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Organelle-specific regulation of ferroptosis.
Chen, X, Kang, R, Kroemer, G, Tang, D
Cell death and differentiation. 2021;(10):2843-2856
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Abstract
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.
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Posttranslational Modifications in Ferroptosis.
Wei, X, Yi, X, Zhu, XH, Jiang, DS
Oxidative medicine and cellular longevity. 2020;:8832043
Abstract
Ferroptosis was first coined in 2012 to describe the form of regulated cell death (RCD) characterized by iron-dependent lipid peroxidation. To date, ferroptosis has been implicated in many diseases, such as carcinogenesis, degenerative diseases (e.g., Huntington's, Alzheimer's, and Parkinson's diseases), ischemia-reperfusion injury, and cardiovascular diseases. Previous studies have identified numerous targets involved in ferroptosis; for example, acyl-CoA synthetase long-chain family member 4 (ACSL4) and p53 induce while glutathione peroxidase 4 (GPX4) and apoptosis-inducing factor mitochondria-associated 2 (AIFM2, also known as FSP1) inhibit ferroptosis. At least three major pathways (the glutathione-GPX4, FSP1-coenzyme Q10 (CoQ10), and GTP cyclohydrolase-1- (GCH1-) tetrahydrobiopterin (BH4) pathways) have been identified to participate in ferroptosis regulation. Recent advances have also highlighted the crucial roles of posttranslational modifications (PTMs) of proteins in ferroptosis. Here, we summarize the recently discovered knowledge regarding the mechanisms underlying ferroptosis, particularly the roles of PTMs in ferroptosis regulation.
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Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer: focusing on mitochondria.
Zhong, H, Yin, H
Redox biology. 2015;:193-9
Abstract
Oxidative stress-induced lipid peroxidation has been associated with human physiology and diseases including cancer. Overwhelming data suggest that reactive lipid mediators generated from this process, such as 4-hydroxynonenal (4-HNE), are biomarkers for oxidative stress and important players for mediating a number of signaling pathways. The biological effects of 4-HNE are primarily due to covalent modification of important biomolecules including proteins, DNA, and phospholipids containing amino group. In this review, we summarize recent progress on the role of 4-HNE in pathogenesis of cancer and focus on the involvement of mitochondria: generation of 4-HNE from oxidation of mitochondria-specific phospholipid cardiolipin; covalent modification of mitochondrial proteins, lipids, and DNA; potential therapeutic strategies for targeting mitochondrial ROS generation, lipid peroxidation, and 4-HNE.
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Plasma lipoproteins as mediators of the oxidative stress induced by UV light in human skin: a review of biochemical and biophysical studies on mechanisms of apolipoprotein alteration, lipid peroxidation, and associated skin cell responses.
Filipe, P, Morlière, P, Silva, JN, Mazière, JC, Patterson, LK, Freitas, JP, Santus, R
Oxidative medicine and cellular longevity. 2013;:285825
Abstract
There are numerous studies concerning the effect of UVB light on skin cells but fewer on other skin components such as the interstitial fluid. This review highlights high-density lipoprotein (HDL) and low-density lipoprotein (LDL) as important targets of UVB in interstitial fluid. Tryptophan residues are the sole apolipoprotein residues absorbing solar UVB. The UVB-induced one-electron oxidation of Trp produces (•)Trp and (•)O2 (-) radicals which trigger lipid peroxidation. Immunoblots from buffered solutions or suction blister fluid reveal that propagation of photooxidative damage to other residues such as Tyr or disulfide bonds produces intra- and intermolecular bonds in apolipoproteins A-I, A-II, and B100. Partial repair of phenoxyl tyrosyl radicals (TyrO(•)) by α -tocopherol is observed with LDL and HDL on millisecond or second time scales, whereas limited repair of α -tocopherol by carotenoids occurs in only HDL. More effective repair of Tyr and α -tocopherol is observed with the flavonoid, quercetin, bound to serum albumin, but quercetin is less potent than new synthetic polyphenols in inhibiting LDL lipid peroxidation or restoring α -tocopherol. The systemic consequences of HDL and LDL oxidation and the activation and/or inhibition of signalling pathways by oxidized LDL and their ability to enhance transcription factor DNA binding activity are also reviewed.
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Berries: emerging impact on cardiovascular health.
Basu, A, Rhone, M, Lyons, TJ
Nutrition reviews. 2010;(3):168-77
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Abstract
Berries are a good source of polyphenols, especially anthocyanins, micronutrients, and fiber. In epidemiological and clinical studies, these constituents have been associated with improved cardiovascular risk profiles. Human intervention studies using chokeberries, cranberries, blueberries, and strawberries (either fresh, or as juice, or freeze-dried), or purified anthocyanin extracts have demonstrated significant improvements in LDL oxidation, lipid peroxidation, total plasma antioxidant capacity, dyslipidemia, and glucose metabolism. Benefits were seen in healthy subjects and in those with existing metabolic risk factors. Underlying mechanisms for these beneficial effects are believed to include upregulation of endothelial nitric oxide synthase, decreased activities of carbohydrate digestive enzymes, decreased oxidative stress, and inhibition of inflammatory gene expression and foam cell formation. Though limited, these data support the recommendation of berries as an essential fruit group in a heart-healthy diet.
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Roles of the lipid peroxidation product 4-hydroxynonenal in obesity, the metabolic syndrome, and associated vascular and neurodegenerative disorders.
Mattson, MP
Experimental gerontology. 2009;(10):625-33
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Abstract
A rising tide of obesity and type 2 diabetes has resulted from the development of technologies that have made inexpensive high calorie foods readily available and exercise unnecessary for many people. Obesity and the metabolic syndrome (insulin resistance, visceral adiposity and dyslipidemia) wreak havoc on cells throughout the body thereby promoting cardiovascular and kidney disease, and degenerative diseases of the brain and body. Obesity and insulin resistance promote disease by increasing oxidative damage to proteins, lipids and DNA as the result of a combination of increased free radical production and an impaired ability of cells to detoxify the radicals and repair damaged molecules. By covalently modifying membrane-associated proteins, the membrane lipid peroxidation product 4-hydroxynonenal (HNE) may play particularly sinister roles in the metabolic syndrome and associated disease processes. HNE can damage pancreatic beta cells and can impair the ability of muscle and liver cells to respond to insulin. HNE may promote atherosclerosis by modifying lipoproteins and can cause cardiac cell damage by impairing metabolic enzymes. An adverse role for HNE in the brain in obesity and the metabolic syndrome is suggested by studies showing that HNE levels are increased in brain cells with aging and Alzheimer's disease. HNE can cause the dysfunction and degeneration of neurons by modifying membrane-associated glucose and glutamate transporters, ion-motive ATPases, enzymes involved in amyloid metabolism, and cytoskeletal proteins. Exercise and dietary energy restriction reduce HNE production and may also increase cellular systems for HNE detoxification including glutathione and oxidoreductases. The recent development of low molecular weight molecules that scavenge HNE suggests that HNE can be targeted in the design of drugs for the treatment of obesity, the metabolic syndrome, and associated disorders.
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Dynamics of lipid peroxidation and antioxidion of alpha-tocopherol in membranes.
Fukuzawa, K
Journal of nutritional science and vitaminology. 2008;(4):273-85
Abstract
The dynamics of initiation and inhibition of lipid peroxidation by alpha-tocopherol (alpha-Toc) in membranes were investigated under biological conditions using phosphatidylcholine liposomes. First, I examined how superoxide generated in the bulk water phase is able to induce lipid peroxidation in the inner hydrophobic region of the membrane. Second, I studied the localization of the antioxidant OH group of alpha-Toc in membranes and its lipid radical-trapping dynamics. Third, I investigated how alpha-Toc that is oxidized during radical trapping in membranes is recycled by ascorbic acid (AsA) in the bulk water phase. Finally, I studied the deactivation by alpha-Toc of singlet oxygen ((1)O(2)), which was generated by photoirradiation at the membrane surface, in the hydrophobic membrane inner region, and in bulk water, and measured the (1)O(2) deactivating rate constant of alpha-Toc in membranes considering: the concentration and mobility of alpha-Toc molecule in membranes, especially those of its active OH moiety located at the membrane domains, such as the membrane surface polar zone, inner hydrogen belt, and hydrophobic core, and the dielectric constant reflecting the reactivity of the OH moiety and (1)O(2) in the membrane domains where they interact.