mTOR controls mitochondrial dynamics and cell survival via MTFP1 Julien Prudent1, Masahiro Morita2,3, John J. Bergeron4,Heidi H. McBride5, Nahum Sonenberg3 1Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; 2Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A1A3, Canada; 3Department of Molecular Medicine and Barshop Institute of Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX 78229, USA; 4Department of Medicine, McGill University Health Centre Research Institute, Montreal, QC H4A 3J1, Canada; 5Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada
The mechanisms that link environmental and intracellular stimuli to mitochondrial functions, including fission and fusion, ATP production, metabolite biogenesis and apoptosis, are not well understood. Here, we demonstrate that the nutrient-sensing mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates translation of mitochondrial fission process 1 (MTFP1) to control mitochondrial fission and apoptosis. Expression of MTFP1 is coupled to the phosphorylation states and the mitochondrial recruitment of the fission GTPase, dynamin-related protein 1 (DRP1). Potent active-site mTOR inhibitors lead to mitochondrial hyperfusion due to the diminished translation of MTFP1 mediated by the translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs). Uncoupling MTFP1 levels from the mTORC1/4E-BP pathway upon mTOR inhibition blocks the hyperfusion response and leads to mitochondrial fragmentation and apoptosis by converting mTOR inhibitor action from cytostatic to cytotoxic. These data provide direct evidence for the survival function of mitochondrial hyperfusion upon mTOR inhibition by employing MTFP1 as a critical effector of mTORC1 to govern cell fate decisions.
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