MTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation

Masahiro Morita, Simon Pierre Gravel, Valérie Chénard, Kristina Sikström, Liang Zheng, Tommy Alain, Valentina Gandin, Daina Avizonis, Meztli Arguello, Chadi Zakaria, Shannon McLaughlan, Yann Nouet, Arnim Pause, Michael Pollak, Eyal Gottlieb, Ola Larsson, Julie St-Pierre, Ivan Topisirovic, Nahum Sonenberg

Research output: Contribution to journalArticle

337 Scopus citations

Abstract

mRNA translation is thought to be the most energy-consuming process in the cell. Translation and energy metabolism are dysregulated in a variety of diseases including cancer, diabetes, and heart disease. However, the mechanisms that coordinate translation and energy metabolism in mammals remain largely unknown. The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates mRNA translation and other anabolic processes. We demonstrate that mTORC1 controls mitochondrial activity and biogenesis by selectively promoting translation of nucleus-encoded mitochondria-related mRNAs via inhibition of the eukaryotic translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs). Stimulating the translation of nucleus-encoded mitochondria-related mRNAs engenders an increase in ATP production capacity, a required energy source for translation. These findings establish a feed-forward loop that links mRNA translation to oxidative phosphorylation, thereby providing a key mechanism linking aberrant mTOR signaling to conditions of abnormal cellular energy metabolism such as neoplasia and insulin resistance.

Original languageEnglish (US)
Pages (from-to)698-711
Number of pages14
JournalCell Metabolism
Volume18
Issue number5
DOIs
StatePublished - Nov 5 2013
Externally publishedYes

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ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Morita, M., Gravel, S. P., Chénard, V., Sikström, K., Zheng, L., Alain, T., Gandin, V., Avizonis, D., Arguello, M., Zakaria, C., McLaughlan, S., Nouet, Y., Pause, A., Pollak, M., Gottlieb, E., Larsson, O., St-Pierre, J., Topisirovic, I., & Sonenberg, N. (2013). MTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. Cell Metabolism, 18(5), 698-711. https://doi.org/10.1016/j.cmet.2013.10.001