AMPK

AMP-activated protein kinase (AMPK) is a conserved serine/threonine kinase that acts as a central regulator of cellular energy homeostasis. It becomes activated when the cell experiences energy stress, indicated by increased levels of AMP and ADP relative to ATP. Activation occurs through phosphorylation of Thr172 on the catalytic alpha subunit by upstream kinases such as LKB1 and CaMKK2, and is augmented by allosteric binding of AMP and, in some contexts, ADP. Deactivation can occur through phosphatases when energy status improves. AMPK activity can also be influenced by pharmacologic activators, including some indirect activators (for example, metformin) and direct allosteric activators.

AMPK is a heterotrimer composed of a catalytic alpha subunit (with two main isoforms, alpha1 and alpha2), a regulatory beta subunit (beta1 and beta2) that includes a glycogen-binding motif, and a regulatory gamma subunit (gamma1, gamma2, gamma3) containing CBS domains that sense adenine nucleotides. The combination of subunit isoforms provides tissue-specific regulation and localization.

In response to activation, AMPK promotes catabolic pathways that generate ATP and downregulates anabolic processes that consume ATP. It increases glucose uptake and glycolysis, enhances fatty acid oxidation by inhibiting acetyl-CoA carboxylase and lowering malonyl-CoA, and suppresses lipid and cholesterol synthesis. It also inhibits mTORC1 signaling via phosphorylation of TSC2 and raptor, and stimulates autophagy through ULK1 activation. AMPK can influence mitochondrial biogenesis and oxidative stress responses, partly via PGC-1alpha–dependent pathways, supporting metabolic flexibility during energy stress.

Physiologically, AMPK is activated by exercise and caloric restriction and plays a key role in metabolic diseases. Pharmacologic AMPK activators are explored as therapies for type 2 diabetes and obesity, though effects depend on tissue context and regulatory networks.