Effect of Omaveloxolone on Mitochondrial Dynamics Under Oxidative Stress in Cells with Parkinson's Disease Associated Mutation

This study investigates the effects of omaveloxolone, a Keap1 inhibitor, on mitochondrial network (MN) dynamics and cell survival under oxidative stress in control fibroblasts and fibroblasts from a Parkinson's disease patient with a PINK1 mutation. The PINK1-mutant fibroblasts showed increased sensitivity to hydrogen peroxide-induced stress. Omaveloxolone pre-treatment improved cell viability under stress conditions in both cell types. Under normal conditions, PINK1-mutant fibroblasts exhibited lower MN connectivity compared to control cells. Oxidative stress reduced MN density in both cell types, while omaveloxolone treatment normalized MN connectivity in PINK1-mutant cells and maintained higher MN connectivity under stress. Similar effects were observed for mitochondrial branch length. Omaveloxolone (50 nM) also increased mitophagy in both cell types under normal conditions. Our findings demonstrate that omaveloxolone exerts protective effects by maintaining mitochondrial dynamics and activating mitophagy. It enhances mitophagy under normal conditions and supports MN structure under oxidative stress, improving cell viability in both control and PINK1-mutant fibroblasts. These results highlight omaveloxolone's potential as a therapeutic agent for protecting cells in diseases associated with impaired mitochondrial dynamics, particularly Parkinson's disease linked to PINK1 mutations.