Mol. Cell https://doi.org/10.1016/j.molcel.2020.11.024 (2020)
Ferroptosis is a form of iron-dependent cell death caused by elevated lipid peroxidation of polyunsaturated fatty acid-containing (PUFA) phospholipids. Together with glutathione peroxidase 4, both ferroptosis suppressor protein 1 and GTP cyclohydrolase 1 were recently identified as inhibitors of ferroptosis by (re)generating radical-trapping antioxidants that block lipid peroxidation, while a cytochrome P450 oxidoreductase (POR) promotes ferroptosis through increased membrane lipid peroxidation. However, the exact mechanism of how POR enhanced lipid peroxidation is unclear. Yan et al. found that the electron transfer activity of POR was critical for ferroptosis execution, but not its endoplasmic reticulum (ER) localization and cytochrome P450 interactions. POR utilized oxygen and NADPH to generate hydrogen peroxide (H2O2), which enabled ferroptosis. Addition of a proper concentration of H2O2 was sufficient to promote ferroptosis in a POR-deficient background. In a defined biochemical system with phospholipids, oxygen, NADPH and ferric chloride, the addition of POR caused hydroxyl radical production through an iron-mediated Fenton reaction, in turn enabling phospholipid peroxidation. Given that the loss of POR did not result in a complete loss of ferroptosis and lipid peroxidation, the authors performed a screen of ER-residing oxidoreductases and identified CYB5R1, which can perform tasks similar to those of POR but with lower efficacy. POR- and CYB5R1-mediated lipid peroxidation was sufficient to promote membrane leakage in a PUFA-containing liposome system. Together, these findings reveal a model explaining how POR and CYB5R1 may cooperate to enable lipid peroxidation and ferroptosis.
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