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Ito, J. ; Nakamura, T. ; Toyama, T.* ; Chen, D. ; Berndt, C.* ; Poschmann, G.* ; Mourao, A. ; Doll, S. ; Suzuki, M.* ; Zhang, W. ; Zheng, J. ; Trümbach, D. ; Yamada, N. ; Ono, K. ; Yazaki, M.* ; Kawai, Y.* ; Arisawa, M.* ; Ohsaki, Y.* ; Shirakawa, H.* ; Wahida, A. ; Proneth, B. ; Saito, Y.* ; Nakagawa, K.* ; Mishima, E. ; Conrad, M.

PRDX6 dictates ferroptosis sensitivity by directing cellular selenium utilization.

Mol. Cell 84, 4629-4644.e9 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Selenium-dependent glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, preventing unrestrained (phospho)lipid peroxidation by reducing phospholipid hydroperoxides (PLOOH). However, the contribution of other phospholipid peroxidases in ferroptosis protection remains unclear. We show that cells lacking GPX4 still exhibit substantial PLOOH-reducing capacity, suggesting a contribution of alternative PLOOH peroxidases. By scrutinizing potential candidates, we found that although overexpression of peroxiredoxin 6 (PRDX6), a thiol-specific antioxidant enzyme with reported PLOOH-reducing activity, failed to prevent ferroptosis, its genetic loss sensitizes cancer cells to ferroptosis. Mechanistically, we uncover that PRDX6, beyond its known peroxidase activity, acts as a selenium-acceptor protein, facilitating intracellular selenium utilization and efficient selenium incorporation into selenoproteins, including GPX4. Its physiological significance was demonstrated by reduced GPX4 expression in Prdx6-deficient mouse brains and increased sensitivity to ferroptosis in PRDX6-deficient tumor xenografts in mice. Our study highlights PRDX6 as a critical player in directing cellular selenium utilization and dictating ferroptosis sensitivity.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Gpx4 ; Lc-ms/ms ; Brain ; Cell Death ; Cysteine ; Lipid Peroxidation ; Selenite ; Selenocysteine ; Selenoproteins ; Tumor
ISSN (print) / ISBN 1097-2765
e-ISSN 1097-4164
Journal Molecular Cell
Quellenangaben Volume: 84, Issue: 23, Pages: 4629-4644.e9 Article Number: , Supplement: ,
Publisher Elsevier
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Metabolism and Cell Death (MCD)
Institute of Structural Biology (STB)