Formation of protein adducts with Hydroperoxy-PE electrophilic cleavage products during ferroptosis

Amoscato, Andrew A.; Anthonymuthu, Tamil S.; Kapralov, Alexandr A.; Sparvero, Louis J.; Shrivastava, Indira H.; Mikulska-Ruminska, Karolina; Tyurin, Vladimir A.; Shvedova, Anna A.; Tyurina, Yulia Y.; Bahar, İvet; Wenzel, Sally E.; Bayır, Hülya; Kagan, Valerian E.

doi:10.1016/j.redox.2023.102758

Cited by 11 publications

(6 citation statements)

References 64 publications

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“…Indeed, we found that di‐HpETE‐PE is water‐soluble and did not bind membranes but instead could be recovered from the supernatant (Supplementary Figure S4). During lipid peroxidation, not only reactive radical intermediates, but also molecular products—HOO‐lipids and electrophilic oxidatively‐truncated species generated from HOO‐PLs form covalent adducts with proteins [4a] . Because of the transient nature of PLs peroxidation products, the totality of their redox reactions may be better characterized by quantitative assessments of changes in the oxidizable substrates, PUFA‐PLs.…”

Section: Resultsmentioning

confidence: 99%

Strikingly High Activity of 15‐Lipoxygenase Towards Di‐Polyunsaturated Arachidonoyl/Adrenoyl‐Phosphatidylethanolamines Generates Peroxidation Signals of Ferroptotic Cell Death

Samovich,

Mikulska‐Ruminska,

Dar

et al. 2024

Angewandte Chemie

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The vast majority of membrane phospholipids (PLs) include two asymmetrically positioned fatty acyls: oxidizable polyunsaturated fatty acids (PUFA) attached predominantly at the sn2 position, and non‐oxidizable saturated/monounsaturated acids (SFA/MUFA) localized at the sn1 position. The peroxidation of PUFA‐PLs, particularly sn2‐arachidonoyl(AA)‐ and sn2‐adrenoyl(AdA)‐containing phosphatidylethanolamines (PE), has been associated with the execution of ferroptosis, a program of regulated cell death. There is a minor subpopulation (≈1–2 mol %) of doubly PUFA‐acylated phospholipids (di‐PUFA‐PLs) whose role in ferroptosis remains enigmatic. Here we report that 15‐lipoxygenase (15LOX) exhibits unexpectedly high pro‐ferroptotic peroxidation activity towards di‐PUFA‐PEs. We revealed that peroxidation of several molecular species of di‐PUFA‐PEs occurred early in ferroptosis. Ferrostatin‐1, a typical ferroptosis inhibitor, effectively prevented peroxidation of di‐PUFA‐PEs. Furthermore, co‐incubation of cells with di‐AA‐PE and 15LOX produced PUFA‐PE peroxidation and induced ferroptotic death. The decreased contents of di‐PUFA‐PEs in ACSL4 KO A375 cells was associated with lower levels of di‐PUFA‐PE peroxidation and enhanced resistance to ferroptosis. Thus, di‐PUFA‐PE species are newly identified phospholipid peroxidation substrates and regulators of ferroptosis, representing a promising therapeutic target for many diseases related to ferroptotic death.

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Section: Resultsmentioning

confidence: 99%

Strikingly High Activity of 15‐Lipoxygenase Towards Di‐Polyunsaturated Arachidonoyl/Adrenoyl‐Phosphatidylethanolamines Generates Peroxidation Signals of Ferroptotic Cell Death

Samovich,

Mikulska‐Ruminska,

Dar

et al. 2024

Angewandte Chemie

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“…Because polyunsaturated phospholipids, particularly phosphatidyl-ethanolamines (PE), are the major substrates of ferroptosis-induced peroxidation, employment of liquid chromatography-mass spectrometry (LC-MS) is the preferred methodology for the detection and identification of peroxized ferroptosis biomarkers [ 36 ]. Combination of MS-based lipidomics with proteomics can be used for characterization of ferroptotic covalent adducts of oxidatively-truncated electrophilic PE with target proteins [ 278 ]. Recently, imaging mass-spectrometry has been applied for the spatial characterization of intracellular localization of peroxidized phospholipids [ 279 ].…”

Section: Methods For Monitoring Autophagy-dependent Ferroptosismentioning

confidence: 99%

International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis

Chen,

Tsvetkov,

Shen

et al. 2024

Autophagy

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Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an iron-dependent oxidative form of cell death characterized by unrestricted lipid peroxidation in the context of heterogeneous and plastic mechanisms. Recent studies have shed light on the involvement of specific types of autophagy (e.g. ferritinophagy, lipophagy, and clockophagy) in initiating or executing ferroptotic cell death through the selective degradation of anti-injury proteins or organelles. Conversely, other forms of selective autophagy (e.g. reticulophagy and lysophagy) enhance the cellular defense against ferroptotic damage. Dysregulated autophagy-dependent ferroptosis has implications for a diverse range of pathological conditions. This review aims to present an updated definition of autophagy-dependent ferroptosis, discuss influential substrates and receptors, outline experimental methods, and propose guidelines for interpreting the results. Abbreviation : 3-MA:3-methyladenine; 4HNE: 4-hydroxynonenal; ACD: accidentalcell death; ADF: autophagy-dependentferroptosis; ARE: antioxidant response element; BH2:dihydrobiopterin; BH4: tetrahydrobiopterin; BMDMs: bonemarrow-derived macrophages; CMA: chaperone-mediated autophagy; CQ:chloroquine; DAMPs: danger/damage-associated molecular patterns; EMT,epithelial-mesenchymal transition; EPR: electronparamagnetic resonance; ER, endoplasmic reticulum; FRET: Försterresonance energy transfer; GFP: green fluorescent protein;GSH: glutathione;IF: immunofluorescence; IHC: immunohistochemistry; IOP, intraocularpressure; IRI: ischemia-reperfusion injury; LAA: linoleamide alkyne;MDA: malondialdehyde; PGSK: Phen Green™ SK;RCD: regulatedcell death; PUFAs: polyunsaturated fatty acids; RFP: red fluorescentprotein;ROS: reactive oxygen species; TBA: thiobarbituricacid; TBARS: thiobarbituric acid reactive substances; TEM:transmission electron microscopy.

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“…This process drives the propagation of PLOOH production to neighboring PUFA-phospholipids [23]. Furthermore, these toxic lipid products can react with nucleophilic amino acid residues within various proteins, forming covalent adducts and inducing protein lipoxidation [107]. If the defense system cannot effectively remove these toxic products, it can result in an irreversible point of no return in the progression of ferroptosis.…”

Section: Lipid Peroxidationmentioning

confidence: 99%

Ferroptotic therapy in cancer: benefits, side effects, and risks

Diao,

Jia,

Dai

et al. 2024

Mol Cancer

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Ferroptosis is a type of regulated cell death characterized by iron accumulation and uncontrolled lipid peroxidation, leading to plasma membrane rupture and intracellular content release. Originally investigated as a targeted therapy for cancer cells carrying oncogenic RAS mutations, ferroptosis induction now exhibits potential to complement chemotherapy, immunotherapy, and radiotherapy in various cancer types. However, it can lead to side effects, including immune cell death, bone marrow impairment, liver and kidney damage, cachexia (severe weight loss and muscle wasting), and secondary tumorigenesis. In this review, we discuss the advantages and offer an overview of the diverse range of documented side effects. Furthermore, we examine the underlying mechanisms and explore potential strategies for side effect mitigation.

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Formation of protein adducts with Hydroperoxy-PE electrophilic cleavage products during ferroptosis

Cited by 11 publications

References 64 publications

Strikingly High Activity of 15‐Lipoxygenase Towards Di‐Polyunsaturated Arachidonoyl/Adrenoyl‐Phosphatidylethanolamines Generates Peroxidation Signals of Ferroptotic Cell Death

Strikingly High Activity of 15‐Lipoxygenase Towards Di‐Polyunsaturated Arachidonoyl/Adrenoyl‐Phosphatidylethanolamines Generates Peroxidation Signals of Ferroptotic Cell Death

International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis

Ferroptotic therapy in cancer: benefits, side effects, and risks

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