THE EMERGING ROLE OF IDH2-MEDIATED MITOPHAGY AND MTUPR IN ATHEROSCLEROSIS

Abstract

Objective: Mitochondrial dysfunction is a risk factor for vascular disease by overexpressing ROS caused by some stimuli in mitochondria which causes oxidative stress and enhances vascular inflammatory response. Isocitrate dehydrogenase 2 (IDH2) is NADP+ dependent mitochondrial enzyme and an antioxidant enzyme that produces NADPH in the antioxidant system. Mitophagy and mitochondrial Unfolding Protein Response (mtUPR) are internal defense mechanism in mitochondria. In this study, we investigated whether IDH2 knockdown causes mitochondrial dysfunction then Mitophagy and mtUPR in vitro in HUVECs and in vivo in IDH2 knock out mice. Design and method: We examined expression of mitophagy and mtUPR-related gene in IDH2-deficient human umbilical vein endothelial cells (HUVECs) and its role in mitophagy and mtUPR in the endothelial cell and IDH2 KO animal tissues. Mitophagy and mtUPR were measured using the western blotting and qPCR. Results: We showed that knockdown of IDH2 expression induced depolarization of mitochondrial membrane potential (MMP). Mitochondrial dynamics is mitochondrial fusion and fission. Knockdown of IDH2 increased Drp1 (fission protein) and mfn1 (fusion protein) compared with Tom20 (control). IDH2 deficiency increase Mitophagy related protein PINK-1 and Parkin expression and mRNA level (PINK-1, Parkin, BNIP3, NIX, FUNDC-1). Moreover, knockdown of IDH2 induced mtUPR mRNA level (USP30, Clpp) in vitro. In addition, IDH2 deficiency increases mtUPR mRNA level and decreases PINK-1 and Parkin protein expression in vivo. Conclusions: Our data show that IDH2 deficiency induces mitochondrial dysfunction and then Mitophagy and mtUPR expression in endothelial cells. These findings provide novel strategy for the development of therapeutic agents for restoring mitochondrial and endothelial function.