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Mitochondrial Calcium Uniporter Regulates ITAM-Dependent Platelet Activation
Abigail Ajanel1, Izabella Andrianova1, Mia Kowalczyk2
1Department of Emergency Medicine, Washington University School of Medicine, Saint Louis, MO (A.A., I.A., J.M.-P., I.P., F.D., R.A.C.).
Circulation Research
|July 1, 2025
Summary
Mitochondrial calcium uniporter (MCU) regulates platelet activation by controlling calcium flux into mitochondria. Disabling MCU reduces platelet aggregation and thrombosis via decreased mitochondrial reactive oxygen species (ROS) production.
Area of Science:
- Hematology
- Mitochondrial Biology
- Platelet Physiology
Background:
- Platelet activation is critical for hemostasis and thrombosis, involving calcium signaling.
- The role of mitochondrial calcium flux, specifically via the mitochondrial calcium uniporter (MCU), in platelet function remains largely unknown.
- Mitochondria regulate cellular bioenergetics and reactive oxygen species (ROS) production, processes influenced by calcium influx.
Purpose of the Study:
- To investigate the role of the mitochondrial calcium uniporter (MCU) in platelet activation and function.
- To determine if MCU-mediated mitochondrial calcium flux impacts platelet responses to different activation pathways.
- To elucidate the downstream mechanisms, including ROS production, linking MCU to platelet activation.
Main Methods:
- Generated platelet-specific MCU-deficient mice (Mcuplt-/-) and wild-type littermates (Mcuplt+/+).
- Assessed in vitro mitochondrial calcium flux and platelet aggregation upon stimulation of immunoreceptor tyrosine-based activation motif (ITAM) and G protein-coupled receptors (GPCRs).
- Evaluated in vivo hemostasis and thrombosis in Mcuplt-/- mice and treated human platelets with MCU inhibitors.
Main Results:
- Mcuplt-/- platelets exhibited reduced mitochondrial calcium flux and aggregation upon ITAM receptor activation, but not GPCR activation.
- Mcuplt-/- mice showed decreased arterial thrombosis and ischemic stroke brain injury.
- Reduced mitochondrial ROS generation in Mcuplt-/- platelets correlated with decreased ITAM signaling (p-Syk, p-PLCγ2).
Conclusions:
- Mitochondrial calcium flux, regulated by MCU, plays a significant role in ITAM-dependent platelet activation.
- This process is mediated through the generation of mitochondrial reactive oxygen species (ROS).
- Targeting MCU may offer a therapeutic strategy for thrombotic disorders.
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