OC 18.3 - Platelet mitochondrial bioenergetics is critical for clot contraction, hemostasis and thrombosis

Sunday, June 25, 2023

11:15 – 11:30 ET

Room: 518

Session Available As: On-Demand

Presenting Author(s)

Kanakanagavalli Shravani Prakhya, PhD (she/her/hers)

Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA
Lexington, Kentucky, United States

Co-Author(s)

HV

Hemendra Vekaria

Scientist
University of Kentucky
Lexington, Kentucky, United States
JL

Joshua Lykins

Graduate Research Assistant
University of Kentucky
Lexington, Kentucky, United States
Daniëlle M. Coenen, MSc, PhD (she/her/hers)

Postdoctoral Research Fellow
Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA
Lexington, Kentucky, United States
Smita Joshi, PhD (she/her/hers)

Scientist
Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA
Lexington KY, Kentucky, United States
PS

Patrick Sullivan

Professor
University of Kentucky
Lexington, Kentucky, United States
SW

Sidney W. Whiteheart

University Research Professor
Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA
Lexington, Kentucky, United States

Background: Platelets are one of the most metabolically active cells in the bloodstream. They are known to show metabolic flexibility, switching between glycolysis and OxPhos depending on oxygen tension and the availability of substrates.
The goal of this study is to investigate platelet mitochondrial energy metabolism under normal physiological conditions.

Aims: The goal of this study is to investigate platelet mitochondrial metabolism under normal physiological conditions to better understand the relative roles of the OxPhos.

Methods: We developed two novel mouse models with altered mitochondrial function using a platelet-specific deletion of TFAM and QPC. TFAM (Transcription Factor A Mitochondrial), is essential for the maintenance, transcription, and translation of mitochondrial DNA. Its deletion is expected to disrupt platelet mitochondrial DNA, which encodes 13 subunits of OxPhos. QPC is one of the core proteins in Complex III.

Results: We confirmed both the KOs by western blot analysis and complex III activity assay. We also confirmed the disruption of mitochondrial Oxidative phosphorylation by Seahorse analysis. Both the KO animals showed an increase in tail-bleeding time in the KO, and an increase in occlusion time in the FeCl3 carotid injury model, with significantly higher rebleeding indicating that mitochondrial bioenergetics is important for clot stability. Using two novel mouse models with dysfunctional mitochondrial bioenergetics, we show that OxPhos is dispensable for low-energy demanding platelet functions such as aggregation but is important for secretion, clot contraction, hemostasis, and thrombosis.

Conclusion(s): Using the mouse models we developed, we show the relative importance of these energy-producing processes and the fuels and metabolic pathway choices made by platelets at different functional stages. Improving our understanding of platelet metabolism and the relative contributions of each pathway in the future could lead to a better understanding of how metabolic disorders can affect thrombotic risk in diabetic and obese patients.

Learning Objectives:

Upon completion, the participant will be able to describe the importance of bioenergetics in a rapidly changing environment while forming a clot to achieve hemostasis.
The participant will appreciate the importance of mitochondrial bioenergetics in the formation of a heterogenous clot.
The participant will better understand the relationship between platelet metabolism and platelet function.