Energy metabolism of platelets

Aibibula, Miriayi

Medicine
March 2017

Thesis or dissertation


Rights
© 2017 Miriayi Aibibula. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.
Abstract

Undesired platelet activation is associated with a number of diseases characterised by metabolic imbalance, such as hyperlipidaemia. Changes in platelet energy metabolism associated with disease states are unclear. This thesis presents a detailed investigation of platelet energy metabolism under normal physiological conditions as well as platelet mitochondrial dysfunction in hyperlipidaemia.

Platelets rapidly take up exogenous glucose at rest. Following platelet-thrombin activation, the secretion of ADP and TxA2 are the most glucose dependent processes. Platelets have a wide ‘scope’ for glycolysis, which reaches full capacity when activated with thrombin, mainly mediated by the PAR1 receptor. Despite being a major fuel for platelets, the absence of exogenous glucose is not able to prevent platelet adhesion, secretion and aggregation, suggesting metabolic redundancy and an important role for endogenous metabolic fuels. Furthermore, glycogen or endogenous fatty acids alone are sufficient to facilitate platelet activation. Moreover, activated platelets adopt a glycolytic phenotype regardless of extracellular fuel availability and irrespective of the thrombin dose.

Analysis of the mitochondrial function revealed remarkable fuel flexibility for platelets under normal physiological conditions. After identifying that amino acids have a minimal role as an oxidative fuel, it is further revealed that platelets can switch freely between glucose and fatty acid oxidation. Under conditions where these substrates are limited for mitochondrial oxidation, platelets can up-regulate glycolysis to meet the energy demand of activation. The transition of platelets from resting to an activated state is associated with an increase in mitochondrial oxygen consumption, despite the shift to a glycolytic state. Thrombin-stimulated platelets have higher ATP-coupled respiration and higher spare respiratory capacity. Interestingly, platelets from hyperlipidaemic mice show an increased mitochondrial proton leak and a complete loss of mitochondrial spare respiratory capacity.

This thesis presents for the first time the impact of high fat diet on the function of platelet mitochondria. The data are important in investigating the potential impact of altered platelet metabolism on disease outcome.

Publisher
Hull York Medical School, The University of Hull and The University of York
Supervisor
Sturmey, Roger; Naseem, Khalid
Sponsor (Organisation)
University of Hull
Qualification level
Doctoral
Qualification name
PhD
Language
English
Extent
12 MB
Identifier
hull:17367
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