Platelets (PLTs) deteriorate over time when stored within blood banks through a biological process known as PLT storage lesion (PSL). Here, we describe the refinement of the biochemical model of PLT metabolism, iAT-PLT-636, and its application to describe and investigate changes in metabolism during PLT storage. Changes in extracellular acetate and citrate were measured in buffy coat and apheresis PLT units over 10 days of storage in the PLT additive solution T-Sol. Metabolic network analysis of these data was performed alongside our prior metabolomics data to describe the metabolism of fresh (days 1–3), intermediate (days 4–6), and expired (days 7–10) PLTs. Changes in metabolism were studied by comparing metabolic model flux predictions of iAT-PLT-636 between stages and between collection methods. Extracellular acetate and glucose contribute most to central carbon metabolism in PLTs. The anticoagulant citrate is metabolized in apheresis-stored PLTs and is converted into aconitate and, to a lesser degree, malate. The consumption of nutrients changes during storage and reflects altered PLT activation profiles following their collection. Irrespective of the collection method, a slowdown in oxidative phosphorylation takes place, consistent with mitochondrial dysfunction during PSL. Finally, the main contributors to intracellular ammonium and NADPH are highlighted. Future optimization of flux through these pathways provides opportunities to address intracellular pH changes and reactive oxygen species, which are both of importance to PSL. The metabolic models provide descriptions of PLT metabolism at steady state and represent a platform for future PLT metabolic research.
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Illustration of the role of glutathione in the inhibition of sickle hemoglobin polymerization: Two hemoglobin tetramers are shown in the surface representation and helical cartoon, wherein α and β globin chains are coloured magenta and cyan, respectively. The proximity of covalently bound glutathione to βCys93, represented as stick model, to the residues of the groove region is shown in yellow in the inset. βVal6 of the adjacent tetramer, the key residue in the polymerisation, is shown in spacefill model; For details, see pages 2153–2166. Image kindly provided by Amit Kumar Mandal.
Systems analysis of metabolism in platelet concentrates during storage in platelet additive solution
Freyr Jóhannsson, Steinn Guðmundsson, Giuseppe Paglia, Sveinn Guðmundsson, Bernhard Palsson, Ólafur E. Sigurjónsson, Óttar Rolfsson; Systems analysis of metabolism in platelet concentrates during storage in platelet additive solution. Biochem J 16 July 2018; 475 (13): 2225–2240. doi: https://doi.org/10.1042/BCJ20170921
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