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Dominant-negative TERT splice variants contribute to decreased mitochondrial integrity and promote elevated reactive oxygen species production. We hypothesize that a decrease in mitochondrial TERT would increase mtDNA damage, promoting a pro-oxidative redox environment. The goal of this study is to define whether mitochondrial TERT is sufficient to maintain nitric oxide as the underlying mechanism of flow-mediated dilation by preserving mtDNA integrity.Immunoblots and quantitative polymerase chain reaction were used to show elevated levels of splice variants \u03b1- and \u03b2-deletion TERT tissue from subjects with and without CAD. Genetic, pharmacological, and molecular tools were used to manipulate TERT localization. Isolated vessel preparations and fluorescence-based quantification of mtH2O2 and NO showed that reduction of TERT in the nucleus increased flow induced NO and decreased mtH2O2 levels, while prevention of mitochondrial import of TERT augmented pathological effects. Further elevated mtDNA damage was observed in tissue from subjects with CAD and initiation of mtDNA repair mechanisms was sufficient to restore NO-mediated dilation in vessels from patients with CAD. The work presented is the first evidence that catalytically active mitochondrial TERT, independent of its nuclear functions, plays a critical physiological role in preserving NO-mediated vasodilation and the balance of mitochondrial to nuclear TERT is fundamentally altered in states of human disease that are driven by increased expression of dominant negative splice variants.<\/jats:p>","DOI":"10.1093\/function\/zqac043","type":"journal-article","created":{"date-parts":[[2022,9,3]],"date-time":"2022-09-03T10:58:52Z","timestamp":1662202732000},"source":"Crossref","is-referenced-by-count":18,"title":["Noncanonical Role of Telomerase in Regulation of Microvascular Redox Environment With Implications for Coronary Artery Disease"],"prefix":"10.1152","volume":"3","author":[{"given":"K","family":"Ait-Aissa","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Iowa , Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J C","family":"Hockenberry","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical College of Wisconsin , Milwaukee, WI 53226, USA"},{"name":"Cardiovascular Center, Medical College of Wisconsin , Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J E","family":"Beare","sequence":"additional","affiliation":[{"name":"Cardiovascular Innovation Institute, University of Louisville , Louisville, KY 40292, USA"},{"name":"Kentucky Spinal Cord Injury Research Center, University of Louisville , Louisville, KY 40292, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Linn","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical College of Wisconsin , Milwaukee, WI 53226, USA"},{"name":"Cardiovascular Center, Medical College of Wisconsin , Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Kohmoto","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiothoracic Surgery, Medical College of Wisconsin , Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario , London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D H","family":"Betts","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario , London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2507-1203","authenticated-orcid":false,"given":"A 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