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

doi:10.1021/acscentsci.9b01063

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

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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 language	English
Pages (from-to)	41-53
Number of pages	13
Journal	ACS Central Science
Volume	6
Issue number	1
DOIs	https://doi.org/10.1021/acscentsci.9b01063
State	Published - 22 Jan 2020
Externally published	Yes

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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, 6(1), 41-53. https://doi.org/10.1021/acscentsci.9b01063

@article{a592f448950844e58e2e30ec686d1f97,

title = "GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling",

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.",

author = "Kraft, {Vanessa A.N.} and Bezjian, {Carla T.} and Susanne Pfeiffer and Larissa Ringelstetter and Constanze M{\"u}ller and Fereshteh Zandkarimi and Juliane Merl-Pham and Xuanwen Bao and Natasa Anastasov and Johanna K{\"o}ssl and Stefanie Brandner and Daniels, {Jacob D.} and Philippe Schmitt-Kopplin and Hauck, {Stefanie M.} and Stockwell, {Brent R.} and Kamyar Hadian and Schick, {Joel A.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2019 American Chemical Society.",

year = "2020",

month = jan,

day = "22",

doi = "10.1021/acscentsci.9b01063",

language = "English",

volume = "6",

pages = "41--53",

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Kraft, VAN, Bezjian, CT, Pfeiffer, S, Ringelstetter, L, Müller, C, Zandkarimi, F, Merl-Pham, J, Bao, X, Anastasov, N, Kössl, J, Brandner, S, Daniels, JD, Schmitt-Kopplin, P, Hauck, SM, Stockwell, BR, Hadian, K & Schick, JA 2020, 'GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling', ACS Central Science, vol. 6, no. 1, pp. 41-53. https://doi.org/10.1021/acscentsci.9b01063

TY - JOUR

T1 - GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling

AU - Kraft, Vanessa A.N.

AU - Bezjian, Carla T.

AU - Pfeiffer, Susanne

AU - Ringelstetter, Larissa

AU - Müller, Constanze

AU - Zandkarimi, Fereshteh

AU - Merl-Pham, Juliane

AU - Bao, Xuanwen

AU - Anastasov, Natasa

AU - Kössl, Johanna

AU - Brandner, Stefanie

AU - Daniels, Jacob D.

AU - Schmitt-Kopplin, Philippe

AU - Hauck, Stefanie M.

AU - Stockwell, Brent R.

AU - Hadian, Kamyar

AU - Schick, Joel A.

PY - 2020/1/22

Y1 - 2020/1/22

N2 - 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.

AB - 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.

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U2 - 10.1021/acscentsci.9b01063

DO - 10.1021/acscentsci.9b01063

M3 - Article

AN - SCOPUS:85077645887

SN - 2374-7943

VL - 6

SP - 41

EP - 53

JO - ACS Central Science

JF - ACS Central Science

IS - 1

ER -

GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling

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