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

Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada
Cell metabolism (Impact Factor: 17.57). 11/2013; 18(5):698-711. DOI: 10.1016/j.cmet.2013.10.001
Source: PubMed


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.

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Available from: Ivan Topisirovic, Jun 08, 2014
    • "The genomic regions more significantly affected in the oncocytic group (both hyperplastic nodules and tumors) included, among other, gains of chromosomes 7 and 12, and loss of chromosome 2, all genomic events previously associated with oncocytic change in thyroid lesions [11] [14] [15]. Our observation that gains of AKT1 are significantly more frequent in oncocytic than in non-oncocytic lesions is consistent with recent findings suggesting that the PI3K-AKT-mTOR pathway is potentially involved in the development of oncocytic thyroid carcinomas [12] and with the notion that this pathway supports mitochondrial biogenesis [46]. It is plausible that, together with its prosurvival functions, activation of mTOR may also contribute to trigger mitochondrial hyperplasia in thyroid lesions, however we did not observe a significant enrichment for CNAs affecting PI3K- AKT-mTOR-related genes in oncocytic lesions. "
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    ABSTRACT: Oncocytic change is the result of aberrant mitochondrial hyperplasia, which may occur in both neoplastic and non-neoplastic cells and is not infrequent in the thyroid. Despite being a well-characterized histologic phenotype, the molecular causes underlying such a distinctive cellular change are poorly understood. To identify potential genetic causes for the oncocytic phenotype in thyroid, we analyzed copy number alterations in a set of oncocytic (n=21) and non-oncocytic (n=20) thyroid lesions by high-resolution microarray-based comparative genomic hybridization (aCGH). Each group comprised lesions of diverse histologic types, including hyperplastic nodules, adenomas and carcinomas. Unsupervised hierarchical clustering of categorical aCGH data resulted in two distinct branches, one of which was significantly enriched for samples with the oncocytic phenotype, regardless of histologic type. Analysis of aCGH events showed that the oncocytic group harbored a significantly higher number of genes involved in copy number gains, when compared to that of conventional thyroid lesions. Functional annotation demonstrated an enrichment for copy number gains that affect genes encoding activators of mitochondrial biogenesis in oncocytic cases but not in their non-oncocytic counterparts. Taken together, our data suggest that genomic alterations may represent additional/alternative mechanisms underlying the development of the oncocytic phenotype in the thyroid.
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    • "Eukaryotic translation initiation factor 4E (eIF4E)-binding proteins (4E-BP) prevent translation of targets including nuclear encoded mitochondrial protein mRNAs including TFAM (transcription factor A, mitochondrial ) and subunits of complex V and complex I. This inhibition is lifted by the action of mTORC1 which inhibits 4E-BP proteins from binding their targets [108] [109]. "
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    ABSTRACT: Balancing mitophagy and mitochondrial biogenesis is essential for maintaining a healthy population of mitochondria and cellular homeostasis. Coordinated interplay between these two forces that govern mitochondrial turnover plays an important role as an adaptive response against various cellular stresses that can compromise cell survival. Failure to maintain the critical balance between mitophagy and mitochondrial biogenesis or homeostatic turnover of mitochondria results in a population of dysfunctional mitochondria that contribute to various disease processes. In this review we outline the mechanics and relationships between mitophagy and mitochondrial biogenesis, and discuss the implications of a disrupted balance between these two forces, with an emphasis on cardiac physiology. This article is part of a Special Issue entitled 'Mitochondria'. Copyright © 2014. Published by Elsevier Ltd.
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    • "Data analyses were performed using the Chemstation software (Agilent, Santa Clara, USA). Mass isotopomer distribution analyses were performed according to [34,35]. "
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    ABSTRACT: Background Metformin is widely used in the treatment of diabetes, and there is interest in ‘repurposing’ the drug for cancer prevention or treatment. However, the mechanism underlying the metabolic effects of metformin remains poorly understood. Methods We performed respirometry and stable isotope tracer analyses on cells and isolated mitochondria to investigate the impact of metformin on mitochondrial functions. Results We show that metformin decreases mitochondrial respiration, causing an increase in the fraction of mitochondrial respiration devoted to uncoupling reactions. Thus, cells treated with metformin become energetically inefficient, and display increased aerobic glycolysis and reduced glucose metabolism through the citric acid cycle. Conflicting prior studies proposed mitochondrial complex I or various cytosolic targets for metformin action, but we show that the compound limits respiration and citric acid cycle activity in isolated mitochondria, indicating that at least for these effects, the mitochondrion is the primary target. Finally, we demonstrate that cancer cells exposed to metformin display a greater compensatory increase in aerobic glycolysis than nontransformed cells, highlighting their metabolic vulnerability. Prevention of this compensatory metabolic event in cancer cells significantly impairs survival. Conclusions Together, these results demonstrate that metformin directly acts on mitochondria to limit respiration and that the sensitivity of cells to metformin is dependent on their ability to cope with energetic stress.
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