GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling

Vanessa A.N. Kraft, Carla T. Bezjian, Susanne Pfeiffer, Larissa Ringelstetter, Constanze Müller, Fereshteh Zandkarimi, Juliane Merl-Pham, Xuanwen Bao, Natasa Anastasov, Johanna Kössl, Stefanie Brandner, Jacob D. Daniels, Philippe Schmitt-Kopplin, Stefanie M. Hauck, Brent R. Stockwell, Kamyar Hadian, Joel A. Schick

Research output: Contribution to journalArticlepeer-review

596 Scopus citations

Abstract

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 CoQ10, 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.

Original languageEnglish
Pages (from-to)41-53
Number of pages13
JournalACS Central Science
Volume6
Issue number1
DOIs
StatePublished - 22 Jan 2020
Externally publishedYes

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