Abstract B06: Translational control of mitochondria through mTORC1/4E-BP signaling pathway

mRNA translation is the most energy consuming process in the cell. Translation and energy metabolism are dysregulated in a variety of diseases including cancer. However, the mechanisms which coordinate translation and energy metabolism remain largely unknown. The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates mRNA translation and other anabolic processes in response to a variety of extracellular signals and intracellular cues (e.g., growth factors, nutrients, oxygen), ultimately accelerating cellular growth and proliferation. mTORC1 is frequently hyper-activated in a series of cancer, thereby it is targeted for the cancer treatment. We previously carried out a genome-wide polysome profiling analysis using mTORC1 inhibitors, such as rapamycin and active-site mTOR inhibitors. These experiments revealed that mRNAs whose translation is regulated by mTORC1 are enriched in those encoding mitochondrial proteins. Here, by using a combination of pharmacological, genetic, biochemical and metabolomic approaches, we demonstrate that mTORC1 modulates mitochondrial functions and dynamics through translational regulation of mRNAs encoding mitochondrial proteins. Mechanistically, we indicate that the effects of mTORC1 on mitochondria are mediated by the eukaryotic translation initiation factor 4E (eIF4E) binding proteins (4E-BPs). Stimulation of translation of mitochondria-related mRNAs engendered an increase in ATP production, which is required as an energy source for translation. These data support a feed-forward loop model, whereby the mTORC1/4E-BP pathway promotes translation of mitochondria-related mRNAs to increase mitochondrial ATP production to meet the high energy demand of protein synthesis in proliferating cells. This represents a novel paradigm for understanding how cellular energy homeostasis is maintained via direct coordination of energy consumption (translation) and energy production (ATP production in mitochondrion). Thereby, our findings provide a new mechanism linking aberrant mTOR signaling to conditions of abnormal cellular energy metabolism such as neoplasia. In this presentation, we will introduce our recent data and discuss the role of mTORC1/4E-BP signaling pathway on mitochondrial function, cellular metabolism and proliferation. Citation Format: Masahiro Morita, Julien Prudent, Heidi McBride, John Bergeron, Nahum Sonenberg. Translational control of mitochondria through mTORC1/4E-BP signaling pathway. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B06.