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Departments of
1 Biomedical Engineering
2 Physiology & Biophysics
3 Pediatrics
4 Center for Modelling Integrated Metabolic Systems, Case Western Reserve University Cleveland, OH 44106, USA
Ischaemia decreases mitochondrial NADH oxidation, activates glycolysis, increases the NADH/NAD+ ratio, and causes lactate production. The mechanisms that regulate anaerobic glycolysis and the NADH/NAD+ ratio during ischaemia are unclear. Although continuous measurements of metabolic fluxes and NADH/NAD+ in cytosol and mitochondria are not possible in vivo with current experimental techniques, computational models can be used to predict these variables by simulations with in silico experiments. Such predictions were obtained using a mathematical model of cellular metabolism in perfused myocardium. This model, which distinguishes cytosolic and mitochondrial domains, incorporates key metabolic species and processes associated with energy transfer. Simulation of metabolic responses to mild, moderate and severe ischaemia in large animals showed that mitochondrial NADH/NAD+ was rapidly reset to higher values in proportion to the reduced O2 delivery and myocardial oxygen consumption 
. Cytosolic NADH/NAD+, however, showed a biphasic response, with a sharp initial increase that was due to activation of glycogen breakdown and glycolysis, and corresponded with lactate production. Whereas the rate of glycolysis and the malate–aspartate shuttle had a significant effect on the cytosolic NADH/NAD+, their effects on the mitochondrial NADH/NAD+ were minimal. In summary, model simulations of the metabolic response to ischaemia showed that mitochondrial NADH/NAD+ is primarily determined by O2 consumption, while cytosolic NADH/NAD+ is largely a function of glycolytic flux during the initial phase, and is determined by mitochondrial NADH/NAD+ and the malate–aspartate shuttle during the steady state.
(Received 20 June 2005;
accepted after revision 10 October 2005;
first published online 13 October 2005)
Corresponding author M. E Cabrera: Pediatric Cardiology, Rainbow Babies and Children's Hospital 11100 Euclid Avenue, RBC-389 Cleveland, OH 44106-6011, USA. Email: mec6{at}case.edu
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