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Sökning: WFRF:(Whitworth Alexander J) > (2022) > DGAT1 activity sync...

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

Long, Maeve (författare)
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
Sanchez-Martinez, Alvaro (författare)
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom
Longo, Marianna (författare)
MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, The Sir James Black Centre, University of Dundee, Dundee, United Kingdom
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Suomi, Fumi (författare)
Translational Stem Cell Biology & Metabolism Program, Research Programs Unit, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
Stenlund, Hans (författare)
Umeå universitet,Institutionen för fysiologisk botanik,Swedish Metabolomics Centre
Johansson, Annika I. (författare)
Umeå universitet,Institutionen för fysiologisk botanik,Swedish Metabolomics Centre
Ehsan, Homa (författare)
Translational Stem Cell Biology & Metabolism Program, Research Programs Unit, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
Salo, Veijo T. (författare)
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
Montava-Garriga, Lambert (författare)
MRC 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
Naddafi, Seyedehshima (författare)
Translational Stem Cell Biology & Metabolism Program, Research Programs Unit, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
Ikonen, Elina (författare)
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
Ganley, Ian G. (författare)
MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, The Sir James Black Centre, University of Dundee, Dundee, United Kingdom
Whitworth, Alexander J. (författare)
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom
McWilliams, Thomas G. (författare)
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
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 (creator_code:org_t)
2022-04-12
2022
Engelska.
Ingår i: EMBO Journal. - : John Wiley & Sons. - 0261-4189 .- 1460-2075. ; 41
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • 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.

Ämnesord

NATURVETENSKAP  -- Biologi -- Cellbiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Cell Biology (hsv//eng)

Nyckelord

DGAT1
iron
lipid droplet
metabolism
mitophagy

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