Glutathione Peroxidase 4 Senses and Translates Oxidative Stress into 12/15-Lipoxygenase Dependent- and AIF-Mediated Cell Death
Open accessAbstract
Oxidative stress in conjunction with glutathione depletion has been linked with various acute and chronic degenerative disorders, yet the molecular mechanisms have remained unclear. In contrast to the belief that oxygen radicals are detrimental to cells and tissues by unspecific oxidation of essential biomolecules, we now demonstrate that oxidative stress is sensed and transduced by glutathione peroxidase 4 (GPx4) into a-yet-unrecognized cell-death pathway. Inducible GPx4 inactivation in mice and cells revealed 12/15-lipoxygenase-derived lipid peroxidation as specific downstream event, triggering apoptosis-inducing factor (AIF)-mediated cell death. Cell death could be entirely prevented either by alpha-tocopherol (alpha-Toc), 12/15-lipoxygenase inhibitors, or siRNA-mediated AIF silencing. Accordingly, 12/15-lipoxygenase-deficient cells were highly resistant to glutathione depletion. Neuron-specific GPx4 depletion caused neurodegeneration in vivo and ex vivo, highlighting the importance of this pathway in neuronal cells. Since oxidative stress is common in the etiology of many human disorders, the identified pathway reveals promising targets for future therapies.
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GPX4 has emerged as the main endogenous inhibitor of ferroptosis by limiting lipid peroxidation through GSH-dependent reduction of lipid hydroperoxides to lipid alcohols.
“the reduced glutathione (GSH)-dependent enzyme glutathione peroxidase 4 (GPX4)—which is directly targeted by RSL3—has emerged as the main endogenous inhibitor of ferroptosis by virtue of its ability to limit lipid peroxidation by catalyzing the GSH-dependent reduction of lipid hydroperoxides to lipid alcohols [547–550].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [550]
Gpx4−/− mice display embryonic lethality with complete penetrance.
“Gpx4−/− mice display embryonic lethality with complete penetrance [547, 550, 587, 588].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [550]
In ferroptosis, PUFA peroxidation seems mainly regulated by mutually antagonistic activity of LOXs and GPX4.
“In the context of ferroptosis, PUFA peroxidation seems to be mainly regulated by the mutually antagonistic activity of LOXs (which directly catalyze lipid peroxidation) and GPX4 (which indirectly inhibits it) [550, 566].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [550]
Inducible or tissue-specific ablation of Gpx4 in mice provokes acute renal or hepatic injury, neurodegeneration, and defective immunity to infection, all preventable or mitigated by ferroptosis-inhibiting strategies.
“the inducible or tissue-specific ablation of Gpx4 in mice provokes a variety of pathological conditions, including acute renal or hepatic injury [547, 563, 589], neurodegeneration [550, 590, 591], and defective immunity to infection [567], all of which can be prevented or mitigated by ferroptosis-inhibiting strategies.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [550]
Inducible Gpx4 knockout mice show that some cells and tissues, especially brain neurons, accumulate lethal lipid ROS that vitamin E can alleviate, highlighting lethal lipid peroxidation in vivo without Gpx4.
“An inducible Gpx4 knockout mouse model demonstrated that some cells and tissues, particularly neurons in the brain, accumulate lethal lipid ROS that can be alleviated by vitamin E treatment [44], highlighting the lethal nature of lipid peroxidation in vivo in the absence of Gpx4.”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [44]
GPx-4 is expressed as multiple isoforms generated from the same gene; one targets mitochondria where it has a vital role in protecting against membrane lipid peroxidation; in its absence, mitochondria accumulate damaging lipid peroxides, leading to apoptogen release.
“GPx-4 is expressed as multiple isoforms generated from the same gene: one of these targets the mitochondria where it has a vital role in protecting against membrane lipid peroxidation; in its absence, mitochondria accumulate damaging lipid peroxides, leading to apoptogen release (253, 383).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [383]
GPx-4 primarily targets oxidized membrane phospholipids.
“Recent findings, however, suggest that GPx-4 primarily targets oxidized membrane phospholipids (383).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [383]
Deficiency of GPx-4 potentiates 12/15-lipoxygenase-mediated lipid peroxidation to increase cell death via release of AIF from mitochondria.
“Interestingly, a deficiency of GPx-4 appears to potentiate 12/15-lipoxygenase-mediated lipid peroxidation to increase cell death via the release of AIF, an apoptogen from mitochondria (383).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [383]
The role of lipid peroxides in promoting apoptosis is supported by the finding that lipid-soluble α-tocopherol prevents apoptosis, whereas water-soluble antioxidants do not, in GPx-4-deficient cells.
“The role of lipid peroxides in promoting apoptosis was proven by the finding that the lipid-soluble α-tocopherol could prevent apoptosis, whereas N-acetyl Cys or other water-soluble antioxidants could not block cell death in GPx-4-deficient cells (383).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [383]
Deficiency of GPx-4 promotes cellular apoptosis via accumulation of lipid peroxidation in the absence of exogenous oxidants or stimuli.
“and studies show that deficiency of GPx-4 promotes cellular apoptosis via the accumulation of lipid peroxidation in the absence of exogenous oxidants or stimuli (383).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [383]
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- Authors
- Seiler, A., Schneider, M., Förster, H., Roth, S., Wirth, E. K., Culmsee, C., Plesnila, N., Kremmer, E., Rådmark, O., Wurst, W., Bornkamm, G. W., Schweizer, U., & Conrad, M.
- Affiliations
- Helmholtz Munich (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Philipps University of Marburg (DE)
- Ludwig-Maximilians-Universität München (DE)
- Karolinska Institutet (SE)
- Corresponding author
- Conrad, Marcus
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2008-09
- Volume
- 8
- Issue
- 3
- Pages
- 237-248
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2007794772
- Cited by
- 1,470
- References
- 33
- Citations by year
- 2026: 121 · 2025: 157 · 2024: 175 · 2023: 169 · 2022: 140 · 2021: 131 · 2020: 103 · 2019: 70 · 2018: 65 · 2017: 48 · 2016: 40 · 2015: 32 · 2014: 37 · 2013: 27 · 2012: 31
- FWCI
- 16.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Site cant be reached (submittedVersion)
- Funders
- Bundesministerium für Bildung und Forschung (01GN0512, 01GR0430, 01GS0476)
- Verband der Chemischen Industrie
- Boehringer Ingelheim (DFG SFB596, DFG SFB665, Ko922/11-1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- GPX4, oxidative stress sensing, 12/15-lipoxygenase, apoptosis-inducing factor, lipid peroxidation, glutathione depletion, alpha-tocopherol, neurodegeneration, neuronal cell death, cell death signaling
- MeSH terms
- Phospholipid Hydroperoxide Glutathione Peroxidase, Alleles, Animals, Arachidonate 12-Lipoxygenase, Arachidonate 15-Lipoxygenase, Cells, Cultured, Fluorenes, Genotype, Glutathione Peroxidase, Hippocampus, Humans, Mice, Inbred C57BL, Neurons, Lipid Peroxidation, Cell Death, Mice, Knockout, Oxidative Stress, Reverse Transcriptase Polymerase Chain Reaction, Mice, Congenic, alpha-Tocopherol, RNA, Small Interfering, Apoptosis Inducing Factor, Mice
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