نبذة مختصرة : 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. ; Peer reviewed
Relation: We thank A. Suomalainen (Helsinki) for useful discussions. Research in the T.G.M. laboratory is supported by the Academy of Finland (TGM: 310814), the Novo Nordisk Foundation/Novo Nordisk Fonden, the Sigrid Juselius Foundation (TGM: 8045); Sydantutkimussaatio and the University of Helsinki. We are grateful to M. Liljestrom and K. Vonderstein at Biomedicum Imaging Unit (Biocenter Finland and HiLIFE supported infrastructure) for their outstanding expertise and microscopy support. We also thank A. Hassinen (FIMM High Content Imaging and Analysis Unit, HiLIFE, Helsinki) for excellent input and advice with high-throughput microscopy. We further thank P. Bergman for biostatistical advice and K.M. Mattinen and J. Salomaa for technical assistance at the initial phases of the project. Work in A.J.W. laboratory (MRC MBU, Cambridge) is supported by Medical Research Council core funding (AJW: MC_UU_00015/6). Stocks were obtained from the Bloomington Drosophila Stock Center, which is supported by grant NIH P40OD018537. Work in I.G.G. laboratory (MRC PPU, Dundee) is supported by a grant from the Medical Research Council, UK (IGG: MC_UU_00018/2) and excellent technical support from the sequencing service (School of Life Sciences, University of Dundee) and the MRC PPU Reagents and Services antibody purification teams (coordinated by J. Hastie and H. McLauchlan. Work in E.I. laboratory is supported by the Academy of Finland (EI: 324929), Sigrid Juselius Foundation (EI), Jane and Aatos Erkko Foundation (EI), Fondation Leducq (EI: 19CVD04). We acknowledge staff at the Swedish Metabolomics Centre, Umea, Sweden (www.swedishmetabolomicscentre.se) for metabolomics and lipidomics screening.; http://hdl.handle.net/10138/346081; 000780832100001
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