Abstract
Abstract Or101: Targeting mitochondrial calcium uniporter attenuates platelet hyperactivation and procoagulant phenotype associated with obesity in humans and mice
Arteriosclerosis, thrombosis, and vascular biology, Vol.46(Suppl_1)
05/2026
DOI: 10.1161/atvb.46.suppl_1.Or101
Abstract
Abstract only Background: Obesity and non-alcoholic fatty liver disease (NAFLD) is associated with platelet hyperactivity and thrombotic risk, yet its underlying mechanism remains poorly understood. Platelet function depends on spatiotemporal intracellular Ca 2+ signaling, where oscillations support aggregation and sustained rise drive induce procoagulant activity. The regulatory role of mitochondrial calcium uniporter (MCU), the primary route for mitochondrial Ca 2+ uptake, in regulating platelet hyperactivity in obesity and NAFLD remains unexplored. Aim: Determine whether MCU acts as a key regulator of platelet hyperactivity in obesity and NAFLD. Methods: Platelets from obese and NAFLD patients (BMI >30) and matched lean controls (BMI <25) were analyzed. WT and platelet-specific MCU knockout mice were fed chow or high-fat diet for 12–25 weeks. Aggregation and ATP secretion were assessed by aggregometry; αIIbβ3 activation and α-granule secretion by flow cytometry; Ca 2+ mobilization by fluorometry; and signaling pathways by immunoblotting. Results: In both early-onset obesity and obesity with NAFLD (in humans and mice), we observed increased PLC-γ activation, PKC substrate phosphorylation, and enhanced Ca 2+ mobilization, indicating platelet hyperactivity. Platelets from early obesity exhibited GPVI- and GPCR agonist induced hyperaggregation, increased granule secretion, and enhanced αIIbβ3-activation (P<0.05 vs. lean controls). In contrast, platelets from obesity with NAFLD displayed a state of functional exhaustion with a greater propensity toward a procoagulant phenotype, characterized by increased phosphatidyl serine exposure. Next, we assessed platelet function in both conditions using platelet-specific MCU knockout and pharmacological inhibition of MCU. In early obesity, MCU inhibition attenuated GPVI- and GPCR-mediated aggregation and secretion. Similarly, MCU modulation prevented mitochondrial depolarization and procoagulant transformation associated with the exhausted platelet state. These antiplatelet effects were mechanistically linked to the prevention of MCU-mediated Ca 2+ overload and preservation of mitochondrial membrane potential, supporting a central role for MCU in regulating cytosolic and mitochondrial Ca 2+ homeostasis that drives a bioenergetic shift toward metabolic regulated thrombosis. Conclusion: MCU functions a key regulator of platelet hyperactivity in obesity and NAFLD via coupling cytosolic Ca 2+ signaling to mitochondrial bioenergetics.
Details
- Title: Subtitle
- Abstract Or101: Targeting mitochondrial calcium uniporter attenuates platelet hyperactivation and procoagulant phenotype associated with obesity in humans and mice
- Creators
- Madankumar Ghatge - University of IowaGagan Flora - University of IowaMariia Kumskova - University of IowaManasa Nayak - University of IowaPedro Hsieh - University of IowaMarcelo CorreiaAnil Chauhan - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.46(Suppl_1)
- DOI
- 10.1161/atvb.46.suppl_1.Or101
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Language
- English
- Date published
- 05/2026
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9985215766702771
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