Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.
Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
Nat Commun. 2023 Aug 10;14(1):4829. doi: 10.1038/s41467-023-40600-7.
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 Ca-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.
人类 MutT 同源物 1（MTH1）是一种核苷酸池净化酶，可水解氧化核苷酸，以防止其在氧化应激下错误掺入 DNA。MTH1 在血小板中的表达和功能作用尚不清楚。在这里，我们显示了血小板中 MTH1 的表达及其缺乏会损害体内止血和动静脉血栓形成。MTH1 缺乏可减少由凝血酶诱导的血小板聚集、磷脂酰丝氨酸暴露和钙动员，但对胶原相关肽（CRP）诱导的血小板聚集、磷脂酰丝氨酸暴露和钙动员没有影响，同时还降低了线粒体 ATP 的产生。凝血酶而非 CRP 诱导 Ca 依赖性线粒体活性氧的产生。从机制上讲，MTH1 缺乏会导致线粒体 DNA 氧化损伤并降低细胞色素 c 氧化酶 1 的表达。此外，MTH1 在人血小板功能中发挥类似作用。我们的研究表明，MTH1 在血小板中对氧化应激具有保护作用，并表明 MTH1 可能是预防血栓性疾病的潜在治疗靶点。
