Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan, China.
Hunan Key Laboratory of Ophthalmology, Changsha, Hunan, China.
Cell Death Differ. 2023 Jan;30(1):69-81. doi: 10.1038/s41418-022-01046-4. Epub 2022 Aug 6.
Glaucoma can result in retinal ganglion cell (RGC) death and permanently damaged vision. Pathologically high intraocular pressure (ph-IOP) is the leading cause of damaged vision during glaucoma; however, controlling ph-IOP alone does not entirely prevent the loss of glaucomatous RGCs, and the underlying mechanism remains elusive. In this study, we reported an increase in ferric iron in patients with acute primary angle-closure glaucoma (the most typical glaucoma with ph-IOP damage) compared with the average population by analyzing free iron levels in peripheral serum. Thus, iron metabolism might be involved in regulating the injury of RGCs under ph-IOP. In vitro and in vivo studies confirmed that ph-IOP led to abnormal accumulation of ferrous iron in cells and retinas at 1-8 h post-injury and elevation of ferric iron in serum at 8 h post-injury. Nuclear receptor coactivator 4 (NCOA4)-mediated degradation of ferritin heavy polypeptide 1(FTH1) is essential to disrupt iron metabolism in the retina after ph-IOP injury. Furthermore, knockdown of Ncoa4 in vivo inhibited FTH1 degradation and reduced the retinal ferrous iron level. Elevated ferrous iron induced by ph-IOP led to a marked accumulation of pro-ferroptotic factors (lipid peroxidation and acyl CoA synthetase long-chain family member 4) and a depletion of anti-ferroptotic factors (glutathione, glutathione peroxidase 4, and nicotinamide adenine dinucleotide phosphate). These biochemical changes resulted in RGC ferroptosis. Deferiprone can pass through the blood-retinal barrier after oral administration and chelated abnormally elevated ferrous iron in the retina after ph-IOP injury, thus inhibiting RGC ferroptosis and protecting visual function. In conclusion, this study revealed the role of NCOA4-FTH1-mediated disturbance of iron metabolism and ferroptosis in RGCs during glaucoma. We demonstrate the protective effect of Deferiprone on RGCs via inhibition of ferroptosis, providing a research direction to understand and treat glaucoma via the iron homeostasis and ferroptosis pathways.
青光眼可导致视网膜神经节细胞 (RGC) 死亡和永久性视力损伤。病理性高眼压 (ph-IOP) 是青光眼导致视力损害的主要原因；然而，单独控制 ph-IOP 并不能完全防止青光眼 RGC 的损失，其潜在机制仍不清楚。在这项研究中，我们通过分析外周血清中的游离铁水平，报告了急性原发性闭角型青光眼（最典型的 ph-IOP 损伤性青光眼）患者体内铁含量升高，与普通人群相比。因此，铁代谢可能参与调节 ph-IOP 下 RGC 的损伤。体外和体内研究证实，ph-IOP 在损伤后 1-8 小时导致细胞和视网膜中铁离子的亚铁异常积累，在损伤后 8 小时导致血清中铁离子升高。核受体共激活因子 4 (NCOA4) 介导的铁蛋白重链 1 (FTH1) 降解对于 ph-IOP 损伤后视网膜中铁代谢的破坏至关重要。此外，体内敲低 Ncoa4 抑制了 FTH1 的降解并降低了视网膜中的亚铁水平。ph-IOP 诱导的亚铁增加导致促铁死亡因素（脂质过氧化和酰基辅酶 A 合成酶长链家族成员 4）的明显积累和抗铁死亡因素（谷胱甘肽、谷胱甘肽过氧化物酶 4 和烟酰胺腺嘌呤二核苷酸磷酸）的耗竭。这些生化变化导致 RGC 铁死亡。口服后，地拉罗司可穿过血视网膜屏障，螯合 ph-IOP 损伤后视网膜中异常升高的亚铁，从而抑制 RGC 铁死亡并保护视觉功能。总之，这项研究揭示了 NCOA4-FTH1 介导的铁代谢和铁死亡在青光眼期间 RGC 中的作用。我们通过抑制铁死亡证明了地拉罗司对 RGC 的保护作用，为通过铁平衡和铁死亡途径理解和治疗青光眼提供了研究方向。
