mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1

Masahiro Morita, Julien Prudent, Kaustuv Basu, Vanessa Goyon, Sakie Katsumura, Laura Hulea, Dana Pearl, Nadeem Siddiqui, Stefan Strack, Shawn McGuirk, Julie St-Pierre, Ola Larsson, Ivan Topisirovic, Hojatollah Vali, Heidi M. McBride, John J. Bergeron, Nahum Sonenberg

Research output: Contribution to journalArticle

67 Scopus citations

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. Morita et al. show that mTORC1 signaling controls mitochondrial dynamics to govern cell fate decisions. mTORC1 inhibition by asTORi treatment leads to mitochondrial branching and hyperfusion through 4E-BP-dependent suppression of MTFP1 mRNA translation.

Original languageEnglish (US)
Pages (from-to)922-935.e5
JournalMolecular Cell
Volume67
Issue number6
DOIs
StatePublished - Sep 21 2017

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Keywords

  • 4E-BP
  • DRP1
  • mRNA translation
  • mTOR
  • mitochondrial fission

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Morita, 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, H. M., Bergeron, J. J., & Sonenberg, N. (2017). mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1. Molecular Cell, 67(6), 922-935.e5. https://doi.org/10.1016/j.molcel.2017.08.013