Targeting ferroptosis protects against multiorgan dysfunction and death (original) (raw)
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Targeting ferroptosis protects against experimental (multi)organ dysfunction and death
Nature Communications, 2022
The most common cause of death in the intensive care unit (ICU) is the development of multiorgan dysfunction syndrome (MODS). Besides life-supporting treatments, no cure exists, and its mechanisms are still poorly understood. Catalytic iron is associated with ICU mortality and is known to cause free radical-mediated cellular toxicity. It is thought to induce excessive lipid peroxidation, the main characteristic of an iron-dependent type of cell death conceptualized as ferroptosis. Here we show that the severity of multiorgan dysfunction and the probability of death are indeed associated with plasma catalytic iron and lipid peroxidation. Transgenic approaches underscore the role of ferroptosis in iron-induced multiorgan dysfunction. Blocking lipid peroxidation with our highly soluble ferrostatin-analogue protects mice from injury and death in experimental non-septic multiorgan dysfunction, but not in sepsis-induced multiorgan dysfunction. The limitations of the experimental mice mode...
Programmed Cell-Death by Ferroptosis: Antioxidants as Mitigators
International Journal of Molecular Sciences
Iron, the fourth most abundant element in the Earth’s crust, is vital in living organisms because of its diverse ligand-binding and electron-transfer properties. This ability of iron in the redox cycle as a ferrous ion enables it to react with H2O2, in the Fenton reaction, to produce a hydroxyl radical (•OH)—one of the reactive oxygen species (ROS) that cause deleterious oxidative damage to DNA, proteins, and membrane lipids. Ferroptosis is a non-apoptotic regulated cell death that is dependent on iron and reactive oxygen species (ROS) and is characterized by lipid peroxidation. It is triggered when the endogenous antioxidant status of the cell is compromised, leading to lipid ROS accumulation that is toxic and damaging to the membrane structure. Consequently, oxidative stress and the antioxidant levels of the cells are important modulators of lipid peroxidation that induce this novel form of cell death. Remedies capable of averting iron-dependent lipid peroxidation, therefore, are ...
Ferroptosis: A unique form of iron-dependent regulated cell death and its role in different diseases
World Journal of Biology Pharmacy and Health Sciences
Ferroptosis, a unique, non-apoptotic, iron-dependent, controlled cell death associated with excessive iron accumulation and phospholipid peroxidation. It causes a reduction in cell volume and an increased density of the mitochondrial membrane. This form of controlled cell death is genetically, biochemically, and morphologically unique from other cell deaths, such as apoptosis, uncontrolled necrosis, and necroptosis. Directly or indirectly, alteration of glutathione peroxidase by ferroptosis inducers, through various mechanisms, causes a loss of antioxidant potential and a build-up of lipid reactive oxygen species (ROS) in cells. Inhibition of glutathione peroxidase 4 (GPX-4), system Xc-cystine/glutathione antiporter, and arachidonoyl (AA) peroxidation induces ferroptosis in cells, which can be mediated by the mitochondrial VDAC3, p53 genes, and a variety of additional regulator genes such as HSPB1, CARS, and NFR2. Aside from these, a number of drugs like sorafenib, lanperisone, arte...
Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models
Journal of the American Chemical Society, 2014
Ferrostatin-1 (Fer-1) inhibits ferroptosis, a form of regulated, oxidative, 18 nonapoptotic cell death. We found that Fer-1 inhibited cell death in cellular models of 19 Huntington's disease (HD), periventricular leukomalacia (PVL), and kidney dysfunction; 20 Fer-1 inhibited lipid peroxidation, but not mitochondrial reactive oxygen species 21 formation or lysosomal membrane permeability. We developed a mechanistic model to 22 explain the activity of Fer-1, which guided the development of ferrostatins with improved 23 properties. These studies suggest numerous therapeutic uses for ferrostatins, and that lipid 24 peroxidation mediates diverse disease phenotypes.
Oxidative stress induces mitochondrial iron overload and ferroptotic cell death
Scientific Reports
Oxidative stress has been shown to induce cell death in a wide range of human diseases including cardiac ischemia/reperfusion injury, drug induced cardiotoxicity, and heart failure. However, the mechanism of cell death induced by oxidative stress remains incompletely understood. Here we provide new evidence that oxidative stress primarily induces ferroptosis, but not apoptosis, necroptosis, or mitochondria-mediated necrosis, in cardiomyocytes. Intriguingly, oxidative stress induced by organic oxidants such as tert-butyl hydroperoxide (tBHP) and cumene hydroperoxide (CHP), but not hydrogen peroxide (H2O2), promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to increased lipid peroxidation. Moreover, elevated oxidative stress is also linked to labile iron overload through downregulation of the transcription suppressor BTB and CNC homology 1 (Bach1), upregulation of heme oxygenase 1 (HO-1) expression, and enhanced iron release via h...
Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis.
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.
Ferroptosis: regulated cell death
Archives of Industrial Hygiene and Toxicology
Ferroptosis is a recently identified form of regulated cell death that differs from other known forms of cell death morphologically, biochemically, and genetically. The main properties of ferroptosis are free redox-active iron and consequent iron-dependent peroxidation of polyunsaturated fatty acids in cell membrane phospholipids, which results in the accumulation of lipid-based reactive oxygen species due to loss of glutathione peroxidase 4 activity. Ferroptosis has increasingly been associated with neurodegenerative diseases, carcinogenesis, stroke, intracerebral haemorrhage, traumatic brain injury, and ischemia-reperfusion injury. It has also shown a significant therapeutic potential in the treatment of cancer and other diseases. This review summarises current knowledge about and the mechanisms that regulate ferroptosis.
Free Radical Biology and Medicine, 2019
Duality of iron as an essential cofactor of many enzymatic metabolic processes and as a catalyst of poorly controlled redox-cycling reactions defines its possible biological beneficial and hazardous role in the body. In this review, we discuss these two "faces" of iron in a newly conceptualized program of regulated cell death, ferroptosis. Ferroptosis is a genetically programmed irondependent form of regulated cell death driven by enhanced lipid peroxidation and insufficient capacity of thiol-dependent mechanisms (glutathione peroxidase 4, GPX4) to eliminate hydroperoxy-lipids. We present arguments favoring the enzymatic mechanisms of ferroptotically engaged non-heme iron of 15-lipoxygenases (15-LOX) in complexes with phosphatidylethanolamines binding protein 1 (PEBP1) as a catalyst of highly selective and specific oxidation reactions of arachidonoyl-(AA) and adrenoyl-phosphatidylethanolamines (PE). We discuss possible role of iron chaperons as control mechanisms for guided iron delivery directly to their "protein clients" thus limiting non-enzymatic redox-cycling reactions. We also consider opportunities of loosely-bound iron to contribute to the production of proferroptotic lipid oxidation products. Finally, we propose a two-stage iron-dependent mechanism for iron in ferroptosis by *
Targeting Ferroptosis against Ischemia/Reperfusion Cardiac Injury
Antioxidants
Ischemic heart disease is a leading cause of death worldwide. Primarily, ischemia causes decreased oxygen supply, resulting in damage of the cardiac tissue. Naturally, reoxygenation has been recognized as the treatment of choice to recover blood flow through primary percutaneous coronary intervention. This treatment is the gold standard therapy to restore blood flow, but paradoxically it can also induce tissue injury. A number of different studies in animal models of acute myocardial infarction (AMI) suggest that ischemia-reperfusion injury (IRI) accounts for up to 50% of the final myocardial infarct size. Oxidative stress plays a critical role in the pathological process. Iron is an essential mineral required for a variety of vital biological functions but also has potentially toxic effects. A detrimental process induced by free iron is ferroptosis, a non-apoptotic type of programmed cell death. Accordingly, efforts to prevent ferroptosis in pathological settings have focused on th...