Parkin Dependent Mitophagy Protects Macrophage Against Oxidative Injury And Inflammation During Atherogenesis

Abstract Mitochondrial oxidative injury induces macrophage inflammatory activation and apoptosis during atherogenesis. Timely clearance of dysfunctional mitochondria may therefore be beneficial for the survival of macrophages. Based on these principles, our working hypothesis was therefore that mitophagy mediated by the E3 ubiquitin ligase Parkin could have an important role in reducing both oxidative injury and the apoptosis of macrophages under atherogenic conditions. To examine this proposal, in the present study oxidative low-density lipoprotein (ox-LDL) treated THP-1 macrophages were used for the in vitro experiments, and high-cholesterol-fed male apolipoprotein E knockout (ApoE−/−) mice were used for the in vivo investigations. The results demonstrated that mitophagy was activated both in oxidatively stimulated THP-1 macrophages and in aortic plaque macrophages of high-cholesterol-fed ApoE−/− mice. In ox-LDL treated THP-1 macrophages, both the expression level and mitochondrial translocation of Parkin were increased following oxidative stimulation, whereas silencing Parkin led to impaired mitophagy, which exacerbated macrophage oxidative injury, NF-κB activation and apoptosis. Taken together, these results have demonstrated that mitophagy exerts a protective role in macrophages under atherogenic conditions, and that Parkin is a key mediator in this process.