| First Author | Ghatge M | Year | 2023 |
| Journal | J Thromb Haemost | Volume | 21 |
| Issue | 8 | Pages | 2163-2174 |
| PubMed ID | 37061131 | Mgi Jnum | J:338590 |
| Mgi Id | MGI:7512738 | Doi | 10.1016/j.jtha.2023.04.002 |
| Citation | Ghatge M, et al. (2023) Mitochondrial calcium uniporter b deletion inhibits platelet function and reduces susceptibility to arterial thrombosis. J Thromb Haemost 21(8):2163-2174 |
| abstractText | BACKGROUND: Mitochondrial calcium uniporter b (MCUb) is a negative regulator of the mitochondrial calcium uniporter (MCU) and is known to limit mitochondrial calcium ion (Ca(2+)) 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 FeCl(3) 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 Ca(2+) responses concomitant with increased mitochondrial Ca(2+) uptake. MCUb(-/-) platelets displayed reduced agonist-induced platelet aggregation and spreading on fibrinogen and decreased alpha and dense-granule secretion and clot retraction. MCUb(-/-) mice were less susceptible to arterial thrombosis in FeCl(3) injury-induced carotid and laser injury-induced mesenteric thrombosis models with unaltered tail bleeding time. In adoptive transfer experiments, thrombocytopenic hIL-4Ralpha/GPIbalpha-transgenic mice transfused with MCUb(-/-) platelets were less susceptible to FeCl(3) injury-induced carotid thrombosis compared with hIL-4Ralpha/GPIbalpha-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 Ca(2+) mediates bioenergetic changes in platelets. CONCLUSION: Our findings suggest that mitochondrial Ca(2+) signaling and glucose oxidation are functionally linked in activated platelets and reveal a novel role of MCUb in platelet activation and arterial thrombosis. |
