Glucose sensing and physiological functions

We previously delineated a signaling pathway that senses glucose levels and signal to control the activities of AMPK and mTORC1. In low glucose, the v-ATPase/proton pump-associated aldolase senses low levels of fructose-1,6-bisphosphate and inhibits the proton pump. This allows AXIN/LKB1 to translocate to the surface of the lysosome, where LKB1 phosphorylates and activates AMPK, leading to concomitant inhibition of mTORC1. In contrast, high glucose can maintain mTORC1 association on the surface of the lysosome. We have also used aldolase as a target for drug screening, and identified a drug termed as Aldometanib that exhibits the ability to block aldolase binding to FBP, thereby eliciting a pseudo-starvation signal to exert roles including hypoglycemic effect, extension of lifespan and healthspan, inhibition of cancer growth.

Metformin is an anti-diabetic drug. It was known that metformin requires AMPK to lower blood glucose levels. However, the molecular target of metformin remained elusive for many decades. We have identified PEN2 as the metformin target, and demonstrated that metformin takes a ride with the glucose sensing-AMPK route.

Tracking the path to longevity through calorie restriction, we have explored the metabolic pattern shift, from glucose to glutamine after AMPK activation. We found that AMPK phosphorylates a protein called PDZD8, which in turn interacts and promotes the activity of glutaminase. Along with the increased utilization of glutamine, ROS is transiently increased during the lifespan of nematodes. Intriguingly, this ROS burst is required for the extension of lifespan. We have also identified a signaling pathway that senses low glucose metabolite 3-phosphoglycerate (3-PGA). In low 3-PGA, PHGDH (phosphoglycerate dehydrogenase), a catalytic enzyme for biosynthesis of serine from 3-PGA, acts as a scaffold to activate p53 to induce apoptosis.

This seminar will present and discuss our overall finding that glucose is a messenger regulating a myriad of physiological functions.