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GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling
Open accessAbstract
High Resolution Image Download MS PowerPoint Slide 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 (BH 4 /BH 2 ). Synthesis of BH 4 /BH 2 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-BH 4 -phospholipid axis acts as a master regulator of ferroptosis resistance, controlling endogenous production of the antioxidant BH 4, 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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Self-citationRegulation of Ferroptotic Cancer Cell Death by GPX4
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Self-citationFerroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease
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Self-citationRepurposing CRISPR as an RNA-Guided Platform for Sequence-Specific Control of Gene Expression
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Oxidative Stress and Antioxidant Defense
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Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice
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The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis
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The Cell Biology of Ferroptosis
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Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy
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CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4
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Metadata
- Authors
- Kraft, V. A. N., 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. A.
- Venue
- ACS Central Science
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-12-27
- Volume
- 6
- Issue
- 1
- Pages
- 41-53
- ISSN
- 2374-7943 (ISSN-L)
- 2374-7951
- OpenAlex
- W2997323331
- Cited by
- 1,298
- References
- 50
- FWCI
- 44.48
- Type
- journal article
- Language
- en
- Open access
- diamond
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- Kraft, V. A. N., 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. A. (2020). GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling. ACS Central Science. https://doi.org/10.1021/acscentsci.9b01063
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
