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In silico studies on the sensitivity of myocardial PCr/ATP to changes in mitochondrial enzyme activity and oxygen concentration

Citation

Edwards, LM and Ashrafian, H and Korzeniewski, B, In silico studies on the sensitivity of myocardial PCr/ATP to changes in mitochondrial enzyme activity and oxygen concentration, Molecular Biosystems, 7, (12) pp. 3335-3342. ISSN 1742-206X (2011) [Refereed Article]


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Copyright Statement

Copyright 2011 The Royal Society of Chemistry

DOI: doi:10.1039/C1MB05310H

Abstract

The ratio of myocardial phosphocreatine (PCr)/ATP reflects the balance of energy consumption and energy supply in the heart. It is reduced in a range of important physiological conditions including during and after acute hypoxia, after a prolonged visit to high-altitude, and in those suffering from both type 2 diabetes mellitus and various forms of heart failure. Yet despite its significance, the factors underlying the reduced PCr/ATP ratio seen in heart failure remain poorly understood. Given that oxidative phosphorylation is the only viable steady-state provider of ATP in the heart, the argument has been put forward that the observed reduction in myocardial PCr/ATP in all these conditions can be accounted for by some form of mitochondrial insufficiency. Thus we used a computer model of oxidative phosphorylation, coupled with creatine kinase, to study the effects of hypoxia and mitochondrial dysfunction on myocardial PCr/ATP. In physiological normoxia, all oxidative phosphorylation complexes, NADH supply and proton leak exerted comparable (of the same order of magnitude) control over PCr/ATP, as defined within Metabolic Control Analysis (MCA). Under hypoxia, the control increased considerably for all components of the system, especially for cytochrome oxidase and mitochondrial proton leak. Hypoxia alone, without any changes in other factors, exerted a pronounced effect on PCr/ATP. Our simulations support three important ideas: First, that mitochondrial abnormalities can contribute considerably to a blunted PCr/ATP; second, that hypoxia and mitochondrial dysfunction can interact in important ways to determine the energy status of the failing heart; and third, that hypoxia alone can account for significant decreases in cardiac PCr/ATP.

Item Details

Item Type:Refereed Article
Keywords:mitochondria, mitochondrial enzyme activity, mitochondrial dysfunction, oxygen, ATP, phosphocreatine, hypoxia, Metabolic Control Analysis, MCA
Research Division:Medical and Health Sciences
Research Group:Medical Biochemistry and Metabolomics
Research Field:Medical Biochemistry and Metabolomics not elsewhere classified
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Blood Disorders
Author:Edwards, LM (Dr Lindsay Edwards)
ID Code:78007
Year Published:2011
Web of Science® Times Cited:2
Deposited By:Medicine (Discipline)
Deposited On:2012-06-12
Last Modified:2012-08-30
Downloads:0

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