Resolving the paradox of ferroptotic cell death: Ferrostatin-1 binds to 15LOX/PEBP1 complex, suppresses generation of peroxidized ETE-PE, and protects against ferroptosis
| Autor: | Fatma B. Cinemre, Hülya Bayır, Rong-Rong He, Wanyang Sun, Haider H. Dar, Yulia Y. Tyurina, Indira H. Shrivastava, Theodore R. Holman, Tamil S. Anthonymuthu, Valerian E. Kagan, Yoel Sadovsky, Vladimir A. Tyurin, Karolina Mikulska-Ruminska, Ivet Bahar, Brent R. Stockwell, Andrew P. VanDemark |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Programmed cell death Molecular model Radical Short Communication Clinical Biochemistry Allosteric regulation Cell Phenylenediamines Hydroperoxy-eicosatetraenoyl-phosphatidylethanolamines Biochemistry Ferrostatin-1 03 medical and health sciences 0302 clinical medicine medicine Ferroptosis Phosphatidylethanolamine binding lcsh:QH301-705.5 Phospholipid peroxidation lcsh:R5-920 Cyclohexylamines Cell Death Chemistry Organic Chemistry Scavenger (chemistry) Cell biology 030104 developmental biology medicine.anatomical_structure lcsh:Biology (General) lcsh:Medicine (General) Oxidation-Reduction 030217 neurology & neurosurgery 15-Lipoxygenase |
| Zdroj: | Redox Biology Redox Biology, Vol 38, Iss, Pp 101744-(2021) |
| ISSN: | 2213-2317 |
| Popis: | Hydroperoxy-eicosatetraenoyl-phosphatidylethanolamine (HpETE-PE) is a ferroptotic cell death signal. HpETE-PE is produced by the 15-Lipoxygenase (15LOX)/Phosphatidylethanolamine Binding Protein-1 (PEBP1) complex or via an Fe-catalyzed non-enzymatic radical reaction. Ferrostatin-1 (Fer-1), a common ferroptosis inhibitor, is a lipophilic radical scavenger but a poor 15LOX inhibitor arguing against 15LOX having a role in ferroptosis. In the current work, we demonstrate that Fer-1 does not affect 15LOX alone, however, it effectively inhibits HpETE-PE production by the 15LOX/PEBP1 complex. Computational molecular modeling shows that Fer-1 binds to the 15LOX/PEBP1 complex at three sites and could disrupt the catalytically required allosteric motions of the 15LOX/PEBP1 complex. Using nine ferroptosis cell/tissue models, we show that HpETE-PE is produced by the 15LOX/PEBP1 complex and resolve the long-existing Fer-1 anti-ferroptotic paradox. Graphical abstract Image 1 Highlights • Ferrostatin-1 binds and selectively inhibits arachidonoyl-PE oxidation by 15-LOX/PEBP1. • Ferrostatin-1 prevention of ferroptosis is mostly due to suppression of 15-LOX/PEBP1. • Radical scavenging by Ferrostatin-1 in Fe/ascorbate peroxidation is unrelated to ferroptosis. |
| Databáze: | OpenAIRE |
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