Protein synthesis is the most energy-consuming process in the cell. Dysregulation of mRNA translation and energy metabolism is implicated in various diseases, such as cancer and metabolic disorders. However, the mechanisms governing the interplay between protein synthesis and energy homeostasis remain largely unknown. Using a combination of pharmacological, genetic, histological, and omics approaches, we identified a previously unrecognized link between the nutrient-sensing mTORC1 pathway, mRNA translation, mitochondrial dynamics, and cancer. Our investigation reveals that the alterations in mTORC1 activity coincide with dramatic changes in mitochondrial dynamics, characterized by hyper-fusion. mTORC1, through the phosphorylation of the translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs), promotes mitochondrial fission by selectively enhancing the translation of mRNAs encoding mitochondrial fission factors. This discovery underscores the pivotal role of mTORC1 in coupling mRNA translation with mitochondrial dynamics and functions to maintain balanced energy consumption and production. These findings offer a molecular foundation for enhancing the anti-tumor effects of mTOR inhibitors in clinical settings by targeting mitochondria. In addition, I will introduce our recent study linking mRNA degradation to inter-organelle communication and metabolic syndrome.

Morita et al., 2013, Cell Metab; Morita et al., 2017, Mol Cell; Hulea et al., 2018, Cell Metab; Morita et al., 2019, PNAS; Katsumura et al., 2022, Cell Metab

東京大学大学院理学系研究科・生物科学専攻・濡木理

 

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