title: mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation.
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.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Morita
authors.forename: Simon-Pierre
authors.initials: SP
authors.lastname: Gravel
authors.forename: Valérie
authors.initials: V
authors.lastname: Chénard
authors.forename: Kristina
authors.initials: K
authors.lastname: Sikström
authors.forename: Liang
authors.initials: L
authors.lastname: Zheng
authors.forename: Tommy
authors.initials: T
authors.lastname: Alain
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.forename: Daina
authors.initials: D
authors.lastname: Avizonis
authors.forename: Meztli
authors.initials: M
authors.lastname: Arguello
authors.forename: Chadi
authors.initials: C
authors.lastname: Zakaria
authors.forename: Shannon
authors.initials: S
authors.lastname: McLaughlan
authors.forename: Yann
authors.initials: Y
authors.lastname: Nouet
authors.forename: Arnim
authors.initials: A
authors.lastname: Pause
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.forename: Eyal
authors.initials: E
authors.lastname: Gottlieb
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.forename: Julie
authors.initials: J
authors.lastname: St-Pierre
authors.forename: Ivan
authors.initials: I
authors.lastname: Topisirovic
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001343:Autophagy / Q000235:genetics; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D019069:Cell Respiration; D004272:DNA, Mitochondrial / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D063269:Mitochondrial Turnover; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010750:Phosphoproteins / Q000378:metabolism*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; C087000:EIF4EBP1 protein, human; C104151:EIF4EBP2 protein, human; D039642:Eukaryotic Initiation Factors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010750:Phosphoproteins; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; C499631:TFAM protein, human; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases