INVESTIGATING THE ROLES OF PLATELET BIOENERGETICS IN HEMOSTASIS AND THROMBOSIS

Platelets use a series of energy-dependent processes to mediate hemostasis, yet it is unclear which metabolic fuels/pathways are critical for platelet function. Platelets are metabolically flexible, switching between glycolysis and oxidative phosphorylation (OxPhos) depending on oxygen tension and substrate availability. The deletion of GLUT1 and GLUT3 together revealed an essential role in platelet function and hemostasis. To study platelet bioenergetics, we used clot contraction. We created a sensitive and inexpensive method to simultaneously assess clot contraction kinetics to directly compare and define the effects of different treatments or genetic manipulations on platelet function. Since the pharmacological inhibitors cannot be used in vivo due to toxicity, there is a need to develop mouse models to study platelet bioenergetics. We developed two novel mouse models with altered mitochondrial function using a platelet-specific deletion of TFAM (Transcription Factor A Mitochondrial), and QPC (ubiquinol–cytochrome c reductase binding protein). Platelet-specific TFAM deletion (knock-out/KO) disrupts the integrity of platelet mitochondrial DNA that encodes for different subunits of OxPhos. QPC is a subunit of ubiquinol-cytochrome c reductase complex III. Using these two novel mouse models with dysfunctional mitochondrial bioenergetics, our studies demonstrate that platelets show considerable plasticity in energy metabolism. We were able to show that OxPhos is dispensable for low energy platelet functions like aggregation but is important for secretion, clot contraction, hemostasis, and thrombosis. Our data indicate that depending on energy demands, platelets can switch between the two metabolic pathways (glycolysis and OxPhos). We have focused on basal platelet bioenergetics and what metabolic pathways are used for platelet activation. In the absence of a nucleus, platelet health depends on the health of the mitochondria. Our work is applicable to metabolic pathologies such as diabetes mellitus where deviations in platelet metabolism contribute to thrombosis