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

Maeve Long, Alvaro Sanchez-Martinez, Marianna Longo, Fumi Suomi, Hans Stenlund, Annika I. Johansson, Homa Ehsan, Veijo T. Salo, Lambert Montava-Garriga, Seyedehshima Naddafi, Elina Ikonen, Ian G. Ganley, Alexander J. Whitworth, Thomas G. McWilliams (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)
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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.

Original languageEnglish
Article numbere109390
Number of pages25
JournalThe EMBO Journal
Volume41
Issue number10
Early online date12 Apr 2022
DOIs
Publication statusPublished - 16 May 2022

Keywords

  • DGAT1
  • iron
  • lipid droplet
  • metabolism
  • mitophagy

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