We have delineated a lysosomal pathway that senses low glucose and triggers AMPK activation, which concomitantly inhibits mTORC1 and leads to inhibition of anabolic activities. Remarkably, it is the glycolytic aldolase that serves as the sensor of fructose-1,6-bisphosphate, a glucose intermediary metabolite, and links to activation of AMPK and inhibition of mTORC1 at the lysosome. We have also shown that high glucose sustains the activity of mTORC1. We have also identified the molecular target of Metformin, which is PEN2. After binding to metformin, the PEN2-metformin signaling intersects the glucose sensing pathway via v-ATPase to activate AMPK and inhibit mTORC1.
In addition, we have identified a drug that targets aldolase, named as Aldometanib, in a manner that mimics glucose starvation to activate AMPK. The drug has shown efficacies towards lowering glucose, alleviating fatty liver, and extension of lifespan. The metformin signaling and the functions of Aldometanib have hence validated the importance of the glucose sensing-AMPK pathway.
Most recently, we have found that low glucose can trigger assembly of the supramolecular complex consisting of AXIN, PHGDH, HIPK2, TIP60, and 53, where p53 is activated after phosphorylation at Ser-46 by HIPK2, but independently of AMPK.