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  • Long, MaeveTranslational 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 (author)

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

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • 2022-04-12
  • John Wiley & Sons,2022
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:umu-193974
  • https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-193974URI
  • https://doi.org/10.15252/embj.2021109390DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:149301977URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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.

Subject headings and genre

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  • Sanchez-Martinez, AlvaroMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom (author)
  • Longo, MariannaMRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, The Sir James Black Centre, University of Dundee, Dundee, United Kingdom (author)
  • Suomi, FumiTranslational Stem Cell Biology & Metabolism Program, Research Programs Unit, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (author)
  • Stenlund, HansUmeå universitet,Institutionen för fysiologisk botanik,Swedish Metabolomics Centre(Swepub:umu)hasstd97 (author)
  • Johansson, Annika I.Umeå universitet,Institutionen för fysiologisk botanik,Swedish Metabolomics Centre(Swepub:umu)joan5601 (author)
  • Ehsan, HomaTranslational Stem Cell Biology & Metabolism Program, Research Programs Unit, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (author)
  • Salo, Veijo T.Translational Stem Cell Biology & Metabolism Program, Research Programs Unit, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Department of Anatomy, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland; Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany (author)
  • Montava-Garriga, LambertMRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, The Sir James Black Centre, University of Dundee, Dundee, United Kingdom; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, United Kingdom (author)
  • Naddafi, SeyedehshimaTranslational Stem Cell Biology & Metabolism Program, Research Programs Unit, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (author)
  • Ikonen, ElinaTranslational Stem Cell Biology & Metabolism Program, Research Programs Unit, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Department of Anatomy, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland (author)
  • Ganley, Ian G.MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, The Sir James Black Centre, University of Dundee, Dundee, United Kingdom (author)
  • Whitworth, Alexander J.MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom (author)
  • McWilliams, Thomas G.Translational Stem Cell Biology & Metabolism Program, Research Programs Unit, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Department of Anatomy, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (author)
  • 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, SwedenMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom (creator_code:org_t)

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  • In:EMBO Journal: John Wiley & Sons410261-41891460-2075

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