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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Published in:	Molecular cell Vol. 81; no. 2; p. 355
Main Authors:	Yan, Bo, Ai, Youwei, Sun, Qi, Ma, Yan, Cao, Yang, Wang, Jiawen, Zhang, Zhiyuan, Wang, Xiaodong
Format:	Journal Article
Language:	English
Published:	United States 21.01.2021
Subjects:	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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Abstract	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.
AbstractList	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. 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.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.
Author	Wang, Jiawen Zhang, Zhiyuan Yan, Bo Sun, Qi Cao, Yang Wang, Xiaodong Ai, Youwei Ma, Yan
Author_xml	– sequence: 1 givenname: Bo surname: Yan fullname: Yan, Bo email: yanbo@nibs.ac.cn organization: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing, 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 100871, China. Electronic address: yanbo@nibs.ac.cn – sequence: 2 givenname: Youwei surname: Ai fullname: Ai, Youwei email: aiyouwei@nibs.ac.cn organization: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing, 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 100871, China. Electronic address: aiyouwei@nibs.ac.cn – sequence: 3 givenname: Qi surname: Sun fullname: Sun, Qi organization: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing, 102206, China – sequence: 4 givenname: Yan surname: Ma fullname: Ma, Yan organization: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing, 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 100871, China – sequence: 5 givenname: Yang surname: Cao fullname: Cao, Yang organization: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing, 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 100871, China – sequence: 6 givenname: Jiawen surname: Wang fullname: Wang, Jiawen organization: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing, 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 100871, China – sequence: 7 givenname: Zhiyuan surname: Zhang fullname: Zhang, Zhiyuan organization: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing, 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 100871, China – sequence: 8 givenname: Xiaodong surname: Wang fullname: Wang, Xiaodong organization: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing, 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 100871, China
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/33321093$$D View this record in MEDLINE/PubMed
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Snippet	Ferroptosis is a form of necrotic cell death caused by iron-dependent peroxidation of polyunsaturated phospholipids on cell membranes and is actively...
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SubjectTerms	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
Title	Membrane Damage during Ferroptosis Is Caused by Oxidation of Phospholipids Catalyzed by the Oxidoreductases POR and CYB5R1
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