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

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 (), Kailin Xu () and Jianlin Qiao ()
Additional contact information
Yangyang Ding: Xuzhou Medical University
Xiang Gui: Xuzhou Medical University
Xiang Chu: Xuzhou Medical University
Yueyue Sun: Xuzhou Medical University
Sixuan Zhang: Xuzhou Medical University
Huan Tong: Xuzhou Medical University
Wen Ju: Xuzhou Medical University
Yue Li: Xuzhou Medical University
Zengtian Sun: Xuzhou Medical University
Mengdi Xu: Xuzhou Medical University
Zhenyu Li: Xuzhou Medical University
Robert K. Andrews: Australian National University
Elizabeth E. Gardiner: Australian National University
Lingyu Zeng: Xuzhou Medical University
Kailin Xu: Xuzhou Medical University
Jianlin Qiao: Xuzhou Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40600-7

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