Journal article
The mitochondrial calcium uniporter regulates calcium dynamics to drive platelet function, bioenergetics, and thrombosis
Journal of thrombosis and haemostasis, Vol.24(2), pp.716-731
02/2026
DOI: 10.1016/j.jtha.2025.10.019
PMID: 41197806
Abstract
Background: The mitochondrial calcium uniporter (MCU), a selective Ca2+ channel, mediates mitochondrial Ca2+ uptake, supporting Ca2+ homeostasis and mitochondrial bioenergetics. While cytosolic Ca2+ flux from the dense tubular system (DTS) and store-operated Ca2+ entry (SOCE) are known to drive platelet activation, the role of mitochondrial Ca2+ handling in platelet function and thrombosis is not well understood.
Objective: To examine whether targeting MCU-dependent Ca2+ flux could attenuate platelet activation and arterial thrombosis.
Methods: Susceptibility to arterial thrombosis was assessed using the FeCl3-induced carotid injury model in WT and MCU-/- mice. Mitochondrial and cytosolic Ca2+ levels were measured in Rhod-2- and Fura-2-loaded platelets by fluorometry, and platelet bioenergetics were analyzed using a Seahorse extracellular flux analyzer.
Results: Genetic ablation of MCU inhibited agonist-induced platelet functions, including aggregation, fibrinogen binding to integrin αIIbβ3, granule secretion, and spreading on fibrinogen. MCU-/- mice were less susceptible to in vivo arterial thrombosis with unaltered tail bleeding time, suggesting normal hemostasis. Mechanistically, these effects were associated with disruption of Ca2+ homeostasis mediated by reduced mitochondrial Ca2+ uptake, altered release of Ca2+ from DTS, and impaired SOCE in agonist-stimulated MCU-/- platelets. Consistent with this, Ca2+-dependent GPVI signaling events such as PLCγ2 and PKC substrate phosphorylation were significantly reduced in collagen-stimulated MCU-/- platelets. Furthermore, disruption of mitochondrial Ca2+ uptake significantly impaired mitochondrial respiration and associated ATP production in agonist-stimulated MCU-/- platelets.
Conclusion: MCU facilitates platelet activation and thrombosis by regulating calcium flux (mitochondrial and cytosolic), thereby establishing its potential as a target for antithrombotic therapeutic intervention.
Details
- Title: Subtitle
- The mitochondrial calcium uniporter regulates calcium dynamics to drive platelet function, bioenergetics, and thrombosis
- Creators
- Madankumar Ghatge - University of IowaGagan D Flora - University of IowaRakesh B Patel - University of IowaManasa K Nayak - University of IowaMariia Kumskova - University of IowaTam Nguyen - University of Iowa, Neuroscience and PharmacologyYuriy M Usachev - University of IowaAnil K Chauhan - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Journal of thrombosis and haemostasis, Vol.24(2), pp.716-731
- DOI
- 10.1016/j.jtha.2025.10.019
- PMID
- 41197806
- NLM abbreviation
- J Thromb Haemost
- ISSN
- 1538-7836
- eISSN
- 1538-7836
- Publisher
- Elsevier
- Grant note
- National Institutes of Health: R35HL139926
National Institutes of Health, Grant/Award Number: R35HL139926.
- Language
- English
- Electronic publication date
- 11/04/2025
- Date published
- 02/2026
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Iowa Neuroscience Institute; Anesthesia; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9985024166702771
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