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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 -
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 -
Trends in Cell Biology Jun 2020Cell death is an essential feature of development in multicellular organisms, a critical driver of degenerative diseases, and can be harnessed for treating some cancers.... (Review)
Review
Cell death is an essential feature of development in multicellular organisms, a critical driver of degenerative diseases, and can be harnessed for treating some cancers. Understanding the mechanisms governing cell death is critical for addressing its role in disease. Similarly, metabolism is essential for normal energy and biomolecule production, and goes awry in many diseases. Metabolism and cell death are tightly linked in the phenomenon of ferroptosis, a form of regulated cell death driven by peroxidation of phospholipids. Glutathione peroxidase 4 (GPX4) uses glutathione to protect cells from ferroptosis by eliminating phospholipid peroxides. Recent data have revealed glutathione/GPX4-independent axes for suppressing ferroptosis, and insight into the regulation of iron and mitochondria in ferroptosis. Ferroptosis has recently been implicated in multiple diseases, and functions as a tumor suppression mechanism. Ferroptosis induction is a promising approach in treating several conditions, including neoplastic diseases. Here, we summarize these recent advances.
Topics: Animals; Disease; Ferroptosis; Humans; Iron; Lipid Peroxides; Metabolic Networks and Pathways; Neoplasms
PubMed: 32413317
DOI: 10.1016/j.tcb.2020.02.009 -
Inhibition of ferroptosis promotes retina ganglion cell survival in experimental optic neuropathies.Redox Biology Dec 2022Retinal ganglion cell (RGC) death is a hallmark of traumatic optic neuropathy, glaucoma, and other optic neuropathies that result in irreversible vision loss. However,...
Retinal ganglion cell (RGC) death is a hallmark of traumatic optic neuropathy, glaucoma, and other optic neuropathies that result in irreversible vision loss. However, therapeutic strategies for rescuing RGC loss still remain challenging, and the molecular mechanism underlying RGC loss has not been fully elucidated. Here, we highlight the role of ferroptosis, a non-apoptotic form of programmed cell death characterized by iron-dependent lethal lipid peroxides accumulation, in RGC death using an experimental model of glaucoma and optic nerve crush (ONC). ONC treatment resulted in significant downregulation of glutathione peroxidase 4 (GPx4) and system xc(-) cystine/glutamate antiporter (xCT) in the rat retina, accompanied by increased lipid peroxide and iron levels. The reduction of GPx4 expression in RGCs after ONC was confirmed by laser-capture microdissection and PCR. Transmission electron microscopy (TEM) revealed alterations in mitochondrial morphology, including increased membrane density and reduced mitochondrial cristae in RGCs after ONC. Notably, the ferroptosis inhibitor ferrostatin-1 (Fer-1) significantly promoted RGC survival and preserved retinal function in ONC and microbead-induced glaucoma mouse models. In addition, compared to the apoptosis inhibitor Z-VAD-FMK, Fer-1 showed better effect in rescuing RGCs death in ONC retinas. Mechanistically, we found the downregulation of GPx4 mainly occurred in the mitochondrial compartment, accompanied by increased mitochondrial reactive oxygen species (ROS) and lipid peroxides. The mitochondria-selective antioxidant MitoTEMPO attenuated RGC loss after ONC, implicating mitochondrial ROS and lipid peroxides as major mechanisms in ferroptosis-induced RGC death in ONC retinas. Notably, administering Fer-1 effectively prevented the production of mitochondrial lipid peroxides, the impairment of mitochondrial adenosine 5'-triphosphate (ATP) production, and the downregulation of mitochondrial genes, such as mt-Cytb and MT-ATP6, in ONC retinas. Our findings suggest that ferroptosis is a major form of regulated cell death for RGCs in experimental glaucoma and ONC models and suggesting targeting mitochondria-dependent ferroptosis as a protective strategy for RGC injuries in optic neuropathies.
Topics: Mice; Rats; Animals; Retinal Ganglion Cells; Cell Survival; Ferroptosis; Lipid Peroxides; Reactive Oxygen Species; Optic Nerve Injuries; Disease Models, Animal; Retina; Glaucoma; Iron
PubMed: 36413918
DOI: 10.1016/j.redox.2022.102541 -
Biomedicine & Pharmacotherapy =... Jan 2022Ferroptosis is a programmed iron-dependent cell death characterized by accumulation of lipid peroxides (LOOH) and redox disequilibrium. Ferroptosis shows unique...
Ferroptosis is a programmed iron-dependent cell death characterized by accumulation of lipid peroxides (LOOH) and redox disequilibrium. Ferroptosis shows unique characteristics in biology, chemistry, and gene levels, compared to other cell death forms. The metabolic disorder of intracellular LOOH catalyzed by iron causes the inactivity of GPX4, disrupts the redox balance, and triggers cell death. Metabolism of amino acid, iron, and lipid, including associated pathways, is considered as a specific hallmark of ferroptosis. Epidemiological studies and animal experiments have shown that ferroptosis plays an important character in the pathophysiology of cardiovascular disease such as atherosclerosis, myocardial infarction (MI), ischemia/reperfusion (I/R), heart failure (HF), cardiac hypertrophy, cardiomyopathy, and abdominal aortic aneurysm (AAA). This review systematically summarized the latest research progress on the mechanisms of ferroptosis. Then we report the contribution of ferroptosis in cardiovascular diseases. Finally, we discuss and analyze the therapeutic approaches targeting for ferroptosis associated with cardiovascular diseases.
Topics: Animals; Cardiovascular Diseases; Cell Death; Ferroptosis; Humans; Lipid Peroxides; Metabolic Diseases; Oxidation-Reduction
PubMed: 34800783
DOI: 10.1016/j.biopha.2021.112423 -
British Journal of Cancer Apr 2023Colorectal cancer (CRC) is the third leading cause of cancer deaths worldwide and is characterised by frequently mutated genes, such as APC, TP53, KRAS and BRAF. The... (Review)
Review
Colorectal cancer (CRC) is the third leading cause of cancer deaths worldwide and is characterised by frequently mutated genes, such as APC, TP53, KRAS and BRAF. The current treatment options of chemotherapy, radiation therapy and surgery are met with challenges such as cancer recurrence, drug resistance, and overt toxicity. CRC therapies exert their efficacy against cancer cells by activating biological pathways that contribute to various forms of regulated cell death (RCD). In 2012, ferroptosis was discovered as an iron-dependent and lipid peroxide-driven form of RCD. Recent studies suggest that therapies which target ferroptosis are promising treatment strategies for CRC. However, a greater understanding of the mechanisms of ferroptosis initiation, propagation, and resistance in CRC is needed. This review provides an overview of recent research in ferroptosis and its potential role as a therapeutic target in CRC. We also propose future research directions that could help to enhance our understanding of ferroptosis in CRC.
Topics: Humans; Ferroptosis; Iron; Lipid Peroxides; Colorectal Neoplasms
PubMed: 36703079
DOI: 10.1038/s41416-023-02149-6 -
Frontiers in Endocrinology 2022Ferroptosis is a newly discovered form of cell death that differs from other forms of regulated cell death at morphological, biochemical, and genetic levels, and is... (Review)
Review
Ferroptosis is a newly discovered form of cell death that differs from other forms of regulated cell death at morphological, biochemical, and genetic levels, and is characterized by iron-dependent accumulation of lipid peroxides. Ferroptosis is closely related to intracellular metabolism of amino acids, lipids, and iron. Hence, its regulation may facilitate disease intervention and treatment. Diabetic kidney disease is one of the most serious complications of diabetes, which leads to serious psychological and economic burdens to patients and society when it progresses to end-stage renal disease. At present, there is no effective treatment for diabetic kidney disease. Ferroptosis has been recently identified in animal models of diabetic kidney disease. Herein, we systematically reviewed the regulatory mechanism of ferroptosis, its association with different forms of cell death, summarized its relationship with diabetic kidney disease, and explored its regulation to intervene with the progression of diabetic kidney disease or as a treatment.
Topics: Amino Acids; Animals; Diabetes Mellitus; Diabetic Nephropathies; Ferroptosis; Iron; Lipid Peroxides
PubMed: 36246888
DOI: 10.3389/fendo.2022.945976 -
Cell Death & Disease Sep 2022The therapeutic effect of mesenchymal stem cells (MSCs) on sepsis has been well-known. However, a comprehensive understanding of the relationship between MSCs and...
The therapeutic effect of mesenchymal stem cells (MSCs) on sepsis has been well-known. However, a comprehensive understanding of the relationship between MSCs and macrophages remains elusive. Superparamagnetic iron oxide (SPIO) is one of the most commonly used tracers for MSCs. Our previous study has shown that SPIO enhanced the therapeutic effect of MSCs in a macrophage-dependent manner. However, the fate of SPIO-labeled MSCs (MSC) after infusion remains unknown and the direct interaction between MSC and macrophages remains unclear. Mice were injected intravenously with MSC at 2 h after Escherichia coli infection and sacrificed at different times to investigate their distribution and therapeutic effect. We found that MSC homed to lungs rapidly after infusion and then trapped in livers for more than 10 days. Only a few MSC homed to the spleen and there was no MSC detectable in the brain, heart, kidney, colon, and uterus. MSC tended to stay longer in injured organs compared with healthy organs and played a long-term protective role in sepsis. The mRNA expression profiles between MSCs and MSC were rather different, genes related to lipid metabolism, inflammation, and oxidative stress were changed. The levels of ROS and lipid peroxide were elevated in MSC, which confirmed that SPIO-induced ferroptosis in MSC. Ferroptosis of MSC induced by SPIO enhanced the efferocytosis of macrophages and thus enhanced the protective effect on septic mice, while the benefits were impaired after MSC were treated with Ferrostatin-1 (Fer-1) or Liproxtatin-1 (Lip-1), the inhibitors of ferroptosis. SPIO-induced ferroptosis in MSCs contributes to better therapeutic effects in sepsis by enhancing the efferocytosis of macrophages. Our data showed the efficacy and advantage of MSC as a therapeutic tool and the cell states exert different curative effects on sepsis.
Topics: Animals; Female; Ferric Compounds; Lipid Peroxides; Macrophages; Magnetic Resonance Imaging; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; RNA, Messenger; Reactive Oxygen Species; Sepsis
PubMed: 36163182
DOI: 10.1038/s41419-022-05264-z -
Current Biology : CB Apr 2023The ongoing metabolic and microbicidal pathways that support and protect cellular life generate potentially damaging reactive oxygen species (ROS). To counteract damage,...
The ongoing metabolic and microbicidal pathways that support and protect cellular life generate potentially damaging reactive oxygen species (ROS). To counteract damage, cells express peroxidases, which are antioxidant enzymes that catalyze the reduction of oxidized biomolecules. Glutathione peroxidase 4 (GPX4) is the major hydroperoxidase specifically responsible for reducing lipid peroxides; this homeostatic mechanism is essential, and its inhibition causes a unique type of lytic cell death, ferroptosis. The mechanism(s) that lead to cell lysis in ferroptosis, however, are unclear. We report that the lipid peroxides formed during ferroptosis accumulate preferentially at the plasma membrane. Oxidation of surface membrane lipids increased tension on the plasma membrane and led to the activation of Piezo1 and TRP channels. Oxidized membranes thus became permeable to cations, ultimately leading to the gain of cellular Na and Ca concomitant with loss of K. These effects were reduced by deletion of Piezo1 and completely inhibited by blocking cation channel conductance with ruthenium red or 2-aminoethoxydiphenyl borate (2-APB). We also found that the oxidation of lipids depressed the activity of the Na/K-ATPase, exacerbating the dissipation of monovalent cation gradients. Preventing the changes in cation content attenuated ferroptosis. Altogether, our study establishes that increased membrane permeability to cations is a critical step in the execution of ferroptosis and identifies Piezo1, TRP channels, and the Na/K-ATPase as targets/effectors of this type of cell death.
Topics: Cations; Ferroptosis; Glutathione Peroxidase; Lipid Peroxidation; Lipid Peroxides; Phospholipid Hydroperoxide Glutathione Peroxidase; Membrane Proteins
PubMed: 36898371
DOI: 10.1016/j.cub.2023.02.060 -
Redox Biology Nov 2022Loss of innervation is a key driver of age associated muscle atrophy and weakness (sarcopenia). Our laboratory has previously shown that denervation induced atrophy is...
Loss of innervation is a key driver of age associated muscle atrophy and weakness (sarcopenia). Our laboratory has previously shown that denervation induced atrophy is associated with the generation of mitochondrial hydroperoxides and lipid mediators produced downstream of cPLA and 12/15 lipoxygenase (12/15-LOX). To define the pathological impact of lipid hydroperoxides generated in denervation-induced atrophy in vivo, we treated mice with liproxstatin-1, a lipid hydroperoxide scavenger. We treated adult male mice with 5 mg/kg liproxstain-1 or vehicle one day prior to sciatic nerve transection and daily for 7 days post-denervation before tissue analysis. Liproxstatin-1 treatment protected gastrocnemius mass and fiber cross sectional area (∼40% less atrophy post-denervation in treated versus untreated mice). Mitochondrial hydroperoxide generation was reduced 80% in vitro and by over 65% in vivo by liproxstatin-1 treatment in denervated permeabilized muscle fibers and decreased the content of 4-HNE by ∼25% post-denervation. Lipidomic analysis revealed detectable levels of 25 oxylipins in denervated gastrocnemius muscle and significantly increased levels for eight oxylipins that are generated by metabolism of fatty acids through 12/15-LOX. Liproxstatin-1 treatment reduced the level of three of the eight denervation-induced oxylipins, specifically 15-HEPE, 13-HOTrE and 17-HDOHE. Denervation elevated protein degradation rates in muscle and treatment with liproxstatin-1 reduced rates of protein breakdown in denervated muscle. In contrast, protein synthesis rates were unchanged by denervation. Targeted proteomics revealed a number of proteins with altered expression after denervation but no effect of liproxstain-1. Transcriptomic analysis revealed 203 differentially expressed genes in denervated muscle from vehicle or liproxstatin-1 treated mice, including ER stress, nitric oxide signaling, Gαi signaling, glucocorticoid receptor signaling, and other pathways. Overall, these data suggest lipid hydroperoxides and oxylipins are key drivers of increased protein breakdown and muscle loss associated with denervation induced atrophy and a potential target for sarcopenia intervention.
Topics: Male; Mice; Animals; Lipid Peroxides; Oxylipins; Sarcopenia; Muscular Atrophy; Muscle, Skeletal; Protein Biosynthesis; Denervation
PubMed: 36283174
DOI: 10.1016/j.redox.2022.102518