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Depending on cellular glucose levels as well as energy states, AMPK is regulated in a hierarchical spatiotemporal manner 9, 10, 11, 12. It comprises a heterotrimeric complex of a catalytic α-subunit and regulatory β- and γ-subunits, among which the γ-subunit provides binding sites for the regulatory adenine nucleotides AMP, ADP and ATP, whose occupancy depends on the cellular AMP:ATP and ADP:ATP ratios 4, 5, 6, 7, 8. Taken together, aldometanib mimics and adopts the lysosomal AMPK activation pathway associated with glucose starvation to exert physiological roles, and might have potential as a therapeutic for metabolic disorders in humans.ĪMPK is a pivotal controller of metabolic homeostasis 1, 2, 3. Moreover, aldometanib extends lifespan and healthspan in both Caenorhabditis elegans and mice. Aldometanib also alleviates fatty liver and nonalcoholic steatohepatitis in obese male rodents. In male mice, aldometanib elicits an insulin-independent glucose-lowering effect, without causing hypoglycaemia. We identify aldometanib in a screen for aldolase inhibitors and show that it prevents FBP from binding to v-ATPase-associated aldolase and activates lysosomal AMPK, thereby mimicking a cellular state of glucose starvation. Here, we show that blocking FBP binding to aldolase with the small molecule aldometanib selectively activates the lysosomal pool of AMPK and has beneficial metabolic effects in rodents. When glucose levels are low, the glycolytic enzyme aldolase is not bound to fructose-1,6-bisphosphate (FBP) and, instead, signals to activate lysosomal AMPK. The activity of 5′-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability of glucose. Nature Metabolism volume 4, pages 1369–1401 ( 2022) Cite this article

The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK

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