mTORC1 Controls Mitochondrial Activity and Biogenesis through 4E-BP-Dependent Translational Regulation

• Published in: Cell metabolism Vol. 18; no. 5; pp. 698 - 711
• Main Authors: Morita, Masahiro, Gravel, Simon-Pierre, Chénard, Valérie, Sikström, Kristina, Zheng, Liang, Alain, Tommy, Gandin, Valentina, Avizonis, Daina, Arguello, Meztli, Zakaria, Chadi, McLaughlan, Shannon, Nouet, Yann, Pause, Arnim, Pollak, Michael, Gottlieb, Eyal, Larsson, Ola, St-Pierre, Julie, Topisirovic, Ivan, Sonenberg, Nahum
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.11.2013
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Adenosine Triphosphate - biosynthesis; Animals; Autophagy - genetics; Cell Nucleus - metabolism; Cell Respiration; DNA, Mitochondrial - biosynthesis; DNA-Binding Proteins - metabolism; Eukaryotic Initiation Factors - metabolism; Gene Expression Regulation; Genome, Human - genetics; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Medicin och hälsovetenskap; Mice; Mitochondria - metabolism; Mitochondrial Proteins - metabolism; Mitochondrial Turnover; Models, Biological; Multiprotein Complexes - metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphoproteins - metabolism; Protein Biosynthesis; Ribosomal Protein S6 Kinases - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; TOR Serine-Threonine Kinases - metabolism; Transcription Factors - metabolism
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2013.10.001

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. •mTORC1 regulates synthesis of nucleus-encoded mitochondrial proteins via 4E-BPs•mTORC1 controls mitochondrial activity and biogenesis largely through 4E-BPs•mTORC1 coordinates energy consumption and production via 4E-BPs•An active-site mTOR inhibitor impairs respiration and energy metabolism in mice