Journal article
Mitochondrial Oxidants Promote Platelet Activation and Thrombotic Susceptibility in Prediabetes
The Journal of clinical investigation, Vol.136(4), e195662
02/16/2026
DOI: 10.1172/JCI195662
PMCID: PMC12904718
PMID: 41433113
Abstract
Recent studies suggest that prediabetes is an independent risk factor for cardiovascular thrombotic events. However, the mechanisms that may promote platelet activation and thrombosis in prediabetes remain elusive. To determine mechanisms linking prediabetes and thrombosis as a function of age, we recruited prediabetic and normoglycemic Veterans in young and middle-age groups. Compared to normoglycemic subjects, platelets from those with prediabetes exhibited increased activation, mitochondrial-oxidant load, mitochondrial-membrane hyperpolarization, and greater thrombus formation ex vivo regardless of age. Preincubation of platelets with mitochondria targeted antioxidants such as superoxide dismutase (SOD) mimetic or Mito quinol (MitoQ), rescued this prothrombotic phenotype. These phenotypes were recapitulated in C57BL6/J mice exhibiting early onset of glucose intolerance when fed high fat (HF) diet for two weeks. Treatment of HF-fed mice with a SOD-mimetic or MitoQ, or genetic overexpression of catalase within mitochondria, not only lowered mitochondrial-oxidants, hyperpolarization, Ca2+ levels and platelet activation, but also protected against increased potential for carotid and pulmonary thrombosis. We also observed a bidirectional regulation of platelet activation by Ca2+ and mitochondrial oxidants. These findings support the idea that mitochondrial-oxidant dependent platelet activation induces a prothrombotic state in clinical prediabetes and preclinical models of short-term glucose intolerance and can be reversed by mitochondria-targeted antioxidants.
Details
- Title: Subtitle
- Mitochondrial Oxidants Promote Platelet Activation and Thrombotic Susceptibility in Prediabetes
- Creators
- Azaj Ahmed - University of IowaPooja Yadav - University of IowaMelissa Jensen - University of IowaKatharine Geasland - University of IowaJagadish S Swamy - University of IowaDouglas R Spitz - University of IowaE Dale Abel - University of IowaDiana Jalal - University of IowaSanjana Dayal - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.136(4), e195662
- DOI
- 10.1172/JCI195662
- PMID
- 41433113
- PMCID
- PMC12904718
- NLM abbreviation
- J Clin Invest
- ISSN
- 1558-8238
- eISSN
- 1558-8238
- Publisher
- American Society for Clinical Investigation
- Grant note
- Office of Research and Development and Department of Veterans Affairs: I01CX001932, 2I01BX007087 NIH National Institute of Allergy and Infectious Diseases: AI162778 NIH: U01AI184289 NIH National Heart, Lung, and Blood Institute: HL168630, HL134738, HL141783 NIH National Institute of Diabetes and Digestive and Kidney Diseases: DK133240 NIH National Cancer Institute: CA217797, CA302572, CA244091, P30 CA086862 Institute for Clinical and Translational Science at the University of Iowa, CTSA program grant: UM1TR004403 American Heart Association Postdoctoral Fellowship: 24POST1195019
This work is also the result of NIH funding, in part, and is subject to the NIH Public Access Policy. Through acceptance of this federal funding, the NIH has been given a right to make the work publicly available in PubMed Central. center dot Office of Research and Development and Department of Veterans Affairs (grants I01CX001932 and 2I01BX007087 to SD). center dot NIH National Institute of Allergy and Infectious Diseases (grant AI162778 to SD). center dot NIH U01AI184289 to DRS. center dot NIH National Heart, Lung, and Blood Institute (grants HL168630 to SD, HL134738 to DJ, and HL141783 to EDA). center dot NIH National Institute of Diabetes and Digestive and Kidney Diseases (grant DK133240 to DJ). center dot NIH National Cancer Institute (grants CA217797, CA302572, CA244091, and P30 CA086862 to DRS). center dot Institute for Clinical and Translational Science at the University of Iowa, CTSA program grant UM1TR004403. center dot American Heart Association Postdoctoral Fellowship to AA (award 24POST1195019; (https://doi.org/10.58275/AHA.24POST1195019.pc.gr.190825).
- Language
- English
- Electronic publication date
- 12/23/2025
- Date published
- 02/16/2026
- Academic Unit
- Clinical Research Unit; Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Iowa Neuroscience Institute; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Nephrology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9985093888002771
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