Branched-Chain Amino Acids and Brain Metabolism

The mammalian TOR (mTOR) pathway is a key regulator of cell growth and proliferation and increasing evidence suggests that its deregulation is associated with human diseases, including cancer and diabetes. The mTOR pathway integrates signals from nutrients, energy status and growth factors to regulate many processes, including autophagy, ribosome biogenesis and metabolism. Recent work identifying two structurally and functionally distinct mTOR-containing multiprotein complexes and TSC1/2, rheb, and AMPK as upstream regulators of mTOR is beginning to reveal how mTOR can sense diverse signals and produce a myriad of responses.

The mechanistic target of rapamycin complex I (mTORC1) is a central regulator of cellular and organismal growth, and hyperactivation of this pathway is implicated in the pathogenesis of many human diseases including cancer and diabetes. mTORC1 promotes growth in response to the availability of nutrients, such as amino acids, which drive mTORC1 to the lysosomal surface, its site of activation. How amino acid levels are communicated to mTORC1 is only recently coming to light by the discovery of a lysosome-based signaling system composed of Rags (Ras-related GTPases) and Ragulator v-ATPase, GATOR (GAP activity towards Rags), and folliculin (FLCN) complexes. Increased understanding of this pathway will not only provide insight into growth control but also into the human pathologies triggered by its deregulation. Copyright © 2014 Elsevier Ltd. All rights reserved.

For organisms to coordinate their growth and development with nutrient availability, they must be able to sense nutrient levels in their environment. Here, we review select nutrient-sensing mechanisms in a few diverse organisms. We discuss how these mechanisms reflect the nutrient requirements of specific species and how they have adapted to the emergence of multicellularity in eukaryotes.