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DGAT1 activity synchronises with mitophagy to protect cells from metabolic rewiring by iron depletion
Translational Stem Cell Biology & Metabolism Program, Research Programs Unit, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom.
MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, The Sir James Black Centre, University of Dundee, Dundee, United Kingdom.
Translational Stem Cell Biology & Metabolism Program, Research Programs Unit, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
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2022 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 41, article id e109390Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022. Vol. 41, article id e109390
Keywords [en]
DGAT1, iron, lipid droplet, metabolism, mitophagy
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:umu:diva-193974DOI: 10.15252/embj.2021109390ISI: 000780832100001PubMedID: 35411952Scopus ID: 2-s2.0-85128030914OAI: oai:DiVA.org:umu-193974DiVA, id: diva2:1655463
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Novo NordiskAvailable from: 2022-05-02 Created: 2022-05-02 Last updated: 2023-03-24Bibliographically approved

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Stenlund, HansJohansson, Annika I.

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