FIGURE 5.

AMPK integration of energy stress shapes mTORC1 activity at the lysosome. ATP and glycolytic activity are sensed and integrated by the AMPK regulatory machinery on the lysosome, allowing for cross-talk to the mTORC1 pathway. (A) In conditions of energy sufficiency, there is high ATP levels relative to AMP, which permits ATP to compete with AMP for binding to AMPK, maintaining the inactive heterotrimeric AMPK complex. Moreover, high glycolytic activity produces abundant fructose-1,6-bisphosphate (FBP), which forms a complex with aldolase. The aldolase-FBP complex interacts with the V-ATPase to thwart recruitment of LKB1 and AXIN to the lysosome and protect V-ATPase-Ragulator association. Collectively, these events abate AMPK and stimulate mTORC1 activity. (B) During conditions of energy insufficiency, AMP concentrations rise, increasing the frequency of AMP-bound AMPK, priming AMPK for activation. Moreover, decreased glycolysis activity drops the levels of FBP and FBP-aldolase. This permits the formation of a complex between Ragulator, V-ATPase, Axin and LKB. Collectively, this allows LKB1 to phosphorylate and release the catalytic α subunit, allowing it to promote catabolic cellular programs, while preventing Ragulator from promoting mTORC1 function.