Journal article
Mitochondrial calcium uniporter b deletion inhibits platelet function and reduces susceptibility to arterial thrombosis
Journal of thrombosis and haemostasis, Vol.21(8), pp.2163-2174
08/2023
DOI: 10.1016/j.jtha.2023.04.002
PMID: 37061131
Abstract
The mitochondrial calcium uniporter b (MCUb) is a negative regulator of the mitochondrial calcium uniporter and is known to limit mitochondrial Ca2+ uptake. The role of MCUb in platelet function remains unclear.
Utilizing MCUb-/- mice, we examined the role of MCUb in regulating platelet function and thrombosis.
Platelet activation was evaluated in agonist-induced standardized in vitro assays. Susceptibility to arterial thrombosis was evaluated in FeCl3 injury-induced carotid artery and laser-injury-induced mesenteric artery thrombosis models. The glycolytic Proton Efflux Rate and oxygen consumption rate were measured to evaluate aerobic glycolysis.
Upon stimulation, MCUb-/- platelets exhibited reduced cytoplasmic Ca2+ responses concomitant with increased mitochondrial Ca2+ uptake. MCUb-/- platelets displayed a reduction in agonist-induced platelet aggregation, a decrease in α and dense-granule secretion, reduced spreading on fibrinogen, and decreased clot retraction. MCUb-/- mice were less susceptible to arterial thrombosis in FeCl3 injury-induced carotid and the laser injury-induced mesenteric thrombosis models with unaltered tail bleeding time. In adoptive transfer experiments, thrombocytopenic hIL-4Rα/GPIbα-transgenic mice transfused with MCUb-/- platelets were less susceptible to FeCl3 injury-induced carotid thrombosis compared to hIL-4Rα/GPIbα-Tg mice transfused with WT platelets, suggesting a platelet-specific role of MCUb in thrombosis. MCUb-/- stimulated platelets exhibited reduced glucose uptake, decreased glycolytic rate, and lowered pyruvate dehydrogenase phosphorylation, suggesting mitochondrial Ca2+ mediates bioenergetic changes in platelets.
Our findings suggest that mitochondrial Ca2+ signaling and glucose oxidation are functionally linked in activated platelets and reveal a novel role of MCUb in platelet activation and arterial thrombosis.
Details
- Title: Subtitle
- Mitochondrial calcium uniporter b deletion inhibits platelet function and reduces susceptibility to arterial thrombosis
- Creators
- Madankumar Ghatge - Department of Internal Medicine, Division of Hematology/Oncology, The University of Iowa, Iowa City, Iowa, USAManasa K. Nayak - University of IowaGagan D. Flora - University of IowaMariia Kumskova - University of IowaAditi Jain - Department of Internal Medicine, Division of Hematology/Oncology, The University of Iowa, Iowa City, Iowa, USARakesh B. Patel - University of IowaZhihong Lin - University of IowaYuriy M. Usachev - Department of Neuroscience and Pharmacology, The University of Iowa, Iowa City, Iowa, USAAnil K. Chauhan - Department of Internal Medicine, Division of Hematology/Oncology, The University of Iowa, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- Journal of thrombosis and haemostasis, Vol.21(8), pp.2163-2174
- DOI
- 10.1016/j.jtha.2023.04.002
- PMID
- 37061131
- NLM abbreviation
- J Thromb Haemost
- ISSN
- 1538-7836
- eISSN
- 1538-7836
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: R01DK116624, R01NS109910, R01NS125884, R35HL139926, U01NS130587
- Language
- English
- Electronic publication date
- 04/13/2023
- Date published
- 08/2023
- 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
- 9984398348402771
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