Abstract
Purpose :
Oxidative stress is considered the central pathogenesis of age-related cataractogenesis. Aged and cataractous human lenses manifest with increased reactive oxygen species (ROS) formation, elevated lipid peroxidation, and accumulative intracellular redox-active iron. Interestingly, ample evidence suggests that there is no remarkable apoptosis present in aged and cataractous human lenses despite the profound disruption of redox homeostasis, raising an essential question regarding the existence of other cell death mechanisms. Here we sought to explore the role of lipid peroxidation in lens epithelial cell death.
Methods :
Cell death pathways were explored using both in vitro cell aging model and ex vivo mouse lens capsule aging model. Lipid peroxidation and cell apoptosis markers were determined. Gene expression was performed by the deep sequencing approach.
Results :
Here we show that the aging lens epithelium is susceptible to ferroptosis-mediated cell death via lipid peroxidation. We show that very low concentrations of system Xc- inhibitor Erastin (0.5uM) and glutathione peroxidase 4 (GPX4) inhibitor RSL3 (0.1uM) can drastically induce human LEC (FHL124) ferroptosis in vitro and mouse lens epithelium ferroptosis ex vivo. Depletion of intracellular glutathione (GSH) in human LECs and mouse lens epithelium significantly sensitizes ferroptosis, particularly under the RSL3 challenge. Intriguingly, both human LECs and the mouse lens epithelium demonstrate an age-related sensitization of ferroptosis. Transcriptome analysis indicates that clusters of genes are up-or down-regulated in aged LECs, impacting cellular redox and iron homeostases, such as downregulation of both cystine/glutamate antiporter subunits SLC7A11 and SLC3A2 and iron exporter ferroportin (SLC40A1).
Conclusions :
Here, for the first time, we are suggesting that LECs are highly susceptible to ferroptosis. Moreover, aged and cataractous human lenses may possess more pro-ferroptosis criteria than any other organ in the human body.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.