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Kraft, V. ; Bezjian, C.T.* ; Pfeiffer, S. ; Ringelstetter, L. ; Müller, C. ; Zandkarimi, F.* ; Merl-Pham, J. ; Bao, X. ; Anastasov, N. ; Kössl, J. ; Brandner, S. ; Daniels, J.D.* ; Schmitt-Kopplin, P. ; Hauck, S.M. ; Stockwell, B.R.* ; Hadian, K. ; Schick, J.

GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling.

ACS Cent. Sci. 6, 41-53 (2020)
Verlagsversion Forschungsdaten DOI
Open Access Gold
Creative Commons Lizenzvertrag
Ferroptosis is an iron-dependent form of regulated cell death linking iron, lipid, and glutathione levels to degenerative processes and tumor suppression. By performing a genome-wide activation screen, we identified a cohort of genes antagonizing ferroptotic cell death, including GTP cyclohydrolase-1 (GCH1) and its metabolic derivatives tetrahydrobiopterin/dihydrobiopterin (BH4/BH2). Synthesis of BH4/BH2 by GCH1-expressing cells caused lipid remodeling, suppressing ferroptosis by selectively preventing depletion of phospholipids with two polyunsaturated fatty acyl tails. GCH1 expression level in cancer cell lines stratified susceptibility to ferroptosis, in accordance with its expression in human tumor samples. The GCH1-BH4-phospholipid axis acts as a master regulator of ferroptosis resistance, controlling endogenous production of the antioxidant BH4, abundance of CoQ(10), and peroxidation of unusual phospholipids with two polyunsaturated fatty acyl tails. This demonstrates a unique mechanism of ferroptosis protection that is independent of the GPX4/glutathione system.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Cell-death; Oxidative Stress; Tetrahydrobiopterin; Peroxidation; Activation; Mechanisms; Growth; Gch1; Bh4
ISSN (print) / ISBN 2374-7943
e-ISSN 2374-7951
Zeitschrift ACS central science
Quellenangaben Band: 6, Heft: 1, Seiten: 41-53 Artikelnummer: , Supplement: ,
Verlag ACS
Verlagsort Washington, DC
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Toxicology and Pharmacology (TOXI)
Research Unit Analytical BioGeoChemistry (BGC)
CF Metabolomics & Proteomics (CF-MPC)
Institute of Radiation Biology (ISB)