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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)
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords Cell-death; Oxidative Stress; Tetrahydrobiopterin; Peroxidation; Activation; Mechanisms; Growth; Gch1; Bh4
Language
Publication Year 2020
Prepublished in Year 2019
HGF-reported in Year 2019
ISSN (print) / ISBN 2374-7943
e-ISSN 2374-7951
Journal ACS central science
Quellenangaben Volume: 6, Issue: 1, Pages: 41-53 Article Number: , Supplement: ,
Publisher ACS
Publishing Place Washington, DC
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Toxicology and Pharmacology (TOX)
Research Unit BioGeoChemistry and Analytics (BGC)
CF Metabolomics & Proteomics (CF-MPC)
Institute of Radiation Biology (ISB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
30202 - Environmental Health
Research field(s) Enabling and Novel Technologies
Environmental Sciences

Radiation Sciences
PSP Element(s) G-505200-006
G-505200-001
G-505293-001
G-504800-001
G-505700-001
A-630700-001
G-500200-001
DOI 10.1021/acscentsci.9b01063
WOS ID WOS:000517831400009
Scopus ID 85077645887
Erfassungsdatum 2020-01-16
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