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    • At the heart of ferroptosis is a process of

    2021-11-26

    At the heart of ferroptosis is a process of lethal lipid peroxidation, which is the oxidative addition of molecular oxygen (O2) to lipids, such as polyunsaturated fatty acyl tails in phospholipids. The first descriptions of such enzymatic reactions were in 1955 by Peterson and colleagues [50] and Rothberg and colleagues [51] independently; since then, lipid peroxidation by lipoxygeneses and other mechanisms for the peroxidation of lipids have received a great deal of attention in diverse biological contexts [52], [53], [54]. The first suggestion of lipid peroxidation as a prime cause of cellular damage was in 1965, when two separate groups studying drug toxicology showed increases in lipid peroxidation in the liver of CCl4-treated rats [55], [56]. By the 1980s, it was well established that lipid peroxidation is one of the major forms of oxidative damage through destruction of unsaturated lipid moieties of cell membranes, lipoproteins and other structures [57], [58], and was correlated with a number of pathological conditions [59]. However, these events were associated with other cellular damage mechanisms and not recognized as a cell death mechanism per se. Due to the dual contribution of cellular ROS to signaling mechanisms and cell lethality, enzymatic control of redox regulation is an essential regulatory mechanism for normal cell homeostasis [60]. Redox-sensitive cysteine residues in enzymes exploit the unique ability of sulfur to best quality between oxidation states. Selenoproteins that carry a catalytically active selenocysteine can also contribute to redox control [61]. In a seminal discovery, the membrane-associated ‘phospholipid hydroperoxide glutathione peroxidase 4’ (PHGPX or GPX4) was isolated as the second known selenoperoxidase, after the identification of the cytosolic glutathione peroxidase (GPX1) [62], [63]. GPX4 was first isolated and purified from pig liver in 1982 by Urisini and colleagues [64] and was identified on the basis of its ability to inhibit iron-catalyzed lipid peroxidation in microsomes. The enzyme was first given the functional name ‘peroxidation-inhibiting protein’, that was later changed to its current name [65]. This enzyme was described as a glutathione peroxidase that protects phosphatidylcholine-containing liposomes and biological membranes from peroxidative degradation, and is now known to be the key enzymatic inhibitor of ferroptosis. Early work also showed a similar protective role for the lipophilic antioxidant α-tocopherol (vitamin E) in rat liver mitoplasts and microsomes, which was supported by previous similar observations [66]. In the late 1980s, GPX4 was shown to have lipid-peroxidation-protective effects in mammalian spermatozoa, which were known to be sensitive to the deleterious effects of oxygen free radicals, due to their rich polyunsaturated fatty acid content [67], [68]. This finding was in line with the notion that selenium is essential for male fertility [69], [70], and was further demonstrated by the identification of GPX4 as a major structural component of the mitochondrial capsule, which embeds sperm mitochondria and is thus required for structural sperm stability [71]. The cloning of GPX4 in 1991 revealed its similarity to the classical cytosolic glutathione peroxidase (GPX1), but also its unique properties in inhibiting peroxidation of lipids due to its hydrophobic nature and monomeric form [72]. By the beginning of 1990s, there were several lines of evidence supporting the notion that GPX4 plays a unique role in protecting cells against the damaging and lethal effects of lipid peroxidation [73], [74], [75], [76]. Shortly after the isolation of human GPX4 from human liver in 1994 [77], several groups demonstrated that overexpression of this enzyme in human cells results in resistance to lipid peroxide cytotoxicity compared to parental cells [78], [79], [80], [81], [82], an effect that was consistently attributed to being protective of oxidative-stress-induced apoptotic cell death [83]. Transgenic and knockout mouse models of glutathione-dependent peroxidases stressed the importance of GPX4 in protecting against cell lethality, as GPX4 knockout was the only one (out of GPX1-, GPX2-, GPX3- [84], [85] and GPX4-knockout mouse models) to induce embryonic lethality [86], [87], [88]. Heterozygous GPX4 mouse models (GPX4+/-) have contributed to the understanding of its protective role against a unique form of cell death, as these mice were shown to be more sensitive to death induced by γ-irradiation and tert-butyl hydroperoxide [88], [89]. It was surprising that these heterozygous GPX4 knockout mice live longer than wild-type mice due to delayed pathologies such as fatal lymphoma [90], that can now be explained as increased sensitivity of such nascent cancer cells to ferroptotic death (see below), implying that GPX4 may be oncogenic. In line with GPX4 overexpression in cell culture, overexpression of GPX4 in mouse models was also shown to be protective from oxidative-stress-induced death [91].