Regulation of Autophagy by Amino Acid Starvation Involving Ca2

Macroautophagy is an evolutionarily conserved catabolic process whose main role is to degrade intracellular cargo for the supply of metabolites and energy to the cells. It consists of various vesicle trafficking events, generally triggered by stress conditions such as starvation. Macroautophagy is strictly regulated and the second messenger Ca 2+ has been recently shown to regulate starvation-induced macroautophagy. Withdrawal of essential amino acids increases intracellular Ca 2+ , which is provided from both the extracellular medium and intracellular stores. This leads to the activation, via Ca 2+ /calmodulin-dependent kinase kinase-β, of adenosine monophosphate-activated protein kinase and the inhibition of the mammalian target of rapamycin complex 1. Downstream of these kinases, UNC-51-like kinase, a mammalian autophagy-initiating protein, is activated, which leads to an enhanced formation of autophagosomes. We discuss here the importance of this pathway within the autophagy signaling network activated under amino acid starvation and pay attention to energy considerations in the induction of autophagy by intracellular Ca 2+ and its sensor Ca 2+ /calmodulin-dependent kinase kinase-β.