Platelet respiration

Abstract

Historically, metabolic studies in platelets have primarily investigated events occurring during ex vivo platelet storage, less so the consequences of metabolic alterations on platelet homeostasis and physiologic function. The importance of such studies is emphasized by the recent finding of platelet mitochondrial dysfunction in type 2 diabetes, sickle cell disease, and sepsis. [1][2][3][4][5][6][7] These early investigations used radiometric methods with labeled glucose to study glycolysis and oxidative phosphorylation in platelets. 8,9 Recently, these techniques have been supplanted by more sophisticated investigative tools that allow more rapid analysis of small volume samples, including high-resolution respirometry 10,11 and Seahorse extracellular flux analysis. [12][13][14] Glycolysis and oxidative phosphorylation, as well as glutaminolysis and fatty acid b oxidation, all function to support the metabolic demand in platelets. 10,[14][15][16] The metabolic flexibility of the platelet has been emphasized by investigations demonstrating that activated platelets exhibit a glycolytic phenotype while preserving mitochondrial function and can easily switch between glucose and fatty acid catabolism to support activation. 12 The recently published study by A. K. Chauhan's group further advances our understanding of the understudied field of platelet metabolism. 13 In this paper, the authors demonstrate that dichloroacetate, an inhibitor of pyruvate dehydrogenase kinases, alters platelet metabolism and function. 13 Finding salutary antiaggregatory and antithrombotic effects of dichloroacetate, the authors propose targeting of the platelet metabolic response as a novel antithrombotic approach. However, there are few points of clarification we would like to add, which we believe will be of great benefit for the platelet and mitochondria research community in their exploration of this new therapeutic avenue. 13

Antioxidant prevents clearance of hemostatically competent platelets after long‐term cold storage

“…PLTs are highly dependent on mitochondrial activity and aerobic respiration 30 . Acetate is the major source of energy in PAS‐containing PLTs.…”

“…A key parameter defining mitochondrial activity is the oxygen consumption rate (OCR). Aerobic respiration is characterized by increased OCR, while alternative anaerobic respiration is independent of oxygen consumption 30 . Intuitively, refrigeration should result in a decrease in the metabolic needs of stored PLTs.…”

Long-term treated HIV infection is associated with platelet mitochondrial dysfunction

“…MtDNA copy number is considered to reflect mitochondrial function 24 . Healthy platelets contain between 5 and 8 mitochondria, which serve important processes such as platelet activation, ATP production and platelet viability 25 – 29 . Platelets are traditionally known for their role in hemostasis, but an increasing body of evidence supports their role in key processes beyond hemostasis, including inflammation and immunoregulation 23 .…”

Isotopically Nonstationary13C Metabolic Flux Analysis in Resting and Activated Human Platelets

“…Platelet activation with thrombin has been reported to cause significant changes to platelet metabolism, particularly in regard to glucose uptake, extracellular acidification, and oxygen consumption (Aibibula et al, 2018, Nayak et al, 2018, Ravi et al, 2015). Agonist induced platelet activation initiates a step change in energy requirements, and as a result, activated platelets exhibit increased oxidative phosphorylation and glycolysis to accommodate increased ATP demands (Kholmukhamedov and Jobe, 2019). Previous studies have observed that activated platelets show increased glycolysis relative to mitochondrial phosphorylation (Kramer, 2014).…”