DGAT1 activity synchronises with mitophagy to protect cells from metabolic rewiring by iron depletion
| Autor: | 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, McWilliams, Thomas G |
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| Přispěvatelé: | STEMM - Stem Cells and Metabolism Research Program, Faculty of Medicine, Medicum, University of Helsinki, Research Programs Unit, Department of Anatomy, Lipid Trafficking Lab, Long, Maeve [0000-0001-5146-0750], Sanchez-Martinez, Alvaro [0000-0002-2728-6251], Suomi, Fumi [0000-0001-8883-3338], Stenlund, Hans [0000-0001-9943-296X], Johansson, Annika I [0000-0001-5000-1288], Ehsan, Homa [0000-0001-5252-4015], Salo, Veijo T [0000-0002-6991-2142], Montava-Garriga, Lambert [0000-0003-0025-5700], Naddafi, Seyedehshima [0000-0001-6187-1967], Ikonen, Elina [0000-0001-8382-1135], Ganley, Ian G [0000-0003-1481-9407], Whitworth, Alexander J [0000-0002-1154-6629], McWilliams, Thomas G [0000-0002-9570-4152], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Cellbiologi
Ubiquitin-Protein Ligases GLYCOLYSIS ENDOPLASMIC-RETICULUM lipid droplet General Biochemistry Genetics and Molecular Biology iron MITOCHONDRIA Animals OXIDATIVE STRESS Molecular Biology ULK1 DGAT1 Mammals General Immunology and Microbiology General Neuroscience OPHTHALMIC ACID Cell Biology mitophagy MITO-QC LIPID DROPLETS 1182 Biochemistry cell and molecular biology AUTOPHAGY FATTY-ACIDS Lysosomes Protein Kinases metabolism |
| Popis: | Funder: Novo Nordisk Foundation/Novo Nordisk Fonden; Id: http://dx.doi.org/10.13039/501100011747 Funder: Helsingin Yliopisto (HY); Id: http://dx.doi.org/10.13039/100007797 Funder: Sydäntutkimussäätiö (Finnish Foundation for Cardiovascular Research); Id: http://dx.doi.org/10.13039/501100005633 Funder: Jane and Aatos Erkko Foundation; Id: http://dx.doi.org/10.13039/501100004012 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. |
| Databáze: | OpenAIRE |
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