Ferroptosis: bug or feature? Dixon, Scott J.
Immunological reviews,
20/May , Letnik:
277, Številka:
1
Journal Article
Recenzirano
Summary
Ferroptosis is an iron‐dependent, oxidative form of non‐apoptotic cell death. This form of cell death does not share morphological, biochemical, or genetic similarities with classic necrosis, ...necroptosis, parthanatos, or other forms of non‐apoptotic cell death. Ferroptosis can be triggered by depleting the cell of the amino acid cysteine, or by inhibiting the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4). Why certain stimuli trigger ferroptosis instead of another form of cell death, and whether this process could be adaptive in vivo, are two major unanswered questions concerning this process. Emerging evidence and consideration of related non‐apoptotic pathways suggest that ferroptosis could be an adaptive process, albeit one regulated and executed in a manner very different from apoptosis and other forms of cell death.
Mechanisms of ferroptosis Cao, Jennifer Yinuo; Dixon, Scott J.
Cellular and molecular life sciences : CMLS,
06/2016, Letnik:
73, Številka:
11-12
Journal Article
Recenzirano
Odprti dostop
Ferroptosis is a non-apoptotic form of cell death that can be triggered by small molecules or conditions that inhibit glutathione biosynthesis or the glutathione-dependent antioxidant enzyme ...glutathione peroxidase 4 (GPX4). This lethal process is defined by the iron-dependent accumulation of lipid reactive oxygen species and depletion of plasma membrane polyunsaturated fatty acids. Cancer cells with high level RAS-RAF-MEK pathway activity or p53 expression may be sensitized to this process. Conversely, a number of small molecule inhibitors of ferroptosis have been identified, including ferrostatin-1 and liproxstatin-1, which can block pathological cell death events in brain, kidney and other tissues. Recent work has identified a number of genes required for ferroptosis, including those involved in lipid and amino acid metabolism. Outstanding questions include the relationship between ferroptosis and other forms of cell death, and whether activation or inhibition of ferroptosis can be exploited to achieve desirable therapeutic ends.
The transition metal iron is essential for life, yet potentially toxic iron-catalyzed reactive oxygen species (ROS) are unavoidable in an oxygen-rich environment. Iron and ROS are increasingly ...recognized as important initiators and mediators of cell death in a variety of organisms and pathological situations. Here, we review recent discoveries regarding the mechanism by which iron and ROS participate in cell death. We describe the different roles of iron in triggering cell death, targets of iron-dependent ROS that mediate cell death and a new form of iron-dependent cell death termed ferroptosis. Recent advances in understanding the role of iron and ROS in cell death offer unexpected surprises and suggest new therapeutic avenues to treat cancer, organ damage and degenerative disease.
Oxygen is necessary for aerobic metabolism but can cause the harmful oxidation of lipids and other macromolecules. Oxidation of cholesterol and phospholipids containing polyunsaturated fatty acyl ...chains can lead to lipid peroxidation, membrane damage, and cell death. Lipid hydroperoxides are key intermediates in the process of lipid peroxidation. The lipid hydroperoxidase glutathione peroxidase 4 (GPX4) converts lipid hydroperoxides to lipid alcohols, and this process prevents the iron (Fe2+)‐dependent formation of toxic lipid reactive oxygen species (ROS). Inhibition of GPX4 function leads to lipid peroxidation and can result in the induction of ferroptosis, an iron‐dependent, non‐apoptotic form of cell death. This review describes the formation of reactive lipid species, the function of GPX4 in preventing oxidative lipid damage, and the link between GPX4 dysfunction, lipid oxidation, and the induction of ferroptosis.
The Hallmarks of Ferroptosis Dixon, Scott J; Stockwell, Brent R
Annual review of cancer biology,
03/2019, Letnik:
3, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Ferroptosis is a nonapoptotic, iron-dependent form of cell death that can be activated in cancer cells by natural stimuli and synthetic agents. Three essential hallmarks define ferroptosis, namely: ...the loss of lipid peroxide repair capacity by the phospholipid hydroperoxidase GPX4, the availability of redox-active iron, and oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids. Several processes including RAS MAPK signaling, amino acid and iron metabolism, ferritinophagy, epithelial-to-mesenchymal transition, cell adhesion, and mevalonate and phospholipid biosynthesis can modulate susceptibility to ferroptosis. Ferroptosis sensitivity is also governed by p53 and KEAP1 NRF2 activity, linking ferroptosis to the function of key tumor suppressor pathways. Together these findings highlight the role of ferroptosis as an emerging concept in cancer biology and an attractive target for precision cancer medicine discovery.
Cysteine is a conditionally essential amino acid required for the synthesis of proteins and many important intracellular metabolites. Cysteine depletion can trigger iron‐dependent nonapoptotic cell ...death–ferroptosis. Despite this, cysteine itself is normally maintained at relatively low levels within the cell, and many mechanisms that could act to buffer cysteine depletion do not appear to be especially effective or active, at least in cancer cells. How do we reconcile these seemingly paradoxical features? Here, we describe the regulation of cysteine and its contribution to ferroptosis and speculate about how the levels of this amino acid are controlled to govern nonapoptotic cell death.
The amino acid cysteine inhibits ferroptosis. And yet, cysteine is maintained at low concentrations within the cell, and mechanisms to respond to acute cysteine deprivation do not appear to function especially well. In this viewpoint, we propose that low cysteine levels and weak defenses against acute cysteine depletion are not accidental, and are exploited by tumor suppressors and the immune system to trigger ferroptosis in vivo.
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 xc−), 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.
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► Iron-dependent cell death is similar to glutamate-induced excitotoxicity ► Ferroptosis is distinct from apoptosis, necrosis, and autophagy ► Ferroptosis is triggered by inhibition of cystine uptake ► Reduced cystine uptake leads to the production of lethal lipid ROS
The mechanism of drug-induced iron-dependent cell death in RAS-driven cancers relies on cystine/glutamate antiport and the accumulation of hydroxylated lipids. This type of death is similar to glutamate-induced excitotoxicity in neurons, and both types of cell death can be blocked with a specific small-molecule inhibitor called ferrostatin-1.
Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids
. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ...ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols
. Ferroptosis has previously been implicated in the cell death that underlies several degenerative conditions
, and induction of ferroptosis by the inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death
. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines
, which suggests that additional factors govern resistance to ferroptosis. Here, using a synthetic lethal CRISPR-Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis-resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q
(CoQ) (also known as ubiquinone-10), which acts as a lipophilic radical-trapping antioxidant that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumour xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutic agents.
Apoptosis is one type of programmed cell death. Increasingly, non-apoptotic cell death is recognized as being genetically controlled, or 'regulated'. However, the full extent and diversity of ...alternative cell death mechanisms remain uncharted. Here we surveyed the landscape of pharmacologically accessible cell death mechanisms. In an examination of 56 caspase-independent lethal compounds, modulatory profiling showed that 10 compounds induced three different types of regulated non-apoptotic cell death. Optimization of one of those ten resulted in the discovery of FIN56, a specific inducer of ferroptosis. Ferroptosis has been found to occur when the lipid-repair enzyme GPX4 is inhibited. FIN56 promoted degradation of GPX4. FIN56 also bound to and activated squalene synthase, an enzyme involved in isoprenoid biosynthesis, independent of GPX4 degradation. These discoveries show that dysregulation of lipid metabolism is associated with ferroptosis. This systematic approach is a means to discover and characterize novel cell death phenotypes.
Dietary lipids impact development, homeostasis, and disease, but links between specific dietary fats and cell fates are poorly understood. Ferroptosis is an iron-dependent form of nonapoptotic cell ...death associated with oxidized polyunsaturated phospholipids. Here, we show that dietary ingestion of the polyunsaturated fatty acid (PUFA) dihomogamma-linolenic acid (DGLA; 20:3n-6) can trigger germ-cell ferroptosis and sterility in the nematode Caenorhabditis elegans. Exogenous DGLA is also sufficient to induce ferroptosis in human cells, pinpointing this omega-6 PUFA as a conserved metabolic instigator of this lethal process. In both C. elegans and human cancer cells, ether-lipid synthesis protects against ferroptosis. These results establish C. elegans as a powerful animal model to study the induction and modulation of ferroptosis by dietary fats and indicate that endogenous ether lipids act to prevent this nonapoptotic cell fate.
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•Germ-cell death induced by dietary DGLA occurs via ferroptosis in C. elegans•Ferroptotic cell death is alleviated by antioxidants and iron chelators•DGLA specifically induces ferroptosis in human cancer cells•Ether lipids protect cells from DGLA-induced ferroptosis
Ferroptosis is a form of regulated cell death associated with oxidized lipids. Perez et al. report that the ingestion of polyunsaturated fatty acids can trigger ferroptosis in C. elegans germ cells and human cancer cells. In both systems, endogenous ether lipids protect cells from ferroptotic cell death.
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