AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance

AMPK is a highly conserved master regulator of metabolism, which restores energy balance during metabolic stress both at the cellular and physiological levels. The identification of numerous AMPK targets has helped explain how AMPK restores energy homeostasis. Recent advancements illustrate novel mechanisms of AMPK regulation, including changes in subcellular localization and phosphorylation by non-canonical up-stream kinases. Notably, the therapeutic potential of AMPK is widely recognized and heavily pursued for treatment of metabolic diseases such as diabetes, but also obesity, inflammation, and cancer. Moreover, the recently solved crystal structure of AMPK has shed light both into how nucleotides activate AMPK and, importantly, also into the sites bound by small molecule activators, thus providing a path for improved drugs. Introduction Maintenance of energy homeostasis and the execution of adap-tive responses during periods of low nutrients are critical func-tions of all cells. The main sensor of cellular energy status in effec-tively all eukaryotic cells is the AMP-activated protein kinase (AMPK), which is highly conserved across all eukaryotic species. In general, AMPK is activated in response to energy stress by sensing increases in AMP:ATP and ADP:ATP ratios and restores energy balance by inhibiting anabolic processes that consume ATP, while promoting catabolic processes that generate ATP. Moreover, the activity of AMPK is extensively regulated by multiple upstream signals, thus making AMPK a central node exploited by cells to coordinate their metabolism with specific energy demands. Importantly, the primordial role of AMPK as an energy sensor has been co-opted in higher eukaryotes, such as mammals, to also coordinate growth and metabolism both in specialized tissues and at the whole-body level. Therefore, this ability of AMPK to reprogram metabolism is heavily pursued as a therapeutic avenue for the treatment of several metabolic diseases, especially diabetes, but also for obesity, inflammation, and cancer. Here we review recent advances in our under-standing of AMPK structure, its complex upstream regulation, and downstream effects and provide perspective on novel ap-proaches for the therapeutic activation of AMPK. The AMPK Trimeric Complex AMPK exists as a trimeric complex consisting of a catalytic sub-unit (a subunit) and two regulatory subunits (b and g subunits). In mammals, the a subunit is encoded by two isoforms, and the b and g subunits are encoded by two and three isoforms,