A Molecular Mechanism of Blue Light Toxicity Impacting the Visual Cycle

About This Grant

PROJECT SUMMARY Retinal degeneration is a leading cause of blindness, with mounting evidence implicating environmental factors such as blue light (430–470 nm) exposure in its progression. A key pathological mechanism involves the phototoxic byproduct A2E, which accumulates in retinal pigment epithelium (RPE) cells and undergoes photoactivation by blue light to generate reactive oxygen species (ROS). These ROS, in turn, drive lipid peroxidation (LPO) of polyunsaturated fatty acids (PUFAs), producing electrophilic metabolites that contribute to retinal injury. Our recent studies have identified epoxyketooctadecenoic acids (EKODEs) as prominent LPO byproducts formed via A2E-induced oxidation, with the ability to covalently modify proteins via cysteine adducts. This proposal investigates the hypothesis that blue light–activated A2E promotes EKODE formation, which in turn inhibits lecithin retinol acyltransferase (LRAT), a critical enzyme in the visual cycle responsible for regenerating the light-sensitive chromophore. Disruption of LRAT function is strongly associated with severe visual dysfunction and photoreceptor degeneration. By directly linking A2E-mediated oxidation to the generation of EKODEs and their inhibitory effects on LRAT, this study will address a critical gap in our understanding of blue light–induced retinal damage at the molecular level. To test this hypothesis, Aim 1 will define the wavelength-dependent conditions under which photoactivated A2E catalyzes LPO and promotes EKODE formation. Using novel LC-MS/MS methods, we will characterize these lipid oxidation products in vitro and in biologically relevant models, such as bovine eyecups. Aim 2 will investigate the impact of EKODEs on LRAT activity, employing proteomic approaches to detect and map EKODE-protein adducts in vitro and in vivo. By elucidating how blue light exposure, in the presence of A2E, leads to electrophilic EKODE production and LRAT inhibition, this research will provide novel insights into the biochemical pathways driving retinal degeneration. The findings could inform the development of targeted interventions, such as antioxidant therapies or optical filters, to mitigate blue light–induced retinal damage and preserve visual function.