Regulation of lipid peroxidation and ferroptosis in diverse species

Conrad, Marcus; Kagan, Valerian E.; Bayır, Hülya; Pagnussat, Gabriela Carolina; Head, Brian; Traber, Maret G.; Stockwell, Brent R.

doi:10.1101/gad.314674.118

Cited by 392 publications

(304 citation statements)

References 220 publications

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“…Although other constraints such as membrane fatty acid composition and iron availability must be fulfilled, it is the insufficient reduction of lipid hydroperoxides, from which lipid peroxidation is activated, which is the critical event priming ferroptosis . Consistent with the notion of ‘regulated’, the execution of cell death by ferroptosis evolves through a patterned morphological pathway . In this perspective, compounds targeting GPx4 activity can be seen as agonists in the frame of an ordered process.…”

Section: Discussionmentioning

confidence: 98%

Inactivation of the glutathione peroxidase GPx4 by the ferroptosis‐inducing molecule RSL3 requires the adaptor protein 14‐3‐3ε

et al. 2019

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Ras‐selective lethal small molecule 3 (RSL3), a drug candidate prototype for cancer chemotherapy, triggers ferroptosis by inactivating the glutathione peroxidase glutathione peroxidase 4 (GPx4). Here, we report the purification of the protein indispensable for GPx4 inactivation by RSL3. Mass spectrometric analysis identified 14‐3‐3 isoforms as candidates, and recombinant human 14‐3‐3ε confirms the identification. The function of 14‐3‐3ε is redox‐regulated. Moreover, overexpression or silencing of the gene coding for 14‐3‐3ε consistently controls the inactivation of GPx4 by RSL3. The interaction of GPx4 with a redox‐regulated adaptor protein operating in cell signaling further contributes to frame it within redox‐regulated pathways of cell survival and death and opens new therapeutic perspectives.

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Section: Discussionmentioning

confidence: 98%

Inactivation of the glutathione peroxidase GPx4 by the ferroptosis‐inducing molecule RSL3 requires the adaptor protein 14‐3‐3ε

et al. 2019

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“…That pathway, triggered by a 50ºC heat shock (HS), is characterized by a strong decrease in GSH levels, a feature commonly observed in eukaryotic ferroptosis (Conrad et al, 2018;Distefano et al, 2017;Dixon et al, 2012). To examine whether ferroptosis plays a role during stress-induced cell death in the cyanobacterium, cells were exposed to H2O2 or to high temperatures at 50ºC, or at 77°C (to trigger unregulated necrosis), in the presence of two canonical ferroptosis inhibitors: the lipophilic antioxidant ferrostatin-1 (Fer-1) or the membrane-permeable iron chelator ciclopirox olamine (CPX).…”

Section: °C-heat Shock In Cyanobacteriamentioning

confidence: 99%

“…Long-chain acyl-CoA synthetase-4 (ACSL4) modulate the metabolic fates of PUFAs in human and mouse cells and deletion of the ACSL4 gene causes resistance to ferroptosis in mammals (Conrad et al, 2018). The Synechocystis genome contain s sequence that encodes a putative acyl-acyl carrier protein synthetase (SynAas, Slr1609) that is a homologue of the A. thaliana long chain acyl-CoA synthetase 9 (LACS9).…”

Section: Molecular Mechanisms Governing Ferroptosis In Synechocystismentioning

confidence: 99%

“…Vitamin E (alpha-tocopherol) has been reported to prevent ferroptosis in human and mouse cells (Conrad et al, 2018;Hinman et al, 2018). Alpha-tocopherol is synthesized by some cyanobacteria and remarkably, it has a role protecting Synechocystis from lipid peroxidation and high light stress (Maeda et al, 2005).…”

Section: Molecular Mechanisms Governing Ferroptosis In Synechocystismentioning

confidence: 99%

“…Different types of RCD have been described in eukaryotes (Melino et al, 2005;Minina et al, 2013). Among them, ferroptosis was recently reported as an oxidative, iron-dependent form of RCD associated with lipid peroxidation and ROS accumulation present in animals, plants and protozoan parasites (Bogacz and Krauth-Siegel, 2018;Conrad et al, 2018;Dangol et al, 2018;Distéfano et al, 2017;Dixon et al, 2012;Stockwell et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Heat stress induces ferroptosis in a photosynthetic prokaryote

Aguilera

Berdun

Bártoli

et al. 2019

Preprint

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Aguilera et al, show that ferroptosis, an oxidative and iron-dependent form of regulated cell death, plays an important role in the cyanobacterium Synechocystis sp.PCC 6803 in response to heat stress. AbstractFerroptosis is an oxidative and iron-dependent form of regulated cell death (RCD) recently described in eukaryotic organisms like animals, plants and parasites.Here we report that a similar process takes place in the photosynthetic prokaryote Synechocystis sp. PCC 6803 in response to heat stress. After a heat shock, Synechocystis PCC 6803 cells undergo a cell death pathway that can be suppressed by the canonical ferroptosis inhibitors, CPX or Fer-1, or by external addition of calcium (Ca ++ ), glutathione (GSH) or ascorbic acid (AsA). Moreover, as described for eukaryotic cells ferroptosis, this pathway is characterized by an early depletion of the antioxidants GSH and AsA, and by lipid peroxidation. In general, prokaryotes membranes contain poorly oxidizable saturated or monounsaturated lipid molecules, it was thought that free prokaryotes were not susceptible to ferroptosis but interestingly, that is not the case of cyanobacteria, which contain thylakoid membranes that are enriched in polyunsaturated-fatty-acid-containing phospholipids. These results indicate that all of the hallmarks described for eukaryotic ferroptosis are conserved in photosynthetic prokaryotes and suggest that ferroptosis might be an ancient cell death program.

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The role of ferroptosis as a regulator of oxidative stress in the pathogenesis of ischemic stroke

Delgado‐Martín,

Martínez‐Ruiz

2024

FEBS Letters

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Ferroptosis is a unique form of cell death that was first described in 2012 and plays a significant role in various diseases, including neurodegenerative conditions. It depends on a dysregulation of cellular iron metabolism, which increases free, redox‐active, iron that can trigger Fenton reactions, generating hydroxyl radicals that damage cells through oxidative stress and lipid peroxidation. Lipid peroxides, resulting mainly from unsaturated fatty acids, damage cells by disrupting membrane integrity and propagating cell death signals. Moreover, lipid peroxide degradation products can further affect cellular components such as DNA, proteins, and amines. In ischemic stroke, where blood flow to the brain is restricted, there is increased iron absorption, oxidative stress, and compromised blood–brain barrier integrity. Imbalances in iron‐transport and ‐storage proteins increase lipid oxidation and contribute to neuronal damage, thus pointing to the possibility of brain cells, especially neurons, dying from ferroptosis. Here, we review the evidence showing a role of ferroptosis in ischemic stroke, both in recent studies directly assessing this type of cell death, as well as in previous studies showing evidence that can now be revisited with our new knowledge on ferroptosis mechanisms. We also review the efforts made to target ferroptosis in ischemic stroke as a possible treatment to mitigate cellular damage and death.

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Regulation of lipid peroxidation and ferroptosis in diverse species

Cited by 392 publications

References 220 publications

Inactivation of the glutathione peroxidase GPx4 by the ferroptosis‐inducing molecule RSL3 requires the adaptor protein 14‐3‐3ε

Inactivation of the glutathione peroxidase GPx4 by the ferroptosis‐inducing molecule RSL3 requires the adaptor protein 14‐3‐3ε

Heat stress induces ferroptosis in a photosynthetic prokaryote

The role of ferroptosis as a regulator of oxidative stress in the pathogenesis of ischemic stroke

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