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Fumarate induces redox-dependent senescence by modifying glutathione metabolism

Author

Listed:
  • Liang Zheng

    (Cancer Research UK, Beatson Institute)

  • Simone Cardaci

    (Cancer Research UK, Beatson Institute)

  • Livnat Jerby

    (The Blavatnik School of Computer Science—Tel Aviv University)

  • Elaine D. MacKenzie

    (Cancer Research UK, Beatson Institute)

  • Marco Sciacovelli

    (MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre)

  • T. Isaac Johnson

    (MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre)

  • Edoardo Gaude

    (MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre)

  • Ayala King

    (Institute of Cancer Sciences, University of Glasgow)

  • Joshua D. G. Leach

    (School of Veterinary Medicine, College of Medical Veterinary and Life Sciences, University of Glasgow)

  • RuAngelie Edrada-Ebel

    (Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde)

  • Ann Hedley

    (Cancer Research UK, Beatson Institute)

  • Nicholas A. Morrice

    (Cancer Research UK, Beatson Institute)

  • Gabriela Kalna

    (Cancer Research UK, Beatson Institute)

  • Karen Blyth

    (Cancer Research UK, Beatson Institute)

  • Eytan Ruppin

    (The Blavatnik School of Computer Science—Tel Aviv University
    The Sackler School of Medicine—Tel Aviv University)

  • Christian Frezza

    (MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre)

  • Eyal Gottlieb

    (Cancer Research UK, Beatson Institute)

Abstract

Mutations in the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) are associated with a highly malignant form of renal cancer. We combined analytical chemistry and metabolic computational modelling to investigate the metabolic implications of FH loss in immortalized and primary mouse kidney cells. Here, we show that the accumulation of fumarate caused by the inactivation of FH leads to oxidative stress that is mediated by the formation of succinicGSH, a covalent adduct between fumarate and glutathione. Chronic succination of GSH, caused by the loss of FH, or by exogenous fumarate, leads to persistent oxidative stress and cellular senescence in vitro and in vivo. Importantly, the ablation of p21, a key mediator of senescence, in Fh1-deficient mice resulted in the transformation of benign renal cysts into a hyperplastic lesion, suggesting that fumarate-induced senescence needs to be bypassed for the initiation of renal cancers.

Suggested Citation

  • Liang Zheng & Simone Cardaci & Livnat Jerby & Elaine D. MacKenzie & Marco Sciacovelli & T. Isaac Johnson & Edoardo Gaude & Ayala King & Joshua D. G. Leach & RuAngelie Edrada-Ebel & Ann Hedley & Nichol, 2015. "Fumarate induces redox-dependent senescence by modifying glutathione metabolism," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7001
    DOI: 10.1038/ncomms7001
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    1. Stefano Suzzi & Tommaso Croese & Adi Ravid & Or Gold & Abbe R. Clark & Sedi Medina & Daniel Kitsberg & Miriam Adam & Katherine A. Vernon & Eva Kohnert & Inbar Shapira & Sergey Malitsky & Maxim Itkin &, 2023. "N-acetylneuraminic acid links immune exhaustion and accelerated memory deficit in diet-induced obese Alzheimer’s disease mouse model," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Aditya Kshirsagar & Svetlana Maslov Doroshev & Anna Gorelik & Tsviya Olender & Tamar Sapir & Daisuke Tsuboi & Irit Rosenhek-Goldian & Sergey Malitsky & Maxim Itkin & Amir Argoetti & Yael Mandel-Gutfre, 2023. "LIS1 RNA-binding orchestrates the mechanosensitive properties of embryonic stem cells in AGO2-dependent and independent ways," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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