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MTH1 protects platelet mitochondria from oxidative damage and regulates platelet function and thrombosis

Author

Listed:
  • Yangyang Ding

    (Xuzhou Medical University
    The Affiliated Hospital of Xuzhou Medical University
    Key Laboratory of Bone Marrow Stem Cell)

  • Xiang Gui

    (Xuzhou Medical University
    The Affiliated Hospital of Xuzhou Medical University
    Key Laboratory of Bone Marrow Stem Cell)

  • Xiang Chu

    (Xuzhou Medical University
    The Affiliated Hospital of Xuzhou Medical University
    Key Laboratory of Bone Marrow Stem Cell)

  • Yueyue Sun

    (Xuzhou Medical University
    The Affiliated Hospital of Xuzhou Medical University
    Key Laboratory of Bone Marrow Stem Cell)

  • Sixuan Zhang

    (Xuzhou Medical University
    The Affiliated Hospital of Xuzhou Medical University
    Key Laboratory of Bone Marrow Stem Cell)

  • Huan Tong

    (Xuzhou Medical University
    The Affiliated Hospital of Xuzhou Medical University
    Key Laboratory of Bone Marrow Stem Cell)

  • Wen Ju

    (Xuzhou Medical University
    The Affiliated Hospital of Xuzhou Medical University
    Key Laboratory of Bone Marrow Stem Cell)

  • Yue Li

    (Xuzhou Medical University)

  • Zengtian Sun

    (Xuzhou Medical University
    The Affiliated Hospital of Xuzhou Medical University
    Key Laboratory of Bone Marrow Stem Cell)

  • Mengdi Xu

    (Xuzhou Medical University
    The Affiliated Hospital of Xuzhou Medical University
    Key Laboratory of Bone Marrow Stem Cell)

  • Zhenyu Li

    (Xuzhou Medical University
    The Affiliated Hospital of Xuzhou Medical University
    Key Laboratory of Bone Marrow Stem Cell)

  • Robert K. Andrews

    (Australian National University)

  • Elizabeth E. Gardiner

    (Australian National University)

  • Lingyu Zeng

    (Xuzhou Medical University
    The Affiliated Hospital of Xuzhou Medical University
    Key Laboratory of Bone Marrow Stem Cell
    Xuzhou Medical University)

  • Kailin Xu

    (Xuzhou Medical University
    The Affiliated Hospital of Xuzhou Medical University
    Key Laboratory of Bone Marrow Stem Cell)

  • Jianlin Qiao

    (Xuzhou Medical University
    The Affiliated Hospital of Xuzhou Medical University
    Key Laboratory of Bone Marrow Stem Cell)

Abstract

Human MutT Homolog 1 (MTH1) is a nucleotide pool sanitization enzyme that hydrolyzes oxidized nucleotides to prevent their mis-incorporation into DNA under oxidative stress. Expression and functional roles of MTH1 in platelets are not known. Here, we show MTH1 expression in platelets and its deficiency impairs hemostasis and arterial/venous thrombosis in vivo. MTH1 deficiency reduced platelet aggregation, phosphatidylserine exposure and calcium mobilization induced by thrombin but not by collagen-related peptide (CRP) along with decreased mitochondrial ATP production. Thrombin but not CRP induced Ca2+-dependent mitochondria reactive oxygen species generation. Mechanistically, MTH1 deficiency caused mitochondrial DNA oxidative damage and reduced the expression of cytochrome c oxidase 1. Furthermore, MTH1 exerts a similar role in human platelet function. Our study suggests that MTH1 exerts a protective function against oxidative stress in platelets and indicates that MTH1 could be a potential therapeutic target for the prevention of thrombotic diseases.

Suggested Citation

  • Yangyang Ding & Xiang Gui & Xiang Chu & Yueyue Sun & Sixuan Zhang & Huan Tong & Wen Ju & Yue Li & Zengtian Sun & Mengdi Xu & Zhenyu Li & Robert K. Andrews & Elizabeth E. Gardiner & Lingyu Zeng & Kaili, 2023. "MTH1 protects platelet mitochondria from oxidative damage and regulates platelet function and thrombosis," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40600-7
    DOI: 10.1038/s41467-023-40600-7
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    References listed on IDEAS

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    1. Helge Gad & Tobias Koolmeister & Ann-Sofie Jemth & Saeed Eshtad & Sylvain A. Jacques & Cecilia E. Ström & Linda M. Svensson & Niklas Schultz & Thomas Lundbäck & Berglind Osk Einarsdottir & Aljona Sale, 2014. "MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool," Nature, Nature, vol. 508(7495), pages 215-221, April.
    2. Sheila S. David & Valerie L. O'Shea & Sucharita Kundu, 2007. "Base-excision repair of oxidative DNA damage," Nature, Nature, vol. 447(7147), pages 941-950, June.
    3. Bo Shen & Xiaojuan Zhao & Kelly A. O’Brien & Aleksandra Stojanovic-Terpo & M. Keegan Delaney & Kyungho Kim & Jaehyung Cho & Stephen C.-T. Lam & Xiaoping Du, 2013. "A directional switch of integrin signalling and a new anti-thrombotic strategy," Nature, Nature, vol. 503(7474), pages 131-135, November.
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