal metabolomics on mammalian cells treated with deferiprone, a therapeutic iron chelator that stimulates PINK1/PARKIN‐independent mitophagy. Iron depletion profoundly rewired the metabolome, hallmarked by remodelling of lipid metabolism within minutes of treatment. DGAT1‐dependent lipid droplet biosynthesis occurred several hours before mitochondrial clearance, with lipid droplets bordering mitochondria upon iron chelation. We demonstrate that DGAT1 inhibition restricts mitophagy in vitro, with impaired lysosomal homeostasis and cell viability. Importantly, genetic depletion of DGAT1 in vivo significantly impaired neuronal mitophagy and locomotor function in Drosophila. Our data define iron depletion as a potent signal that rapidly reshapes metabolism and establishes an unexpected synergy between lipid homeostasis and mitophagy that safeguards cell and tissue integrity.

AI-guided screen identifies probucol-mediated mitophagy enhancement through modulation of lipid droplets

“…and by Long et al . which demonstrate increase lipid droplet levels upon starvation-induced autophagy and deferiprone-induced mitophagy 25,26 . The two studies attribute different roles for LDs in these contexts.…”

The goodies of chelated fat: iron‐regulated lipid droplet biogenesis precedes and preserves mitophagy

“…The data by Long et al (2022) support that increased NEFA esterification, rather than de novo NEFA synthesis, is the main process contributing to DFP‐induced lipid droplet expansion. While no metabolite tracing and fluxes measurements were performed to directly measure de novo NEFA synthesis, the dependency on DGAT1, rather than DGAT2, supports that DFP selectively increases NEFA esterification.…”

“…In this issue of The EMBO Journal , Long et al (2022) determine the metabolic effects induced by iron chelation that precede the onset of mitophagic events. The first unexpected finding was that just 2 h of DFP treatment induced a metabolomics profile characteristic of a selective downregulation in peroxisomal fatty acid oxidation, rather than of mitochondrial beta oxidation.…”

“…Then, Long et al (2022) determined whether lipid droplet expansion mediated by DGAT1 was required for mitophagy. To this end, the different stages of the mitophagic process were measured in DFP‐treated cells in the presence of DGAT1 inhibitors, and in flies with a knock down for their DGAT1 homologue.…”

“…The findings by Long et al (2022) open new interesting avenues of research: The first one is to determine the exact molecular mechanism by which iron chelation acutely regulates lipid metabolism. Is it via direct changes on peroxisome function?…”