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) protein to control mitochondrial fission and apoptosis. Expression of MTFP1 is coupled to pro-fission phosphorylation and mitochondrial recruitment of the fission GTPase,
dynamin-related protein 1 (DRP1). Potent active-site mTOR inhibitors engender 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 mTORC1/4EBP
pathway upon mTOR inhibition blocks the hyperfusion response and leads to 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
