Pathologically high intraocular pressure disturbs normal iron homeostasis and leads to retinal ganglion cell ferroptosis in glaucoma

Abstract

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.

Ferritinophagy, a form of autophagic ferroptosis: New insights into cancer treatment

“…Research with the 293T, U2OS, HCT116, and K562 cell lines shows that NCOA4 binds the ubiquitin E3 ligase HERC2 and is targeted for degradation through the ubiquitin proteasome system when the cellular iron levels are high (Mancias et al, 2015) (Figure 3). This finding ensures that the NCOA4 levels are low under high iron pressure (Yao et al, 2022), which can decrease ferritinophagy and increase ferritin iron storage. In contrast, when cellular iron is low, NCOA4 and HERC2 binding is decreased, causing elevated NCOA4 levels and promoting ferritinophagic flux to restore the cellular iron levels (Ryu et al, 2018).…”

Neuroprotective Effects of Transferrin in Experimental Glaucoma Models

“…In this sense, a direct link between ocular hypertension and iron accumulation has been recently reported in mice where rapid retinal iron accumulation was observed within 1 to 8 h after induction of pathologically high intraocular pressure. Disturbance of iron metabolism in this model was associated with nuclear receptor coactivator 4 (NCOA4)-mediated degradation of ferritin [ 46 ]. Although there is no published data reporting a direct link between normotensive glaucoma (NTG) and intraretinal iron accumulation, some evidence suggests a dysregulation of iron metabolism in normotensive glaucoma, too.…”

GSK872 and necrostatin-1 protect retinal ganglion cells against necroptosis through inhibition of RIP1/RIP3/MLKL pathway in glutamate-induced retinal excitotoxic model of glaucoma

“…The R28 retinal precursor cell line, an immortalized adherent retinal precursor cell line derived from infantile Sprague-Dawley rat retinas, is used for in vitro studies of neuroprotection, cytotoxicity, and physiological function of RGCs [10][11][12]81]. The R28 cells were cordially provided by the Department of Anatomy and Neurobiology of Central South University (Changsha, China).…”

“…Thus, in order to demonstrate the exact mechanisms of RGCs death caused by glutamate excitotoxicity, we established a mouse model of glaucoma by intravitreal injection of N-Methyl-d-aspartate (NMDA), the agonist molecule of glutamate that selectively binds to NMDARs. Moreover, we used R28 cells, a retinal precursor cell line with biological properties similar to RGCs, which is commonly applied for in vitro studies of the neuroprotection and physiological function of RGCs [10][11][12], to establish a glutamate excitotoxicity model in vitro.…”