How does mTOR sense glucose starvation? AMPK is the usual suspect

Abstract

Glucose is a major requirement for biological life. Its concentration is constantly sensed at the cellular level, allowing for adequate responses to any changes of glucose availability. Such responses are mediated by key sensors and signaling pathway components that adapt cellular metabolism to glucose levels. One of the major hubs of these responses is mechanistic target of rapamycin (mTOR) kinase, which forms the mTORC1 and mTORC2 protein complexes. Under physiological glucose concentrations, mTORC1 is activated and stimulates a number of proteins and enzymes involved in anabolic processes, while restricting the autophagic process. Conversely, when glucose levels are low, mTORC1 is inhibited, in turn leading to the repression of numerous anabolic processes, sparing ATP and antioxidants. Understanding how mTORC1 activity is regulated by glucose is not only important to better delineate the biological function of mTOR, but also to highlight potential therapeutic strategies for treating diseases characterized by deregulated glucose availability, as is the case of cancer. In this perspective, we depict the different sensors and upstream proteins responsible of controlling mTORC1 activity in response to changes in glucose concentration. This includes the major energy sensor AMP-activated protein kinase (AMPK), as well as other independent players. The impact of such modes of regulation of mTORC1 on cellular processes is also discussed. Facts

BVR-A Deficiency Leads to Autophagy Impairment through the Dysregulation of AMPK/mTOR Axis in the Brain—Implications for Neurodegeneration

“…Remarkably, we observed that AMPK protein expression is almost null in BVR-A −/− mice at 2 months ( Figure 5B.1) and we cannot exclude that a BVR-A-mediated transcriptional control of AMPK exists. However, we believe that reduced AMPK and pAMPK Thr172 levels greatly contribute to the marked hyper-activation of mTOR observed in young BVR-A −/− mice at 2 months, in agreement with the regulatory role for AMPK [76][77][78]. Intriguingly, an increase of both AMPK protein and pAMPK Thr172 levels in adult and aged BVR-A −/− mice, was observed.…”

“…Under condition of energy depletion, AMPK directly senses increases in AMP:ATP and ADP:ATP ratios, thus promoting the inhibition of mTORC1 complex to inhibit protein synthesis and cell cycle progression, controlling cell size and preventing apoptosis, downstream of mTORC1 inhibition, at times of energy crisis [76]. Moreover, AMPK is activated in response to nitrosative stress and that occurs independently of AMP/ATP levels [77].…”

The Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease

“…Autophagosome formation is negatively regulated by the (mammalian) target of rapamycin (mTOR) ( 64 ) which activity is inhibited under starvation conditions ( 65 ).…”

Does mTORC1 inhibit autophagy at dual stages?

“…[ 42 ] Though these mechanisms of mTORC1 regulation in response to glucose starvation exist, a complete picture of other glucose sensors fine‐tuning mTORC1's lysosomal localization and downstream activity is still an open question. [ 43 ]…”