Moreover, it has been proposed that 4-HNE can induce cell death by modulating several transcription factors, such as Nrf2 and peroxisome proliferator-activated receptors PPARs , as well as other signaling pathways, such as cell-cycle regulators and caspases [ 57 ]. It has also been found that whether cells undergo apoptosis or necrosis depends on the cellular concentration of 4-HNE [ 58 ]. Finally, selection of erastin-resistant clones of DU cells revealed that resistant cells had dramatic upregulation of AKR1C genes, which are involved in detoxifying aldehydes such as 4-HNE [ 40 ][ 59 ].
A recent study profiled the protein carbonylation events induced during ferroptosis, presumably through such electrophilic products of lipid peroxidation [ 60 ]. Further studies need to be carried out to define the significance of 4-HNE during ferroptotic cell death. It is worth noting that lipid peroxidation has also been associated in the literature with other modes of cell death, including apoptosis, in some cases.
There are two key points to note about these prior studies. First, apoptosis was, for many years, considered synonomous with cell death, and many studies before the year simply termed cell death as apoptosis without any rigorous evaluation of the mode of cell death. Thus, these early studies that refer to apoptosis need to be reevaluated to examine the precise mode of cell death involved and whether indeed ferroptosis may have been induced. Second, in many cases, multiple cell death modes can be activated by pleiotropic triggers and stresses.
In such cases, detection of lipid peroxidation during apoptosis may simply reflect a low-level stimulation of ferroptosis during apoptotic cell death. However, the possibility does remain that other models of cell death might be associated with nonlethal degrees of lipid peroxidation; such cases need to be carefully examined. Some clues have emerged, pointing to possible solutions to these three mysteries. Regarding the mechanism of lipid peroxidation, as noted above, both Fenton chemistry and LOXs may contribute to ferroptosis.
Iron metabolism and availability play key roles in both processes. Ferritinophagy, the autophagic degradation of ferritin, contributes to iron availability for Fenton chemistry and is involved in ferroptosis [ 61 ]. Additional links between iron metabolism and ferroptosis may help in clarifying the role of iron in ferroptosis.
In addition, lipidomic studies may help to identify substrates of LOXs during ferroptotic cell death and to define which ferroptosis contexts primarily use LOXs versus Fenton chemistry. Where lipid peroxidation occurs during ferroptosis is the second significant mystery. The plasma membrane, mitochondria, ER, and lysosomes are all candidates. As noted above, mitochondria-deficient cells revealed that mitochondria are not required for ferroptotic cell death. By reducing the extent of molecular trapping through the lysosomotropic effect, lysosomes were also shown to be unnecessary for erastin-induced and RSL3-induced cell death, as well as ferroptosis suppression by ferrostatins.
Moreover, when SRS imaging was used to detect the localization of a diyne ferrostatin, no detectable signal was found in the plasma membrane. Therefore, we hypothesize that the ER might be a key subcellular location for ferroptosis, at least in the cancer cell lines studied in these experiments. Lipid peroxidation during ferroptosis may as well occur in multiple organelles.
The vulnerability of each organelle to lipid peroxidation may be different because of differences in lipid compositions, iron storage, GSH level, LOX expression, and GPX4 localization. For example, mitochondria are rich in iron and GPX4. Depletion of mitochondria might change the cellular level of iron and GPX4 and regulate ferroptosis in other organelles. Defining the lipid composition of different organelles and how these lipids promote or suppress lipid peroxidation and ferroptosis may aid in solving this mystery. Recently, a study reported that cyclic-di-adenosine monophosphate c-di-AMP in live gram-positive bacteria could interact with the innate sensor stimulator of interferon genes STING to mediate ER stress and induce mechanistic target of rapamycin mTOR inactivation, resulting in ER-phagy [ 62 ].
This study provides a strategy to induce ER-phagy in cells. To date, three proteins family with sequence similarity member B [FAMB], SEC62, and reticulon-3 [RTN3] have been identified as ER-phagy receptors in mammalian cells [ 63 — 65 ]; further elucidation of the components of this process may reveal links to ferroptosis. Since generation of mitochondria-deficient cells was possible using mitophagy, perhaps it will be possible to generate ER-deficient cells using ER-phagy.
It is possible that ER stress is simply a consequence of GSH depletion during ferroptosis and does not contribute to the lethal mechanism, but more studies are needed to address this question. How lipid peroxidation leads to ferroptosis is the third open question. Computational approaches such as molecular dynamics simulations may aid the study of membrane properties during ferroptosis.
The secondary products of lipid peroxidation, such as MDA and 4-HNE, may also be good targets to examine for their roles during ferroptosis. Although these two aldehydes have been extensively studied, and excessive accumulation of 4-HNE has been shown to promote apoptosis and necrosis, their role in ferroptosis is unclear. By solving these mysteries of ferroptosis, we may discover new insights and therapeutic strategies for ferroptosis-related human diseases, such as numerous cancers and degenerative diseases.
Abstract Ferroptosis is a cell death process driven by damage to cell membranes and linked to numerous human diseases. Introduction The fundamental building block of life is the cell, the smallest living unit within multicellular organisms. Download: PPT. What causes lipid peroxidation: Fenton chemistry or LOXs? Fig 2. Fenton chemistry and lipid peroxidation in ferroptosis. Where does lipid peroxidation take place? Fig 3. Subcellular model of the location of lipid peroxidation in ferroptosis.
How does lipid peroxidation lead to ferroptotic cell death? Solving the mysteries Some clues have emerged, pointing to possible solutions to these three mysteries. References 1. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death Cell Death Differ. Ferroptosis: an iron-dependent form of nonapoptotic cell death.
Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc. Increased erythrophagocytosis induces ferroptosis in red pulp macrophages in a mouse model of transfusion. Ferroptosis as a pmediated activity during tumour suppression. Front Endocrinol Lausanne. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Ferroptosis is newly characterized form of neuronal cell death in response to arsenite exposure.
Regulation of ferroptotic cancer cell death by Gpx4. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis.
Nat Chem Biol. Epub May 9. ACS Chem Biol. Gaschler MM, Andia A. A et al. FINO2 initiates ferroptosis through Gpx4 inactivation and driving lipid peroxidation. Nature chemical biology. Non-thermal plasma as a simple ferroptosis inducer in cancer cells: A possible role of ferritin.
Pathol Int. Free radical lipid peroxidation: mechanisms and analysis. Chem Rev. ACS Cent Sci.
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Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxynonenal. Oxidative medicine and cellular longevity. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.
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Winterbourn CC. Toxicity of iron and hydrogen peroxide: the Fenton reaction. Toxicology letters. Yehuda S, Mostofsky DI. Totowa, NJ: Humana Press; Lipid peroxidation in cell death. Biochem Biophys Res Commun. Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease. Chemical reviews. Biochim Biophys Acta. Cell metabolism. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. Identification of baicalein as a ferroptosis inhibitor by natural product library screening.
Lipoxygenase-mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3. Cancer Sci. Widespread mitochondrial depletion via mitophagy does not compromise necroptosis. Cell reports.
Determination of the subcellular localization and mechanism of action of ferrostatins in suppressing ferroptosis. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Schroder M, Kaufman RJ. ER stress and the unfolded protein response. Mutat Res. Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest. Oslowski CM, Urano F. Measuring ER stress and the unfolded protein response using mammalian tissue culture system.
Methods Enzymol. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. Int J Mol Sci. An essential role for functional lysosomes in ferroptosis of cancer cells. Biochem J. Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Nat Chem. Catala A, Diaz M.
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Front Physiol. Thermodynamic and kinetic investigations of the release of oxidized phospholipids from lipid membranes and its effect on vascular integrity. Chem Phys Lipids. Effect of lipid peroxidation on the properties of lipid bilayers: a molecular dynamics study. Biophys J. Oxidation of unsaturated phospholipids in membrane bilayer mixtures is accompanied by membrane fluidity changes. Conformation of an endogenous ligand in a membrane bilayer for the macrophage scavenger receptor CD Modeling the effects of lipid peroxidation during ferroptosis on membrane properties.
Sci Rep. Emerging roles for lipids in non-apoptotic cell death. Agmon E, Stockwell BR. Lipid homeostasis and regulated cell death. Curr Opin Chem Biol.
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Pathophysiological relevance of aldehydic protein modifications. J Proteomics. Evaluation of lipid damage related to pathological and physiological conditions. Drug Chem Toxicol. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med. Schaur RJ. Basic aspects of the biochemical reactivity of 4-hydroxynonenal. Mol Aspects Med. Cell death and diseases related to oxidative stress: 4-hydroxynonenal HNE in the balance.
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Mechanisms of 4-hydroxynonenal induced pro- and anti-apoptotic signaling. Front Pharmacol. Latunde-Dada GO. Ferroptosis: Role of lipid peroxidation, iron and ferritinophagy. Regulation of endoplasmic reticulum turnover by selective autophagy. Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery. Full length RTN3 regulates turnover of tubular endoplasmic reticulum via selective autophagy. Defining human ERAD networks through an integrative mapping strategy. Skip to content Skip to search. Published Champaign, Ill. Language English View all editions Prev Next edition 2 of 2.
Other Authors Kamal-Eldin, Afaf. Physical Description vii, p. Subjects Lipids -- Oxidation. Contents Ch. The challening contribution of hydroperoxides to the lipid oxidation mechanism Ch. Competitive oxidation between tocopherol and unsaturated fatty acids under themooxidation conditions Ch. Kinetic evaluation of the antioxidant activity in lipid oxidation Ch. Glycerophospholipid core aldehydes : mechanisms of formation, methods of detection, natural occurrence, and biological significance Ch.
Lipid oxidation in emulsions Ch. Oxidation in dried microencapsulated oils Ch.
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Protein alterations due to lipid oxidation in multiphase systems Ch. Notes First volume not designated "Vol. Includes bibliographical references and index. View online Borrow Buy Freely available Show 0 more links Set up My libraries How do I set up "My libraries"? University of Queensland Library. Open to the public ; QP L Book; Illustrated English Show 0 more libraries