1. DGAT1 activity synchronises with mitophagy to protect cells from metabolic rewiring by iron depletion.
- Author
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Long, Maeve, Sanchez‐Martinez, Alvaro, Longo, Marianna, Suomi, Fumi, Stenlund, Hans, Johansson, Annika I, Ehsan, Homa, Salo, Veijo T, Montava‐Garriga, Lambert, Naddafi, Seyedehshima, Ikonen, Elina, Ganley, Ian G, Whitworth, Alexander J, and McWilliams, Thomas G
- Subjects
IRON ,IRON chelates ,LIPID metabolism ,LYSOSOMES ,CELL survival ,CELLULAR signal transduction ,HOMEOSTASIS ,CHELATION - 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. Synopsis: Whether removal of defective mitochondria is cause or consequence of metabolic reprogramming in highly energy‐demanding cells remains unclear. This study reports metabolic effects of mitochondrial iron depletion, as well as unexpected synergy between lipid droplet (LD) biogenesis and mitophagy sustaining cell and tissue integrity. Mitophagy‐inducing iron depletion reshapes the mammalian metabolome with highly selective effects on lipid metabolism.Loss of iron induces diacylglycerol O‐acyltransferase 1 (DGAT1)‐dependent LD biosynthesis upstream of PINK1/Parkin‐independent mitophagy.Impaired LD biogenesis restricts mitophagy, triggering aberrant lipid metabolism, endolysosomal dysfunction and impaired cell viability.Neuron‐specific depletion of DGAT1 (mdy) impairs physiological mitophagy and leads to locomotor dysfunction in Drosophila. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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