CLUH coordinates mitochondrial metabolism with the mTORC1 signaling upon energy stress Désirée Schatton1,2, David Pla-Martin1,2, Marie-Charlotte Marx1,2, Jie Gao1,2, Christian Frese2,Elena I. Rugarli1,2,* 1Institute for Genetics, University of Cologne, 50931 Cologne, Germany 2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany *Corresponding Author Mitochondrial gene expression is an intricate process that not only requires synchronization of two genomes of different origin but also involves transcriptional and post-transcriptional regulation. Upon changes of nutrient availability the cell needs to flexibly reshape the mitochondrial proteome to sustain energy demands and ensure survival. However, how this mechanism is integrated with nutrient sensing pathways in the cell is so far unexplored. The RNA-binding protein CLUH (clustered mitochondria homolog) specifically binds hundreds of mRNAs encoding nuclear-encoded mitochondrial proteins. Recently, we have unraveled a role of CLUH in mediating a mitochondrial metabolic switch from anabolism towards catabolism by promoting stabilization and efficient translation of its target mRNAs. Here, we identified an unexpected link between CLUH and the mTOR complex 1 (mTORC1), the master regulator of nutrient sensing. CLUH regulates astrin, a negative regulator of mTORC1, in a dual fashion. It interacts with astrin on both protein and mRNA level and regulates its abundance by promoting protein stability and synthesis. Absence of CLUH causes hyperactivation of mTORC1 which in turn results in decreased autophagy activation leading to mitochondrial clustering close to the nucleus, the conserved hallmark of CLUH depletion. Remarkably, inhibition by rapamycin treatment rescues the abnormal mitochondrial distribution phenotype. Furthermore, we discovered that CLUH forms RNA granules upon energy stress as well as upon overexpression recruiting astrin and raptor, an essential component of mTORC1, into these structures. In conclusion, hereby we have identified a novel link between the post-transcriptional regulation of mitochondrial gene expression and the main nutrient sensing pathway promoting their communication and regulating cellular metabolism upon energy stress.
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