Superoxide Activates Ferroptosis via the Haber-Weiss Reaction and Enhances Age-Related Macular Degeneration.

Ying Huang, Zhenxing Zhou, Mengjia Huan, Qi Guo, Xiaoqian Zhang, Ruiqi Lu, Lushu Chen, Xiumiao Li, Jin Yao, Qin Jiang, Yong Xu

The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, P. R. China.The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, P. R. China. · pubmed

Paper

Abstract

Antioxidant decline is crucial to driving age-related macular degeneration (AMD). Ferroptosis, a regulated cell death mediated by iron-dependent hydroxyl radical-catalyzed phospholipid peroxidation through the Fenton reaction, is implicated in various chronic degenerative diseases. Here, we show that superoxide activates ferroptosis in retinal pigment epithelium (RPE) cells via the Haber-Weiss reaction, thereby contributing to dry AMD. We silenced manganese superoxide dismutase (MnSOD/SOD2) in RPE cells and exposed the cells to blue light to induce ferroptosis by increasing superoxide anions. Additionally, MnSOD deficiency triggered the Hsp70-linked ubiquitin-dependent degradation of GPX4, further aggravating ferroptosis. We validated blue light-induced ferroptosis in the RPE layer as a driver of the dry AMD phenotype in Sod2

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Research summary

Superoxide activates ferroptosis in retinal pigment epithelium cells, contributing to age-related macular degeneration. The study addresses a mechanism related to oxidative stress and cell death in the context of aging, which is relevant to understanding and potentially mitigating age-related diseases.

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