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. 2021 Feb 8;8(2):1881393.
doi: 10.1080/23723556.2021.1881393. eCollection 2021.

The oxidoreductases POR and CYB5R1 catalyze lipid peroxidation to execute ferroptosis

Youwei Ai  1   2 , Bo Yan  1 , Xiaodong Wang  1   2
Affiliations

The oxidoreductases POR and CYB5R1 catalyze lipid peroxidation to execute ferroptosis

Youwei Ai et al. Mol Cell Oncol. .

Abstract

Our recent study showed that two oxidoreductases - NADPH-cytochrome P450 reductase (POR) and NADH-cytochrome b5 reductase (CYB5R1) - transfer electrons to oxygen to generate hydrogen peroxide (H2O2). H2O2 then reacts with ferrous iron, generating hydroxyl radicals that cause peroxidation of polyunsaturated-fatty-acid chains of membrane phospholipids, resulting in plasma membrane rupture and ferroptosis.

Keywords: CYB5R1; FSP1; Ferroptosis; GPX4; H2O2; POR; PUFA; hydroxyl radicals; lipid peroxidation; oxidoreductase.

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Figures

Figure 1.
Figure 1.
Potential mechanisms of lipid peroxidation by POR/CYB5R1 in the context of ferroptosis. (a) Scheme of the reaction mechanism of NADPH-cytochrome P450 reductase (POR) and NADH-cytochrome b5 reductase (CYB5R1) catalyzed lipid peroxidation. The lipid peroxidation begins with the hydrogen peroxide (H2O2) produced by POR/CYB5R1. H2O2 reacts with ferrous ion to produce hydroxyl radicals, which can abstract the bis-allylic hydrogen, rearrange the resonance radical structure in polyunsaturated-fatty-acid (PUFA) phospholipids. Then, oxygen was added into the radicals leading to the formation of peroxyl radicals, and then the hydroperoxyl phospholipids are formed. (b) In normal conditions, POR/CYB5R1 can catalyze lipid peroxidation as a consequence of its electron transfer process, but the produced lipid peroxides are typically eliminated by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) antioxidant systems to maintain cell survival. Upon disruption of GPX4 antioxidant systems, the lipid peroxides produced by POR/CYB5R1 accumulate, eventually levels high enough to initiate ferroptosis. Fe(II), ferrous iron; Fe(III), ferric iron; •OH, hydroxyl free radical; •OOH, peroxyl free radical; NADPH, nicotinamide adenine dinucleotide phosphate; NADH, nicotinamide adenine dinucleotide; GSH, glutathione; e, electron; O2, oxygen; PL, phospholipid
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