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FSP1 is a glutathione-independent ferroptosis suppressor

Author

Listed:
  • Sebastian Doll

    (Institute of Developmental Genetics, Helmholtz Zentrum München)

  • Florencio Porto Freitas

    (University of Würzburg)

  • Ron Shah

    (University of Ottawa)

  • Maceler Aldrovandi

    (Institute of Developmental Genetics, Helmholtz Zentrum München
    Systems Immunity Research Institute, School of Medicine, Cardiff University)

  • Milene Costa Silva

    (Institute of Developmental Genetics, Helmholtz Zentrum München)

  • Irina Ingold

    (Institute of Developmental Genetics, Helmholtz Zentrum München)

  • Andrea Goya Grocin

    (Imperial College London)

  • Thamara Nishida Xavier da Silva

    (University of Würzburg)

  • Elena Panzilius

    (Institute of Stem Cell Biology, Helmholtz Zentrum München)

  • Christina H. Scheel

    (Institute of Stem Cell Biology, Helmholtz Zentrum München
    St Josef Hospital Bochum, University of Bochum)

  • André Mourão

    (Institute of Structural Biology, Helmholtz Zentrum München)

  • Katalin Buday

    (Institute of Developmental Genetics, Helmholtz Zentrum München)

  • Mami Sato

    (Institute of Developmental Genetics, Helmholtz Zentrum München)

  • Jonas Wanninger

    (Institute of Developmental Genetics, Helmholtz Zentrum München)

  • Thibaut Vignane

    (Institute of Developmental Genetics, Helmholtz Zentrum München)

  • Vaishnavi Mohana

    (Institute of Developmental Genetics, Helmholtz Zentrum München)

  • Markus Rehberg

    (Institute of Lung Biology and Disease, Helmholtz Zentrum München)

  • Andrew Flatley

    (Helmholtz Zentrum München)

  • Aloys Schepers

    (Helmholtz Zentrum München)

  • Andreas Kurz

    (Biocenter, University of Würzburg)

  • Daniel White

    (Systems Immunity Research Institute, School of Medicine, Cardiff University)

  • Markus Sauer

    (Biocenter, University of Würzburg)

  • Michael Sattler

    (Institute of Structural Biology, Helmholtz Zentrum München)

  • Edward William Tate

    (Imperial College London)

  • Werner Schmitz

    (Theodor Boveri Institute, Biocenter, University of Würzburg)

  • Almut Schulze

    (Theodor Boveri Institute, Biocenter, University of Würzburg)

  • Valerie O’Donnell

    (Systems Immunity Research Institute, School of Medicine, Cardiff University)

  • Bettina Proneth

    (Institute of Developmental Genetics, Helmholtz Zentrum München)

  • Grzegorz M. Popowicz

    (Institute of Structural Biology, Helmholtz Zentrum München)

  • Derek A. Pratt

    (University of Ottawa)

  • José Pedro Friedmann Angeli

    (University of Würzburg)

  • Marcus Conrad

    (Institute of Developmental Genetics, Helmholtz Zentrum München)

Abstract

Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids1,2. To date, ferroptosis has been thought to be controlled only by the phospholipid hydroperoxide-reducing enzyme glutathione peroxidase 4 (GPX4)3,4 and radical-trapping antioxidants5,6. However, elucidation of the factors that underlie the sensitivity of a given cell type to ferroptosis7 is crucial to understand the pathophysiological role of ferroptosis and how it may be exploited for the treatment of cancer. Although metabolic constraints8 and phospholipid composition9,10 contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been identified that account for the resistance of cells to ferroptosis. Here we used an expression cloning approach to identify genes in human cancer cells that are able to complement the loss of GPX4. We found that the flavoprotein apoptosis-inducing factor mitochondria-associated 2 (AIFM2) is a previously unrecognized anti-ferroptotic gene. AIFM2, which we renamed ferroptosis suppressor protein 1 (FSP1) and which was initially described as a pro-apoptotic gene11, confers protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that the suppression of ferroptosis by FSP1 is mediated by ubiquinone (also known as coenzyme Q10, CoQ10): the reduced form, ubiquinol, traps lipid peroxyl radicals that mediate lipid peroxidation, whereas FSP1 catalyses the regeneration of CoQ10 using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. In conclusion, the FSP1–CoQ10–NAD(P)H pathway exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione to suppress phospholipid peroxidation and ferroptosis.

Suggested Citation

  • Sebastian Doll & Florencio Porto Freitas & Ron Shah & Maceler Aldrovandi & Milene Costa Silva & Irina Ingold & Andrea Goya Grocin & Thamara Nishida Xavier da Silva & Elena Panzilius & Christina H. Sch, 2019. "FSP1 is a glutathione-independent ferroptosis suppressor," Nature, Nature, vol. 575(7784), pages 693-698, November.
  • Handle: RePEc:nat:nature:v:575:y:2019:i:7784:d:10.1038_s41586-019-1707-0
    DOI: 10.1038/s41586-019-1707-0
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    Citations

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    Cited by:

    1. Yun Lv & Chunhui Liang & Qichao Sun & Jing Zhu & Haiyan Xu & Xiaoqing Li & Yao-yao Li & Qihai Wang & Huiqing Yuan & Bo Chu & Deyu Zhu, 2023. "Structural insights into FSP1 catalysis and ferroptosis inhibition," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Jun Jiang & Lili Yang & Qianqian Xie & Xi Liu & Jie Jiang & Jie Zhang & Shuping Zhang & Huizhen Zheng & Wenjie Li & Xiaoming Cai & Sijin Liu & Ruibin Li, 2024. "Synthetic vectors for activating the driving axis of ferroptosis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Samya Van Coillie & Emily Van San & Ines Goetschalckx & Bartosz Wiernicki & Banibrata Mukhopadhyay & Wulf Tonnus & Sze Men Choi & Ria Roelandt & Catalina Dumitrascu & Ludwig Lamberts & Geert Dams & Wa, 2022. "Targeting ferroptosis protects against experimental (multi)organ dysfunction and death," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Zhe Wang & Xin Yang & Delin Chen & Yanqing Liu & Zhiming Li & Shoufu Duan & Zhiguo Zhang & Xuejun Jiang & Brent R. Stockwell & Wei Gu, 2024. "GAS41 modulates ferroptosis by anchoring NRF2 on chromatin," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Zifan Ye & Lei Fu & Shuangyu Li & Ziying Chen & Jianhong Ouyang & Xinci Shang & Yanli Liu & Lianghui Gao & Yipeng Wang, 2024. "Synergistic collaboration between AMPs and non-direct antimicrobial cationic peptides," Nature Communications, Nature, vol. 15(1), pages 1-26, December.
    6. Juliane Tschuck & Vidya Padmanabhan Nair & Ana Galhoz & Carole Zaratiegui & Hin-Man Tai & Gabriele Ciceri & Ina Rothenaigner & Jason Tchieu & Brent R. Stockwell & Lorenz Studer & Daphne S. Cabianca & , 2024. "Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    7. Hui Yang & Qingqing Li & Xingxing Chen & Mingzhe Weng & Yakai Huang & Qiwen Chen & Xiaocen Liu & Haoyu Huang & Yanhuizhi Feng & Hanyu Zhou & Mengying Zhang & Weiya Pei & Xueqin Li & Qingsheng Fu & Lia, 2024. "Targeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    8. Giovanni Tosi & Alessandro Paoli & Gaia Zuccolotto & Emilia Turco & Manuela Simonato & Daniela Tosoni & Francesco Tucci & Pietro Lugato & Monica Giomo & Nicola Elvassore & Antonio Rosato & Paola Cogo , 2024. "Cancer cell stiffening via CoQ10 and UBIAD1 regulates ECM signaling and ferroptosis in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    9. Juliane Tschuck & Lea Theilacker & Ina Rothenaigner & Stefanie A. I. Weiß & Banu Akdogan & Van Thanh Lam & Constanze Müller & Roman Graf & Stefanie Brandner & Christian Pütz & Tamara Rieder & Philippe, 2023. "Farnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    10. Yandi Wu & Tongsheng Huang & Xinghui Li & Conghui Shen & Honglin Ren & Haiping Wang & Teng Wu & Xinlu Fu & Shijie Deng & Ziqi Feng & Shijie Xiong & Hui Li & Saifei Gao & Zhenyu Yang & Fei Gao & Lele D, 2023. "Retinol dehydrogenase 10 reduction mediated retinol metabolism disorder promotes diabetic cardiomyopathy in male mice," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    11. Nathan P. Ward & Sang Jun Yoon & Tyce Flynn & Amanda M. Sherwood & Maddison A. Olley & Juliana Madej & Gina M. DeNicola, 2024. "Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    12. Mihee Oh & Seo Young Jang & Ji-Yoon Lee & Jong Woo Kim & Youngae Jung & Jiwoo Kim & Jinho Seo & Tae-Su Han & Eunji Jang & Hye Young Son & Dain Kim & Min Wook Kim & Jin-Sung Park & Kwon-Ho Song & Kyoun, 2023. "The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    13. Da-Yun Jin & Xuejie Chen & Yizhou Liu & Craig M. Williams & Lars C. Pedersen & Darrel W. Stafford & Jian-Ke Tie, 2023. "A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    14. Dadi Jiang & Youming Guo & Tianyu Wang & Liang Wang & Yuelong Yan & Ling Xia & Rakesh Bam & Zhifen Yang & Hyemin Lee & Takao Iwawaki & Boyi Gan & Albert C. Koong, 2024. "IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    15. Pranavi Koppula & Guang Lei & Yilei Zhang & Yuelong Yan & Chao Mao & Lavanya Kondiparthi & Jiejun Shi & Xiaoguang Liu & Amber Horbath & Molina Das & Wei Li & Masha V. Poyurovsky & Kellen Olszewski & B, 2022. "A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    16. Xinyi Shan & Jiahuan Li & Jiahao Liu & Baoli Feng & Ting Zhang & Qian Liu & Huixin Ma & Honghong Wu & Hao Wu, 2023. "Targeting ferroptosis by poly(acrylic) acid coated Mn3O4 nanoparticles alleviates acute liver injury," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    17. Wei Yang & Bo Mu & Jing You & Chenyu Tian & Huachao Bin & Zhiqiang Xu & Liting Zhang & Ronggang Ma & Ming Wu & Guo Zhang & Chong Huang & Linli Li & Zhenhua Shao & Lunzhi Dai & Laurent Désaubry & Sheng, 2022. "Non-classical ferroptosis inhibition by a small molecule targeting PHB2," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    18. Bartosz Wiernicki & Sophia Maschalidi & Jonathan Pinney & Sandy Adjemian & Tom Vanden Berghe & Kodi S. Ravichandran & Peter Vandenabeele, 2022. "Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    19. Xin Chen & Jun Huang & Chunhua Yu & Jiao Liu & Wanli Gao & Jingbo Li & Xinxin Song & Zhuan Zhou & Changfeng Li & Yangchun Xie & Guido Kroemer & Jinbao Liu & Daolin Tang & Rui Kang, 2022. "A noncanonical function of EIF4E limits ALDH1B1 activity and increases susceptibility to ferroptosis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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