Mechanisms and consequences of impaired glutathione homeostasis in the aging lens

Abstract The integrity of the lipid and cholesterol-enriched lens membrane is vital to lens homeostasis, stiffness, and transparency, serving as an impermeable barrier to cations and scaffold for major lens membrane proteins, such as aquaporin 0 (AQP0) and ion pump. Aging is a primary risk factor for cataractogenesis and presbyopia, and it drives a significant degree of lens membrane lipids compositional changes, such as the decline of unsaturated glycerophospholipids and the steady increase of more saturated sphingomyelin lipids. The steep decline of highly unsaturated glycerophospholipids in the lens is believed to result from selective lipid peroxidation, closely associated with lens stiffness and membrane disintegration. Accumulated lens membrane disintegration can cause a cataract, and increased lens stiffness is a primary cause of presbyopia. Despite overwhelming suggestions, the direct link between lipid peroxidation and lens membrane transformation, and its impact on lens stiffness and opacity, has yet to be established. Our studies have suggested that GPX4/GSH plays a crucial role in maintaining lens plasma membrane integrity and transparency, as well as protecting against lipid peroxidation- mediated cell death, such as ferroptosis. In this application, we aim to address these questions using in vitro lens epithelial cell culture and in vivo mouse models directly targeting GPX4. The outcome of this study will provide valuable insights into the lens membrane biology of aging and age-related cataractogenesis and presbyopia.