mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1.

TitlemTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1.
Publication TypeJournal Article
Year of Publication2017
AuthorsMorita, M, Prudent, J, Basu, K, Goyon, V, Katsumura, S, Hulea, L, Pearl, D, Siddiqui, N, Strack, S, McGuirk, S, St-Pierre, J, Larsson, O, Topisirovic, I, Vali, H, McBride, HM, Bergeron, JJ, Sonenberg, N
JournalMol Cell
Volume67
Issue6
Pagination922-935.e5
Date Published2017 Sep 21
ISSN1097-4164
KeywordsApoptosis, Carrier Proteins, Cell Line, Tumor, Cell Survival, CRISPR-Cas Systems, Dynamins, Eukaryotic Initiation Factors, Humans, Membrane Proteins, Mitochondria, Mitochondrial Dynamics, Multiprotein Complexes, Phosphoproteins, Phosphorylation, Protein Kinase Inhibitors, RNA Interference, Signal Transduction, TOR Serine-Threonine Kinases, Transfection
Abstract

The mechanisms that link environmental and intracellular stimuli to mitochondrial functions, including fission/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 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, which is mediated by 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 apoptosis by converting mTOR inhibitor action from cytostatic to cytotoxic. These data provide direct evidence for cell survival upon mTOR inhibition through mitochondrial hyperfusion employing MTFP1 as a critical effector of mTORC1 to govern cell fate decisions.

DOI10.1016/j.molcel.2017.08.013
Alternate JournalMol. Cell
Citation Key10.1016/j.molcel.2017.08.013
PubMed ID28918902