ADaPting to Energetic Stress

What is the true activator of a key enzyme that controls cell energetics? The movement of muscles, the repolarization of neuronal membranes, and the synthesis of cellular building blocks such as proteins and lipids are powered by energy derived from the hydrolysis of adenosine 5′-triphosphate (ATP). Each day, these processes lead to the turnover of 40 kg of ATP in the average adult human being. ATP is indispensable for life, and sophisticated mechanisms for assessing cellular energy status have evolved and been conserved across all eukaryotes. Adenosine 5′-monophosphate (AMP)–activated protein kinase (AMPK; SNF1 in yeast) is a key enzyme that regulates cell energetics. As the name suggests, AMP has long been believed to be the specific metabolite regulating AMPK activity. Oakhill et al. on page 1433 in this issue (1) and a recent report by Xiao et al. (2) propose an alternative model in which the concentration of intracellular adenosine 5′-diphosphate (ADP) signals the energy status of the cell to AMPK, prompting reevaluation of the pathways that govern adaptation to energetic stress.