Inhibition of ferroptosis promotes retina ganglion cell survival in experimental optic neuropathies

作者：Miao Guo, Yanfang Zhu, Ying Shi, Xiangda Meng, Xue Dong, Haokun Zhang, Xiaohong Wang, Mei Du, Hua Yan · 发表于：Redox Biology · 年份：2022 · DOI：10.1016/j.redox.2022.102541 · 被引用次数：126 · 研究领域：Mitochondrial Function and Pathology、S100 Proteins and Annexins、Ferroptosis and cancer prognosis

Retinal ganglion cell (RGC) death is a hallmark of traumatic optic neuropathy, glaucoma, and other optic neuropathies that result in irreversible vision loss. However, therapeutic strategies for rescuing RGC loss still remain challenging, and the molecular mechanism underlying RGC loss has not been fully elucidated. Here, we highlight the role of ferroptosis, a non-apoptotic form of programmed cell death characterized by iron-dependent lethal lipid peroxides accumulation, in RGC death using an experimental model of glaucoma and optic nerve crush (ONC). ONC treatment resulted in significant downregulation of glutathione peroxidase 4 (GPx4) and system xc(-) cystine/glutamate antiporter (xCT) in the rat retina, accompanied by increased lipid peroxide and iron levels. The reduction of GPx4 expression in RGCs after ONC was confirmed by laser-capture microdissection and PCR. Transmission electron microscopy (TEM) revealed alterations in mitochondrial morphology, including increased membrane density and reduced mitochondrial cristae in RGCs after ONC. Notably, the ferroptosis inhibitor ferrostatin-1 (Fer-1) significantly promoted RGC survival and preserved retinal function in ONC and microbead-induced glaucoma mouse models. In addition, compared to the apoptosis inhibitor Z-VAD-FMK, Fer-1 showed better effect in rescuing RGCs death in ONC retinas. Mechanistically, we found the downregulation of GPx4 mainly occurred in the mitochondrial compartment, accompanied by increased mitochond...