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      Melatonin Alleviates Retinal Ischemia–Reperfusion Injury by Inhibiting p53–Mediated Ferroptosis

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      Antioxidants
      MDPI AG

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          Abstract

          Retinal ischemia–reperfusion (RIR) injury caused by high intraocular pressure (IOP) is an important risk factor contributing to retinal ganglion cell (RGC) death, eventually causing blindness. A key progressive pathological process in the development of RIR is the death of RGCs. However, the detailed mechanisms underlying RGC death caused by RIR have not yet been clearly elucidated, and effective treatments are lacking. Ferroptosis is a recently defined form of programmed cell death that is closely related to organ injury. Melatonin (MT) is a promising neuroprotective agent, but its effects on RIR injury remain unclear. In this study, murine models of acute ocular hypertension and oxygen and glucose deprivation/reoxygenation (OGD/R) model were adopted to simulate retinal ischemia. MT alleviated retinal damage and RGC death in RIR mice, significantly attenuating RIR–induced ferroptosis. Furthermore, MT reduced the expression of p53, a master regulator of ferroptosis pathways, and the upregulation of p53 promoted ferroptosis and largely abolished the neuroprotective effects of MT. Mechanistically, the overexpression (OE) of p53 suppressed the expression of the solute carrier family 7 member 11 (Slc7a11), which was accompanied by increased 12–lipoxygenase (Alox12) expression, triggering retinal ferroptosis. Moreover, MT–ameliorated apoptosis, neuroinflammation and microglial activation were observed. In summary, MT conferred neuroprotection against RIR injury by inhibiting p53–mediated ferroptosis. These findings indicate that MT is a retina–specific ferroptosis inhibitor and a promising therapeutic agent for retinal neuroprotection.

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          Most cited references61

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          Ferroptosis: an iron-dependent form of nonapoptotic cell death.

          Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

            Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
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              Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice.

              Ferroptosis is a non-apoptotic form of cell death induced by small molecules in specific tumour types, and in engineered cells overexpressing oncogenic RAS. Yet, its relevance in non-transformed cells and tissues is unexplored and remains enigmatic. Here, we provide direct genetic evidence that the knockout of glutathione peroxidase 4 (Gpx4) causes cell death in a pathologically relevant form of ferroptosis. Using inducible Gpx4(-/-) mice, we elucidate an essential role for the glutathione/Gpx4 axis in preventing lipid-oxidation-induced acute renal failure and associated death. We furthermore systematically evaluated a library of small molecules for possible ferroptosis inhibitors, leading to the discovery of a potent spiroquinoxalinamine derivative called Liproxstatin-1, which is able to suppress ferroptosis in cells, in Gpx4(-/-) mice, and in a pre-clinical model of ischaemia/reperfusion-induced hepatic damage. In sum, we demonstrate that ferroptosis is a pervasive and dynamic form of cell death, which, when impeded, promises substantial cytoprotection.
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                Author and article information

                Journal
                ANTIGE
                Antioxidants
                Antioxidants
                MDPI AG
                2076-3921
                June 2023
                May 29 2023
                : 12
                : 6
                : 1173
                Article
                10.3390/antiox12061173
                37371903
                8af8cb73-bd10-483f-ab1d-64d659b0e70a
                © 2023

                https://creativecommons.org/licenses/by/4.0/

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