AICAR (Acadesine), an AMPK Activator, is an Autophagy, YAP and Mitophagy Inhibitor

AMP-activated protein kinase (AMPK) is an enzyme that plays a role in cellular energy homeostasis. AMPK consists of a catalytic α-subunit and two regulatory subunits, β and γ. In single-cell eukaryotes, the AMPK homologue is responsible for activating alternative carbon source utilization pathways when glucose is absent. In higher eukaryotes, AMPK has acquired the capacity to sense the amount of energy available in the cell by directly binding adenine nucleotides. During energy stress, AMPK directly phosphorylates key factors involved in multiple pathways to restore energy balance.

AMPK has received a lot of attention as a potential target for treating diseases associated with metabolic perturbation. This includes diabetes, obesity and fatty liver diseases and also cancer. The effect of AMPK on metabolism can be broadly divided into two categories: the inhibition of anabolism to minimize ATP consumption and the stimulation of catabolism to stimulate ATP production. Once activated, AMPK redirects metabolism towards increased catabolism and decreased anabolism through the phosphorylation of key proteins in multiple pathways, including mTOR complex 1 (mTORC1), lipid homeostasis, glycolysis and mitochondrial homeostasis.

AICAR (Acadesine) is an adenosine analog and an AMPK activator. And it is also an autophagy, YAP and mitophagy inhibitor. Importantly, AICAR can undergone phosphorylation by adenosine kinase to form 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl monophosphate (ZMP). ZMP binds AMPK at the AMP-binding site on the γ-regulatory subunit, causing allosteric activation of AMPK. Thereby AICAR promotes skeletal muscle glucose uptake. Besides, AICAR causes a variety of AMPK-independent effects. Among them is inhibition of glycolysis and oxidative phosphorylation in the liver, interference with cell cycle progression, inhibition of dendritic cell maturation, and induction of apoptosis. What’s more, AICAR inhibits NFκB DNA binding independently of AMPK to inhibit proinflammatory cytokines and iNOS production.


[1] Herzig S, et, al. Nat Rev Mol Cell Biol. 2018 Feb;19(2):121-135.