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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 Hybrid
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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
Keywords Gpx4 ; Lc-ms/ms ; Brain ; Cell Death ; Cysteine ; Lipid Peroxidation ; Selenite ; Selenocysteine ; Selenoproteins ; Tumor; 1-cys Peroxiredoxin; Oxidative Stress; System X(c)(-); Cancer-cells; Glutathione; Identification; Mice; Peroxidase; Dependency; Separation
Language english
Publication Year 2024
HGF-reported in Year 2024
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
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Metabolism and Cell Death (MCD)
Institute of Structural Biology (STB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Genetics and Epidemiology
Enabling and Novel Technologies
PSP Element(s) G-506900-001
G-503000-001
Grants JSPS KAKENHI
CRC TRR 353
German Federal Ministry of Education and Research (BMBF) FERROPATH
European Research Council (ERC)
Sapporo Bioscience Foundation
Food Science Institute Foundation

Deutsche Forschungsgemeinschaft (DFG)
DOI 10.1016/j.molcel.2024.10.028
WOS ID 001374141500001
Scopus ID 85210556636
PubMed ID 39547222
Erfassungsdatum 2024-11-27
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