Mitochondrial calcium uniporter b deletion inhibits platelet function and reduces susceptibility to arterial thrombosis

Madankumar Ghatge; Manasa K Nayak; Gagan D Flora; Mariia Kumskova; Aditi Jain; Rakesh B Patel; Zhihong Lin; Yuriy M Usachev; Anil K Chauhan

doi:10.1016/j.jtha.2023.04.002

Mitochondrial calcium uniporter b deletion inhibits platelet function and reduces susceptibility to arterial thrombosis

J Thromb Haemost. 2023 Aug;21(8):2163-2174. doi: 10.1016/j.jtha.2023.04.002. Epub 2023 Apr 13.

Authors

Madankumar Ghatge¹, Manasa K Nayak², Gagan D Flora², Mariia Kumskova², Aditi Jain², Rakesh B Patel², Zhihong Lin³, Yuriy M Usachev³, Anil K Chauhan⁴

Affiliations

¹ Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA. Electronic address: madankumar-ghatge@uiowa.edu.
² Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA.
³ Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, Iowa, USA.
⁴ Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA. Electronic address: anil-chauhan@uiowa.edu.

PMID: 37061131
DOI: 10.1016/j.jtha.2023.04.002

Abstract

Background: Mitochondrial calcium uniporter b (MCUb) is a negative regulator of the mitochondrial calcium uniporter (MCU) and is known to limit mitochondrial calcium ion (Ca²⁺) uptake. The role of MCUb in platelet function remains unclear.

Objectives: Utilizing MCUb^-/- mice, we examined the role of MCUb in regulating platelet function and thrombosis.

Methods: 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.

Results: Upon stimulation, MCUb^-/- platelets exhibited reduced cytoplasmic Ca²⁺ responses concomitant with increased mitochondrial Ca²⁺ uptake. MCUb^-/- platelets displayed reduced agonist-induced platelet aggregation and spreading on fibrinogen and decreased α and dense-granule secretion and clot retraction. MCUb^-/- mice were less susceptible to arterial thrombosis in FeCl₃ injury-induced carotid and 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 with hIL-4Rα/GPIbα-Tg mice transfused with wild type 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 that mitochondrial Ca²⁺ mediates bioenergetic changes in platelets.

Conclusion: 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.

Keywords: OXPHOS; aerobic glycolysis; mitochondrial calcium uniporter; platelet activation; thrombosis.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Blood Platelets
Calcium
Hemostasis*
Mice
Mice, Knockout
Mice, Transgenic
Platelet Activation
Platelet Aggregation
Thrombosis*

Substances

ferric chloride
mitochondrial calcium uniporter
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding