Oxidative stress, which underlies numerous cellular disorders, results from the excess production of reactive oxygen species (ROS). These ROS can directly promote lipid peroxidation in cellular membranes. The complex compositions and diverse morphologies of cellular membranes make understanding the mechanisms of lipid peroxidation challenging. In this study, we utilize a fluorescence microscopy based tethered vesicle assay to probe these properties simultaneously. Using the fluorescent oxidation probe C11-BODIPY, we systematically investigated lipid peroxidation as a function of membrane curvature and lipid composition. Our results indicate that highly curved membranes enhance the rate and extent of lipid peroxidation across various membrane compositions due to the increased exposure of lipid tails to the solution, allowing greater transport of ROS into the hydrophobic core of the membrane. Interestingly, compositional dependence on lipid peroxidation is strongest in membranes with low curvature (i.e., greater than 100 nm diameter) and becomes less pronounced when membranes become highly curved. We also found that low to moderate cholesterol content (i.e., 10–25 mol%) ablates curvature sensitive oxidation by regulating lipid packing, while high cholesterol content (i.e., 50 mol%) restores curvature sensitivity by regulating lipid lateral mobility. This work establishes membrane curvature and lipid composition as interdependent determinants of oxidative susceptibility, offering new insight into how cells may regulate or resist oxidative stress.
Kim et al. (Sun,) studied this question.