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Autophagy Sep 2021Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death caused by lipid peroxidation, which is controlled by integrated oxidation and antioxidant... (Review)
Review
Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death caused by lipid peroxidation, which is controlled by integrated oxidation and antioxidant systems. The iron-containing enzyme lipoxygenase is the main promoter of ferroptosis by producing lipid hydroperoxides, and its function relies on the activation of ACSL4-dependent lipid biosynthesis. In contrast, the selenium-containing enzyme GPX4 is currently recognized as a central repressor of ferroptosis, and its activity depends on glutathione produced from the activation of the cystine-glutamate antiporter SLC7A11. Many metabolic (especially involving iron, lipids, and amino acids) and degradation pathways (macroautophagy/autophagy and the ubiquitin-proteasome system) orchestrate the complex ferroptotic response through direct or indirect regulation of iron accumulation or lipid peroxidation. Although the detailed mechanism of membrane injury during ferroptosis remains a mystery, ESCRT III-mediated plasma membrane repair can make cells resistant to ferroptosis. Here, we review the recent rapid progress in understanding the molecular mechanisms of ferroptosis and focus on the epigenetic, transcriptional, and posttranslational regulation of this process. 2ME: beta-mercaptoethanol; α-KG: α-ketoglutarate; ccRCC: clear cell renal cell carcinoma; EMT: epithelial-mesenchymal transition; FAO: fatty acid beta-oxidation; GSH: glutathione; MEFs: mouse embryonic fibroblasts; MUFAs: monounsaturated fatty acids; NO: nitric oxide; NOX: NADPH oxidase; PPP: pentose phosphate pathway; PUFA: polyunsaturated fatty acid; RCD: regulated cell death; RNS: reactive nitrogen species; ROS: reactive oxygen species; RTAs: radical-trapping antioxidants; UPS: ubiquitin-proteasome system; UTR: untranslated region.
Topics: Animals; Autophagy; Ferroptosis; Fibroblasts; Lipid Peroxidation; Mice; Oxidation-Reduction; Reactive Oxygen Species
PubMed: 32804006
DOI: 10.1080/15548627.2020.1810918 -
Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis.International Journal of Molecular... Dec 2022Regulated cell death (RCD) has a significant impact on development, tissue homeostasis, and the occurrence of various diseases. Among different forms of RCD, ferroptosis... (Review)
Review
Regulated cell death (RCD) has a significant impact on development, tissue homeostasis, and the occurrence of various diseases. Among different forms of RCD, ferroptosis is considered as a type of reactive oxygen species (ROS)-dependent regulated necrosis. ROS can react with polyunsaturated fatty acids (PUFAs) of the lipid (L) membrane via the formation of a lipid radical L• and induce lipid peroxidation to form L-ROS. Ferroptosis is triggered by an imbalance between lipid hydroperoxide (LOOH) detoxification and iron-dependent L-ROS accumulation. Intracellular iron accumulation and lipid peroxidation are two central biochemical events leading to ferroptosis. Organelles, including mitochondria and lysosomes are involved in the regulation of iron metabolism and redox imbalance in ferroptosis. In this review, we will provide an overview of lipid peroxidation, as well as key components involved in the ferroptotic cascade. The main mechanism that reduces ROS is the redox ability of glutathione (GSH). GSH, a tripeptide that includes glutamic acid, cysteine, and glycine, acts as an antioxidant and is the substrate of glutathione peroxidase 4 (GPX4), which is then converted into oxidized glutathione (GSSG). Increasing the expression of GSH can inhibit ferroptosis. We highlight the role of the x GSH-GPX4 pathway as the main pathway to regulate ferroptosis. The system x, composed of subunit solute carrier family members (SLC7A11 and SLC3A2), mediates the exchange of cystine and glutamate across the plasma membrane to synthesize GSH. Accumulating evidence indicates that ferroptosis requires the autophagy machinery for its execution. Ferritinophagy is used to describe the removal of the major iron storage protein ferritin by the autophagy machinery. Nuclear receptor coactivator 4 (NCOA4) is a cytosolic autophagy receptor used to bind ferritin for subsequent degradation by ferritinophagy. During ferritinophagy, stored iron released becomes available for biosynthetic pathways. The dysfunctional ferroptotic response is implicated in a variety of pathological conditions. Ferroptosis inducers or inhibitors targeting redox- or iron metabolism-related proteins and signal transduction have been developed. The simultaneous detection of intracellular and extracellular markers may help diagnose and treat diseases related to ferroptotic damage.
Topics: Lipid Peroxidation; Reactive Oxygen Species; Ferroptosis; Iron; Ferritins; Homeostasis; Lipid Peroxides
PubMed: 36613888
DOI: 10.3390/ijms24010449 -
The Journal of Experimental Medicine Jun 2021Ferroptosis is a type of regulated necrosis that is triggered by a combination of iron toxicity, lipid peroxidation, and plasma membrane damage. The upstream inducers of... (Review)
Review
Ferroptosis is a type of regulated necrosis that is triggered by a combination of iron toxicity, lipid peroxidation, and plasma membrane damage. The upstream inducers of ferroptosis can be divided into two categories (biological versus chemical) and activate two major pathways (the extrinsic/transporter versus the intrinsic/enzymatic pathways). Excessive or deficient ferroptotic cell death is implicated in a growing list of physiological and pathophysiological processes, coupled to a dysregulated immune response. This review focuses on new discoveries related to how ferroptotic cells and their spilled contents shape innate and adaptive immunity in health and disease. Understanding the immunological characteristics and activity of ferroptotic death not only illuminates an intersection between cell death and immunity but may also lead to the development of novel treatment approaches for immunopathological diseases.
Topics: Animals; Ferroptosis; Humans; Immunity; Infections; Inflammation; Lipid Peroxidation
PubMed: 33978684
DOI: 10.1084/jem.20210518 -
Oxidative Medicine and Cellular... 2019Reactive oxygen species- (ROS-) induced lipid peroxidation plays a critical role in cell death including apoptosis, autophagy, and ferroptosis. This fundamental and... (Review)
Review
Reactive oxygen species- (ROS-) induced lipid peroxidation plays a critical role in cell death including apoptosis, autophagy, and ferroptosis. This fundamental and conserved mechanism is based on an excess of ROS which attacks biomembranes, propagates lipid peroxidation chain reactions, and subsequently induces different types of cell death. A highly evolved sophisticated antioxidant system exists that acts to protect the cells from oxidative damage. In this review, we discussed how ROS propagate lipid peroxidation chain reactions and how the products of lipid peroxidation initiate apoptosis and autophagy in current models. We also discussed the mechanism of lipid peroxidation during ferroptosis, and we summarized lipid peroxidation in pathological conditions of critical illness. We aim to bring a more global and integrative sight to know how different ROS-induced lipid peroxidation occurs among apoptosis, autophagy, and ferroptosis.
Topics: Acute Kidney Injury; Animals; Antioxidants; Apoptosis; Autophagy; Ferroptosis; Humans; Lipid Peroxidation; Oxidative Stress; Reactive Oxygen Species; Sepsis; Signal Transduction
PubMed: 31737171
DOI: 10.1155/2019/5080843 -
Biochemical and Biophysical Research... Jan 2017Disruption of redox homeostasis is a key phenotype of many pathological conditions. Though multiple oxidizing compounds such as hydrogen peroxide are widely recognized... (Review)
Review
Disruption of redox homeostasis is a key phenotype of many pathological conditions. Though multiple oxidizing compounds such as hydrogen peroxide are widely recognized as mediators and inducers of oxidative stress, increasingly, attention is focused on the role of lipid hydroperoxides as critical mediators of death and disease. As the main component of cellular membranes, lipids have an indispensible role in maintaining the structural integrity of cells. Excessive oxidation of lipids alters the physical properties of cellular membranes and can cause covalent modification of proteins and nucleic acids. This review discusses the synthesis, toxicity, degradation, and detection of lipid peroxides in biological systems. Additionally, the role of lipid peroxidation is highlighted in cell death and disease, and strategies to control the accumulation of lipid peroxides are discussed.
Topics: Alzheimer Disease; Animals; Cell Death; Humans; Lipid Peroxidation; Lipid Peroxides; Lipoxygenase Inhibitors; Metabolic Networks and Pathways; Oxidation-Reduction; Reducing Agents
PubMed: 28212725
DOI: 10.1016/j.bbrc.2016.10.086 -
Cancer Cell Jun 2019One of the key challenges in cancer research is how to effectively kill cancer cells while leaving the healthy cells intact. Cancer cells often have defects in cell... (Review)
Review
One of the key challenges in cancer research is how to effectively kill cancer cells while leaving the healthy cells intact. Cancer cells often have defects in cell death executioner mechanisms, which is one of the main reasons for therapy resistance. To enable growth, cancer cells exhibit an increased iron demand compared with normal, non-cancer cells. This iron dependency can make cancer cells more vulnerable to iron-catalyzed necrosis, referred to as ferroptosis. The identification of FDA-approved drugs as ferroptosis inducers creates high expectations for the potential of ferroptosis to be a new promising way to kill therapy-resistant cancers.
Topics: Animals; Antineoplastic Agents; Drug Resistance, Neoplasm; Ferroptosis; Humans; Iron; Lipid Peroxidation; Molecular Targeted Therapy; Neoplasms; Signal Transduction
PubMed: 31105042
DOI: 10.1016/j.ccell.2019.04.002 -
Cell Death and Differentiation Oct 2021Ferroptosis, a cell death modality characterized by iron-dependent lipid peroxidation, is involved in the development of multiple pathological conditions, including... (Review)
Review
Ferroptosis, a cell death modality characterized by iron-dependent lipid peroxidation, is involved in the development of multiple pathological conditions, including ischemic tissue damage, infection, neurodegeneration, and cancer. The cellular machinery responsible for the execution of ferroptosis integrates multiple pro-survival or pro-death signals from subcellular organelles and then 'decides' whether to engage the lethal process or not. Here, we outline the evidence implicating different organelles (including mitochondria, lysosomes, endoplasmic reticulum, lipid droplets, peroxisomes, Golgi apparatus, and nucleus) in the ignition or avoidance of ferroptosis, while emphasizing their potential relevance for human disease and their targetability for pharmacological interventions.
Topics: Cell Death; Ferroptosis; Humans; Lipid Peroxidation; Mitochondria
PubMed: 34465893
DOI: 10.1038/s41418-021-00859-z -
Progress in Neurobiology Jan 2021Parkinson's Disease (PD) is a common and progressive neurodegenerative disorder characterised by motor impairments as well as non-motor symptoms. While dopamine-based... (Review)
Review
Parkinson's Disease (PD) is a common and progressive neurodegenerative disorder characterised by motor impairments as well as non-motor symptoms. While dopamine-based therapies are effective in fighting the symptoms in the early stages of the disease, a lack of neuroprotective drugs means that the disease continues to progress. Along with the traditionally recognised pathological hallmarks of dopaminergic neuronal death and intracellular α-synuclein (α-syn) depositions, iron accumulation, elevated oxidative stress and lipid peroxidation damage are further conspicuous features of PD pathophysiology. However, the underlying mechanisms linking these pathological hallmarks with neurodegeneration still remain unclear. Ferroptosis, a regulated iron dependent cell death pathway involving a lethal accumulation of lipid peroxides, shares several features with PD pathophysiology. Interestingly, α-syn has been functionally linked with the metabolism of both iron and lipid, suggesting a possible interplay between dysregulated α-syn and other PD pathological hallmarks related to ferroptosis. This review will address the importance for understanding these disease mechanisms that could be targeted therapeutically. Anti-ferroptosis molecules are neuroprotective in PD animal models and the anti-ferroptotic iron chelator, deferiprone, slowed disease progression and improved motor function in two independent clinical trials for PD. An ongoing larger multi-centre phase 2 clinical trial will confirm the therapeutic potential of deferiprone and the relevance of ferroptosis in PD. This review addresses the known pathological features of PD in relation to the ferroptosis pathway with therapeutic implications of targeting this cell death pathway.
Topics: Ferroptosis; Humans; Lipid Peroxidation; Oxidative Stress; Parkinson Disease; alpha-Synuclein
PubMed: 32726602
DOI: 10.1016/j.pneurobio.2020.101890 -
Current Biology : CB Nov 2020Iron is an essential micronutrient for microorganisms, plants, animals, and humans. However, iron overload can damage the organism through a variety of mechanisms,...
Iron is an essential micronutrient for microorganisms, plants, animals, and humans. However, iron overload can damage the organism through a variety of mechanisms, including the induction of cell death. Ferroptosis is defined as an iron-dependent form of regulated cell death caused by unrestricted lipid peroxidation and subsequent membrane damage. Ferroptosis can be triggered through either the extrinsic or the intrinsic pathway. The extrinsic pathway is initiated through the regulation of transporters (e.g., inhibition of the amino acid antiporter system xc or activation of the iron transporters transferrin and lactotransferrin), whereas the intrinsic pathway is mainly induced by blocking the expression or activity of intracellular antioxidant enzymes, such as glutathione peroxidase 4 (GPX4). In addition to small-molecule compounds and drugs, certain stresses (e.g., high temperature, low temperature, hypoxia, and radiation) induce ferroptotic cell death. The abnormal regulation of this process, which is connected to protein degradation pathways, such as autophagy and the ubiquitin-proteasome system, is associated with various pathological conditions, including acute tissue damage, infection, cancer, and neurodegeneration. Here, we discuss the core process and regulation of ferroptosis in mammalian cells, as well as its therapeutic implications in disease.
Topics: Alarmins; Animals; Autophagy; Fatty Acids; Ferroptosis; Glutathione; Humans; Iron; Lipid Peroxidation; Neoplasms; Neurodegenerative Diseases; Nitric Oxide; Phospholipid Hydroperoxide Glutathione Peroxidase; Proteasome Endopeptidase Complex; Proteolysis; Reactive Oxygen Species; Stress, Physiological; Ubiquitination
PubMed: 33142092
DOI: 10.1016/j.cub.2020.09.068 -
Cell May 2020Ferroptosis is a regulated form of cell death that occurs when phospholipids with polyunsaturated fatty acyl tails are oxidized in an iron-dependent manner. Research in...
Ferroptosis is a regulated form of cell death that occurs when phospholipids with polyunsaturated fatty acyl tails are oxidized in an iron-dependent manner. Research in recent years has uncovered complex cellular networks that induce and suppress lethal lipid peroxidation. This SnapShot provides an overview of ferroptosis-related pathways, including relevant biomolecules and small-molecule modulators regulating them.
Topics: Cell Death; Ferroptosis; Humans; Iron; Lipid Peroxidation; Oxidation-Reduction; Phospholipids
PubMed: 32470402
DOI: 10.1016/j.cell.2020.04.039