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Ten-eleven translocation-2 (TET2) as the major demethylase in endothelial cells (ECs) is decreased in diabetic CMD, and the role warrants further exploration. In this study, a multi-modality imaging, consist of transthoracic Doppler echocardiography and artery spin labeling cardiac magnetic resonance, is assessed for coronary microvascular function. The expression of TET2 is down-regulated in the heart of diabetic CMD mice. ECs TET2 conditional knockout increases the severity of CMD in diabetic mice. Mechanistically, TET2 deficiency declined the expression of CMPK2, a mtDNA synthetase. Additionally, the mitochondrial electron transport chain complexes encoded by mitochondrial DNA (mtDNA) are down-regulated, which contributes to the excessive production of reactive oxygen species. This, in turn, exacerbated mitochondrial dysfunction, manifesting as mitochondrial membrane potential depolarization, aberrant opening of the mitochondrial permeability transition pore, and structural abnormalities in mitochondria. Therapeutic research demonstrates that vitamin C improves ECs mitochondrial function in diabetic CMD through the TET2\u2013CMPK2 pathway, revealing its potential clinical therapeutic value. In conclusion, we show that loss of endothelial TET2 impairs endothelial mitochondrial function and exacerbated diabetic CMD by regulating the expression of mitochondria enzyme CMPK2.<\/jats:p>","DOI":"10.1042\/cs20256842","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T09:54:46Z","timestamp":1770630886000},"page":"771-790","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Endothelial TET2 deficiency exacerbates diabetic coronary microvascular dysfunction via CMPK2-mediated mitochondrial impairment"],"prefix":"10.1042","volume":"140","author":[{"given":"Bo","family":"Li","sequence":"first","affiliation":[{"name":"1Department of Cardiology, Shanghai Tenth People\u2019s Hospital, Tongji University, School of Medicine, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yefei","family":"Shi","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Shanghai Tenth People\u2019s Hospital, Tongji University, School of Medicine, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke","family":"Yang","sequence":"additional","affiliation":[{"name":"2Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[{"name":"3Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qinfang","family":"Miao","sequence":"additional","affiliation":[{"name":"4School of Biomedical Engineering, ShanghaiTech University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kadierya","family":"Yibulayin","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Shanghai Tenth People\u2019s Hospital, Tongji University, School of Medicine, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhijun","family":"Lei","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Shanghai Tenth People\u2019s Hospital, Tongji University, School of Medicine, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingyu","family":"Li","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Shanghai Tenth People\u2019s Hospital, Tongji University, School of Medicine, Shanghai, China"},{"name":"5University of Missouri Health System, Columbia, MO, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiyu","family":"Gong","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Shanghai Tenth People\u2019s Hospital, Tongji University, School of Medicine, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Yu","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Shanghai Tenth People\u2019s Hospital, Tongji University, School of Medicine, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhui","family":"Zhuang","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Shanghai Tenth People\u2019s Hospital, Tongji University, School of Medicine, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4709-5185","authenticated-orcid":false,"given":"Haikun","family":"Qi","sequence":"additional","affiliation":[{"name":"4School of Biomedical Engineering, ShanghaiTech University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2937-0024","authenticated-orcid":false,"given":"Wenhui","family":"Peng","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Shanghai Tenth People\u2019s Hospital, Tongji University, School of Medicine, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4421-4284","authenticated-orcid":false,"given":"Weixia","family":"Jian","sequence":"additional","affiliation":[{"name":"2Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2026,5,5]]},"reference":[{"key":"2026050504113985500_B1","doi-asserted-by":"publisher","first-page":"1352","DOI":"10.1016\/j.jacc.2021.07.042","article-title":"Coronary microvascular dysfunction across the spectrum of cardiovascular diseases: JACC state-of-the-art review","volume":"78","author":"Del Buono","year":"2021","journal-title":"J. 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