Multifaceted role of AMPK in autophagy: more than a simple trigger?

AMP-activated protein kinase (AMPK) is a key sensor and regulator of intracellular energy balance. During energy stress, AMPK helps restore cellular ATP levels by preventing anabolic and promoting catabolic processes, such as autophagy. AMPK activates autophagy both posttranslationally and transcriptionally, by suppressing the mechanistic target of rapamycin complex 1 activity and stimulating the activation of unc-51 like autophagy activating kinase (ULK), autophagosome-lysosome fusion, and expression of autophagy-related genes. Recent research, however, suggests an unexpected role of AMPK in energy stress, where AMPK inhibits ULK and suppresses ATP-consuming autophagic response, possibly to save energy and maintain the autophagic machinery for subsequent activation once the stress subsides. The present review elucidates this dual nature of AMPK in autophagy regulation while highlighting its molecular mechanisms and importance for therapeutic approaches involving AMPK modulation.