title: Metabolic plasticity in resting and thrombin activated platelets.
abstract: Platelet thrombus formation includes several integrated processes involving aggregation, secretion of granules, release of arachidonic acid and clot retraction, but it is not clear which metabolic fuels are required to support these events. We hypothesized that there is flexibility in the fuels that can be utilized to serve the energetic and metabolic needs for resting and thrombin-dependent platelet aggregation. Using platelets from healthy human donors, we found that there was a rapid thrombin-dependent increase in oxidative phosphorylation which required both glutamine and fatty acids but not glucose. Inhibition of fatty acid oxidation or glutamine utilization could be compensated for by increased glycolytic flux. No evidence for significant mitochondrial dysfunction was found, and ATP/ADP ratios were maintained following the addition of thrombin, indicating the presence of functional and active mitochondrial oxidative phosphorylation during the early stages of aggregation. Interestingly, inhibition of fatty acid oxidation and glutaminolysis alone or in combination is not sufficient to prevent platelet aggregation, due to compensation from glycolysis, whereas inhibitors of glycolysis inhibited aggregation approximately 50%. The combined effects of inhibitors of glycolysis and oxidative phosphorylation were synergistic in the inhibition of platelet aggregation. In summary, both glycolysis and oxidative phosphorylation contribute to platelet metabolism in the resting and activated state, with fatty acid oxidation and to a smaller extent glutaminolysis contributing to the increased energy demand.
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; UAB Mitochondrial Medicine Laboratory, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Saranya
authors: S
authors: Ravi
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; UAB Mitochondrial Medicine Laboratory, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Balu
authors: B
authors: Chacko
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; UAB Mitochondrial Medicine Laboratory, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Hirotaka
authors: H
authors: Sawada
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; UAB Mitochondrial Medicine Laboratory, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Philip A
authors: PA
authors: Kramer
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; UAB Mitochondrial Medicine Laboratory, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Michelle S
authors: MS
authors: Johnson
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; UAB Mitochondrial Medicine Laboratory, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Gloria A
authors: GA
authors: Benavides
authors: Department of Medical Biochemistry, Cardiff University, Cardiff, United Kingdom.
authors: Valerie
authors: V
authors: O'Donnell
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Marisa B
authors: MB
authors: Marques
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; UAB Mitochondrial Medicine Laboratory, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Victor M
authors: VM
authors: Darley-Usmar
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D006490:Hemostatics / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D012146:Rest / Q000502:physiology*; D013917:Thrombin / Q000494:pharmacology*
chemical_list: D006490:Hemostatics; D000255:Adenosine Triphosphate; D013917:Thrombin