Membrane Damage during Ferroptosis Is Caused by Oxidation of Phospholipids Catalyzed by the Oxidoreductases POR and CYB5R1

Ferroptosis is a form of necrotic cell death caused by iron-dependent peroxidation of polyunsaturated phospholipids on cell membranes and is actively suppressed by the cellular antioxidant systems. We report here that oxidoreductases, including NADPH-cytochrome P450 reductase (POR) and NADH-cytochro...

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Veröffentlicht in:Molecular cell Jg. 81; H. 2; S. 355
Hauptverfasser: Yan, Bo, Ai, Youwei, Sun, Qi, Ma, Yan, Cao, Yang, Wang, Jiawen, Zhang, Zhiyuan, Wang, Xiaodong
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 21.01.2021
Schlagworte:
Animals
Cell Line, Tumor
Cell Membrane - chemistry
Cell Membrane - drug effects
Cell Membrane - metabolism
Concanavalin A - pharmacology
Cytochrome P-450 Enzyme System - deficiency
Cytochrome P-450 Enzyme System - genetics
Cytochrome-B Reductase - deficiency
Cytochrome-B Reductase - genetics
Electron Transport - drug effects
Fatty Acids, Unsaturated - metabolism
Ferroptosis - drug effects
Ferroptosis - genetics
HEK293 Cells
HeLa Cells
Humans
Hydrogen Peroxide - metabolism
Lipid Peroxidation - drug effects
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Nude
NADP - metabolism
Oxygen - metabolism
Phenylurea Compounds - pharmacology
Piperazines - pharmacology
Pyridines - pharmacology
Sorafenib - pharmacology
ISSN:1097-4164, 1097-4164
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Zusammenfassung:Ferroptosis is a form of necrotic cell death caused by iron-dependent peroxidation of polyunsaturated phospholipids on cell membranes and is actively suppressed by the cellular antioxidant systems. We report here that oxidoreductases, including NADPH-cytochrome P450 reductase (POR) and NADH-cytochrome b5 reductase (CYB5R1), transfer electrons from NAD(P)H to oxygen to generate hydrogen peroxide, which subsequently reacts with iron to generate reactive hydroxyl radicals for the peroxidation of the polyunsaturated fatty acid (PUFA) chains of membrane phospholipids, thereby disrupting membrane integrity during ferroptosis. Genetic knockout of POR and CYB5R1 decreases cellular hydrogen peroxide generation, preventing lipid peroxidation and ferroptosis. Moreover, POR knockdown in mouse liver prevents ConA-induced liver damage. Ferroptosis, therefore, is a result of incidental electron transfer carried out by POR/CYB5R1 oxidoreductase and thus needs to be constitutively countered by the antioxidant systems.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2020.11.024