Oxytosis: a novel form of programmed cell death
Abstract
Extensive nerve cell death occurs during the development of the central nervous system as well as in episodes of trauma and in neurodegenerative disease. The mechanistic details of how these cells die are poorly understood. Here we describe a unique oxidative stress-induced programmed cell death pathway called oxytosis, and outline pharmacological approaches which interfere with its execution. Oxidative glutamate toxicity, in which exogenous glutamate inhibits cystine uptake through the cystine/glutamate antiporter leading to a depletion of glutathione, is used as an example of oxytosis. It is shown that there is a sequential requirement for de novo macromolecular synthesis, lipoxygenase activation, reactive oxygen species production, and the opening of cGMP-gated channels which allow the influx of extracellular calcium. The translation initiation factor elF2alpha plays a central role in this pathway by regulating the levels of glutathione. Finally, examples are given in which the reduction in glutathione, the production of reactive oxygen species, and calcium influx can be experimentally manipulated to prevent cell death. Data are reviewed which suggest that oxytosis may be involved in nerve cell death associated with nervous system trauma and disease.
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Glutamate-induced neurotoxicity is oxidative and iron-dependent, suggesting ferroptosis is involved.
“Glutamate-induced neurotoxicity is an oxidative, iron-dependent process, suggesting that ferroptosis is involved [22, 23].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [22]
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Sabogal-Guáqueta, A. M., Hobbie, F., Keerthi, A., Oun, A., Kortholt, A., Boddeke, E., & Dolga, A. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2019.109295 · Cited by 154 · see citing works
Scheiner, M., Dolles, D., Gunesch, S., Hoffmann, M., Nabissi, M., Marinelli, O., Naldi, M., Bartolini, M., Petralla, S., Poeta, E., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00623 · Cited by 49 · see citing works
- Authors
- Shirlee Tan, B. S. P., David Schubert, B. S. P., & Pamela Maher, B. S. P.
- Venue
- Current Topics in Medicinal Chemistry
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2001-12-01
- Volume
- 1
- Issue
- 6
- Pages
- 497-506
- ISSN
- 1568-0266 (ISSN-L)
- OpenAlex
- W2171864779
- Cited by
- 522
- References
- 0
- Citations by year
- 2026: 14 · 2025: 35 · 2024: 38 · 2023: 31 · 2022: 38 · 2021: 45 · 2020: 52 · 2019: 34 · 2018: 26 · 2017: 17 · 2016: 18 · 2015: 13 · 2014: 19 · 2013: 20 · 2012: 16
- FWCI
- 1.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Topics in Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- oxytosis, programmed cell death, oxidative stress, glutamate excitotoxicity, SLC7A11, glutathione depletion, lipoxygenase, reactive oxygen species, cGMP-gated channels, calcium influx, eIF2α, neurodegeneration, neuroprotection
- MeSH terms
- Calcium, Humans, Neurons, Cell Death, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Glutamic Acid
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