New insights into activation and function of the AMPK

The classical role of AMP-activated protein kinase (AMPK) is as a cellular energy sensor activated by falling energy status, signalled by increases in AMP to ATP and ADP to ATP ratios. Once activated, AMPK acts to restore energy homeostasis by promoting ATP-producing catabolic pathways while inhibiting energy-consuming processes. In this Review, we provide an update on this canonical (AMP/ADP-dependent) activation mechanism, but focus mainly on recently described non-canonical pathways, including those by which AMPK senses the availability of glucose, glycogen or fatty acids and by which it senses damage to lysosomes and nuclear DNA. We also discuss new findings on the regulation of carbohydrate and lipid metabolism, mitochondrial and lysosomal homeostasis, and DNA repair. Finally, we discuss the role of AMPK in cancer, obesity, diabetes, nonalcoholic steatohepatitis (NASH) and other disorders where therapeutic targeting may exert beneficial effects. AMP-activated protein kinase (AMPK) is a cellular energy sensor canonically activated by increases in AMP/ADP to ATP ratios. Recent advances revealed several non-canonical pathways for AMPK activation, including roles of calcium, nutrients and metabolites, as well as DNA and lysosome damage, providing novel insights into the pathology of AMPK in cancer, metabolic disease, fibrosis and inflammation.