GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling

By Vanessa A N Kraft, C. T. Bezjian, S. Pfeiffer, L. Ringelstetter, Constanze Müller, Fereshteh Zandkarimi, J. Merl-Pham, Xuanwen Bao, Nataša Anastasov, Johanna Kössl and 7 more. ACS Central Science, 2019

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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 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.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/439195b0ad22666c9e756de03d90aa7bbb80e99f

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Citations in the corpus

Molecular mechanisms of cell death in neurological diseases (2021, background): “[105] and ferroptosis suppressor protein 1 (formerly AIFM2) [106, 107] which use glutathione and ubiquinone, respectively, as reducing substrates, and tetrahydrobiopterin synthesised by GTP cyclohydrolase-1 [108].”
Emerging mechanisms and disease relevance of ferroptosis (2020, background): “BH4was found to suppress ferroptosis by aiding the formation of reduced CoQ10, and by blocking the peroxidation of specific lipids.”
The cell biology of ferroptosis (2024, positive): “In addition to CoQ and vitamin K, other endogenous metabolites can serve as RTA inhibitors of ferroptosis, including tetrahydrobiopterin 23,45 , vitamin E and vitamin A 46 .”
Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis (2022, background): “A recent report found that phospholipids containing two PUFA tails are particularly effective drivers of ferroptosis, suggesting that lipid crosslinking may be an aspect of the membrane damage upon ferroptosis [21].”
Ferroptosis in infection, inflammation, and immunity (2021, background): “…from apoptosis-inducing factor mitochondria-associated 2 [AIFM2/ FSP1]–mediated coenzyme Q production; Bersuker et al., 2019; Doll et al., 2019; and GTP cyclohydrolase 1–regulated tetrahydrobiopterin synthesis; Kraft et al., 2020) play an alternative role in reducing ferroptotic cell death.”