mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation

Cell Metab. 2013 Nov 5;18(5):698-711. doi: 10.1016/j.cmet.2013.10.001.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • 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*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Ribosomal Protein S6 Kinases / metabolism
  • TOR Serine-Threonine Kinases / metabolism*
  • Transcription Factors / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • EIF4EBP1 protein, human
  • EIF4EBP2 protein, human
  • Eukaryotic Initiation Factors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mitochondrial Proteins
  • Multiprotein Complexes
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phosphoproteins
  • Ppargc1a protein, mouse
  • RNA, Messenger
  • TFAM protein, human
  • Transcription Factors
  • Adenosine Triphosphate
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Ribosomal Protein S6 Kinases