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

被引：422

作者：

Yan, Bo ^{[1
,2
]}

Ai, Youwei ^{[1
,2
]}

Sun, Qi ^{[1
]}

Ma, Yan ^{[1
,2
]}

Cao, Yang ^{[1
,2
]}

Wang, Jiawen ^{[1
,2
]}

Zhang, Zhiyuan ^{[1
,2
]}

Wang, Xiaodong ^{[1
,2
]}

机构：

[1] Natl Inst Biol Sci, 7 Sci Pk Rd,Zhongguancun Life Sci Pk, Beijing 102206, Peoples R China

[2] Tsinghua Univ, Tsinghua Inst Multidisciplinary Biomed Res, Beijing 100871, Peoples R China

来源：

MOLECULAR CELL | 2021年 / 81卷 / 02期

关键词：

MUTANT P450 OXIDOREDUCTASE; CELL-DEATH; LIPID-PEROXIDATION; REDUCTASE; MECHANISMS; GENERATION; BIOLOGY; DOMAIN;

D O I：

10.1016/j.molcel.2020.11.024

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：355 / +

页数：25

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