The mitochondrial calcium uniporter regulates procoagulant platelet formation

Kholmukhamedov, Andaleb; Janecke, Rae; Choo, Hyo Jung; Jobe, Shawn M.

doi:10.1111/jth.14284

Cited by 34 publications

(42 citation statements)

References 27 publications

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“…7). 41,50 Understanding the role of NCX in the platelet procoagulant activity and signaling implicated upstream of NCX directionality may reveal important What is known about this topic?…”

Section: Resultsmentioning

confidence: 99%

“…Recent publications reported that high and sustained calcium mobilization during procoagulant response triggers mitochondrial calcium influx, which is responsible for mitochondrial potential loss, mitochondrial permeability transition pore (mPTP) formation, and eventually exposure of PS. 41 Therefore, delayed PS exposure (►Fig. 3A), delayed loss of mitochondrial potential (►Fig.…”

Section: Thrombosis and Haemostasismentioning

confidence: 99%

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Sodium–Calcium Exchanger Reverse Mode Sustains Dichotomous Ion Fluxes Required for Procoagulant COAT Platelet Formation

et al. 2020

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Procoagulant collagen-and-thrombin (COAT)-activated platelets represent a subpopulation of activated platelets, which retain a coat of prohemostatic proteins and express phosphatidylserine on their surface. Dichotomous intracellular signaling generating procoagulant platelet activity instead of traditional aggregating endpoints is still not fully elucidated. It has been demonstrated that secondary messengers such as calcium and sodium play a critical role in platelet activation. Therefore, we developed a flow cytometric analysis to investigate intracellular ion fluxes simultaneously during generation of aggregating and procoagulant platelets. Human platelets were activated by convulxin-plus-thrombin. Cytosolic calcium, sodium, and potassium ion fluxes were visualized by specific ion probes and analyzed by flow cytometry. We observed high and prolonged intracellular calcium concentration, transient sodium increase, and fast potassium efflux in COAT platelets, whereas aggregating non-COAT platelets rapidly decreased their calcium content, maintaining higher cytosolic sodium, and experiencing lower and slower potassium depletion. Considering these antithetical patterns, we investigated the role of the sodium–calcium exchanger (NCX) during convulxin-plus-thrombin activation. NCX inhibitors, CBDMB and ORM-10103, dose-dependently reduced the global calcium mobilization induced by convulxin-plus-thrombin activation and dose-dependently prevented formation of procoagulant COAT platelets. Our data demonstrate that both NCX modes are used after convulxin-plus-thrombin-induced platelet activation. Non-COAT platelets use forward-mode NCX, thus pumping calcium out and moving sodium in, while COAT platelets rely on reverse NCX function, which pumps additional calcium into the cytosol, by extruding sodium. In conclusion, we described for the first time the critical and dichotomous role of NCX function during convulxin-plus-thrombin-induced platelet activation.

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“…7). 41,50 Understanding the role of NCX in the platelet procoagulant activity and signaling implicated upstream of NCX directionality may reveal important What is known about this topic?…”

Section: Resultsmentioning

confidence: 99%

Section: Thrombosis and Haemostasismentioning

confidence: 99%

Sodium–Calcium Exchanger Reverse Mode Sustains Dichotomous Ion Fluxes Required for Procoagulant COAT Platelet Formation

et al. 2020

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“…13 Jobe et al have demonstrated some of the pathways involved in the creation of this phenotype, specifically the Fcγ receptor extracellularly and the mitochondrial calcium uptake channel intracellularly. 14,15 Several studies support this activation and exhaustion phenotype during TIC. Platelets sampled after trauma can express markers of cellular activation in addition to the broad functional impairments mentioned previously.…”

Section: Platelets In Trauma-induced Coagulopathymentioning

confidence: 92%

Platelets and Fibrinogen: Emerging Complexity in Trauma-Induced Coagulopathy

John

White

2020

Semin Thromb Hemost

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Trauma induces a change in nearly every observable aspect of hemostasis, generally tipping the balance toward trauma-induced coagulopathy (TIC) and bleeding in the critical early stages. Two particularly important aspects of TIC are platelets and fibrinogen, which are the primary determinants of clot formation and hemostasis. Their loss and dysfunction represent important transition points between coagulopathy phenotypes, highlighting their mechanistic roles in TIC as well as unveiling new potential avenues toward important diagnostic and therapeutic interventions. This review synthesizes current knowledge of platelets and fibrinogen during TIC, with a focus on emerging concepts related to their dysfunction and development of new therapeutic approaches.

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“…The intracellular Ca 2+ is taken up by the mitochondria via the mitochondrial calcium uniporter. The increasing mitochondrial Ca 2+ level eventually lead to the opening of the mPTP [89][90][91]. Whether the opening of the mPTP results in the release of additional Ca 2+ which induces a procoagulant response, or whether the mPTP has another mechanism of action is currently unknown [90].…”

mentioning

confidence: 99%

“…The increasing mitochondrial Ca 2+ level eventually lead to the opening of the mPTP [89][90][91]. Whether the opening of the mPTP results in the release of additional Ca 2+ which induces a procoagulant response, or whether the mPTP has another mechanism of action is currently unknown [90]. The lack of impact of mPTP inhibition seen upon platelet stimulation with the Ca 2+ -ionophore A23187 [87,88] suggests that the intracellular Ca 2+ concentration is the important trigger.…”

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confidence: 99%

Formation and Relevance of Platelet Subpopulations

Södergren¹

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α α-granules are the most abundant of the secretory granules, with 50-80 α-granules per platelet. The contents of the α-granules are produced by the megakaryocyte or taken up by the megakaryocyte or platelet through endocytosis. Endocytosed proteins found in the α-granule include fibrinogen and coagulation factor (F) V. αgranules contain both membrane proteins, where αIIbβ3 and P-selectin (CD62P) Platelets have two major ADP receptors, P2Y1 and P2Y12, where P2Y12 is the more abundant. The role of P2Y1 and P2Y12 is, similar to the TP receptor, to reinforce platelet activation induced by other agonists having caused dense granule release. P2Y1 and P2Y12 are both GPCRs. P2Y1 couples to Gq and mediates platelet shape change and reversible aggregation. P2Y12 couples to Gi, resulting in intracellular Ca 2+ mobilization via inhibition of adenylate cyclase. P2Y12 is the target for several common anti-platelet drugs, such as clopidogrel and ticagrelor [28]. Upon vessel damage, the extracellular matrix (ECM) becomes exposed. This contains platelet activating substances such as collagen, vWF, fibronectin, laminin and thrombospondin. If the shear rate of the damaged vessel is high, as in arteries, platelet adhesion is mediated through binding of vWF to GPIb-IX-V, whereas this interaction is not essential at lower shear rates, as in veins. Platelets in circulation bind to vWF, immobilized at the site of vessel damage. The GPIb-IX-V receptor complex has a fast on-and off-rate, allowing the platelet to roll along the vWF multimers. This slows down the platelets enough to allow adhesion, via αIIbβ3, and α2β1 [17-19], figure 1A.

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The mitochondrial calcium uniporter regulates procoagulant platelet formation

Cited by 34 publications

References 27 publications

Sodium–Calcium Exchanger Reverse Mode Sustains Dichotomous Ion Fluxes Required for Procoagulant COAT Platelet Formation

Sodium–Calcium Exchanger Reverse Mode Sustains Dichotomous Ion Fluxes Required for Procoagulant COAT Platelet Formation

Platelets and Fibrinogen: Emerging Complexity in Trauma-Induced Coagulopathy

Formation and Relevance of Platelet Subpopulations

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