Inhibition of ferroptosis promotes retina ganglion cell survival in experimental optic neuropathies
Miao Guo,
Yanfang Zhu,
Ying Shi,
Xiangda Meng,
Xue Dong,
Haokun Zhang,
Xiaohong Wang,
Mei Du,
Hua Yan
Affiliations
Miao Guo
Department of Ophthalmology, Tianjin Medical University General Hospital, 300052, Tianjin, China; Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Tianjin Medical University, 300070, Tianjin, China
Yanfang Zhu
Department of Ophthalmology, Tianjin Medical University General Hospital, 300052, Tianjin, China; Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Tianjin Medical University, 300070, Tianjin, China
Ying Shi
Department of Ophthalmology, Tianjin Medical University General Hospital, 300052, Tianjin, China; Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Tianjin Medical University, 300070, Tianjin, China; Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
Xiangda Meng
Department of Ophthalmology, Tianjin Medical University General Hospital, 300052, Tianjin, China; Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Tianjin Medical University, 300070, Tianjin, China
Xue Dong
Department of Ophthalmology, Tianjin Medical University General Hospital, 300052, Tianjin, China; Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Tianjin Medical University, 300070, Tianjin, China
Haokun Zhang
Department of Ophthalmology, Tianjin Medical University General Hospital, 300052, Tianjin, China; Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Tianjin Medical University, 300070, Tianjin, China
Xiaohong Wang
Department of Ophthalmology, Tianjin Medical University General Hospital, 300052, Tianjin, China; Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Tianjin Medical University, 300070, Tianjin, China; Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China; Corresponding author. Tianjin Medical University, No. 22, Qixiangtai Road, Tianjin, 300070, China.
Mei Du
Department of Ophthalmology, Tianjin Medical University General Hospital, 300052, Tianjin, China; Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Tianjin Medical University, 300070, Tianjin, China; Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China; Corresponding author. Tianjin Medical University, No. 22, Qixiangtai Road, Tianjin, 300070, China.
Hua Yan
Department of Ophthalmology, Tianjin Medical University General Hospital, 300052, Tianjin, China; Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Tianjin Medical University, 300070, Tianjin, China; School of Medicine, Nankai University, 300071, Tianjin, China; Corresponding author. Tianjin Medical University General Hospital, No. 154, Anshan Road, Tianjin, 300052, China.
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 mitochondrial reactive oxygen species (ROS) and lipid peroxides. The mitochondria-selective antioxidant MitoTEMPO attenuated RGC loss after ONC, implicating mitochondrial ROS and lipid peroxides as major mechanisms in ferroptosis-induced RGC death in ONC retinas. Notably, administering Fer-1 effectively prevented the production of mitochondrial lipid peroxides, the impairment of mitochondrial adenosine 5′-triphosphate (ATP) production, and the downregulation of mitochondrial genes, such as mt-Cytb and MT-ATP6, in ONC retinas. Our findings suggest that ferroptosis is a major form of regulated cell death for RGCs in experimental glaucoma and ONC models and suggesting targeting mitochondria-dependent ferroptosis as a protective strategy for RGC injuries in optic neuropathies.
