Sufficient glucose and oxygen levels are required for mTORC1 activation, and many sensing mechanisms have been identified. Glucose, glutamine, and oxygen are utilized for ATP production via glycolysis, the TCA cycle, and oxidative phosphorylation. Decreased availability of these nutrients can lower ATP levels, with a subsequent rise in AMP levels, conditions that stimulate the activation of AMPK. AMPK inhibits mTORC1 through activation of the TSC complex, which inhibits Rheb, and phosphorylation of Raptor within mTORC1. Glucose or oxygen deprivation, as well as other forms of energy stress, also stimulates the transcription of REDD1 through the action of either the HIF1, ATF4, or p53 transcription factors. REDD1 somehow cooperates with the TSC complex to inhibit Rheb and mTORC1. Through their sensing of AMP and oxygen, respectively, AMPK and the PHD proteins (in yellow) represent the only known direct sensors of cellular metabolic status within this network. In addition to energy stress, glucose and oxygen can also be sensed through ER homeostasis, as they are required for proper protein glycosylation and disulfide bond formation, respectively. Disrupting these processes results in activation of PERK and inhibition of eIF2a, which results in the selective translation of ATF4. Glucose starvation and energy stress also appear to signal to mTORC1 via the Rag GTPases, albeit through unknown mechanisms, and through a pathway involving the p38 and PRAK kinases leading to direct phosphorylation of Rheb. Severe states of ATP depletion inhibit the ability of the TTT-RUVBL1/2 complex to promote formation of functional mTORC1 dimers. Note: mTORC1 is depicted as a single unit at the lysosome for simplicity. Compounds such as 2-deoxyglucose (2-DG), AICAR, and the biguanides metformin and phenformin also have inputs into these different mechanisms of mTORC1 inhibition. Dashed lines denote unknown molecular mechanisms.