Oxidative stress impairs autophagy through oxidation of ATG3 and ATG7

Dysfunctional macroautophagy/autophagy has been causatively linked to aging and the pathogenesis of many diseases, which are also broadly characterized by dysregulated cellular redox. As the autophagy-related (ATG) conjugation systems that mediate autophagosome maturation are cysteine dependent, their oxidation may account for loss in this catabolic process under conditions of oxidative stress. During active autophagy, LC3 is transferred from the catalytic thiol of ATG7 to the active site thiol of ATG3, where it is conjugated to phosphatidylethanolamine. In our recent study, we show LC3 is bound to the catalytic thiols of inactive ATG3 and ATG7 through a stable thioester, which becomes transient upon autophagy stimulation. Transient interaction with LC3 exposes the catalytic thiols on ATG3 and ATG7, which under pro-oxidizing conditions undergo inhibitory oxidation. This process was found to be upregulated in aged mouse tissue and therefore may account, at least in part, for impaired autophagy observed during aging.