Mechanistic model of cardiac energy metabolism predicts localization of glycolysis to cytosolic subdomain during ischemia

Abstract

The model has three distinct domains (blood, cytosol, and mitochondria) with interdomain transport of chemical species. In addition to distinguishing between cytosol and mitochondria, the model includes a subdomain in the cytosol to account for glycolytic metabolic channeling. Myocardial ischemia was induced by a 60% reduction in coronary blood flow, and model simulations were compared with experimental data from anesthetized pigs. Simulations with a previous model without compartmentation showed a slow activation of glycogen breakdown and delayed lactate production compared with experimental results. The addition of a subdomain for glycolysis resulted in simulations showing faster rates of glycogen breakdown and lactate production that closely matched in vivo experimental data. The dynamics of redox (NADH/NAD ϩ ) and phosphorylation (ADP/ATP) states were also simulated. These controllers are coupled to energy transfer reactions and play key regulatory roles in the cytosol and mitochondria. Simulations showed a similar dynamic response of the mitochondrial redox state and the rate of pyruvate oxidation during ischemia. In contrast, the cytosolic redox state displayed a time response similar to that of lactate production. In conclusion, this novel mechanistic model effectively predicted the rapid activation of glycogen breakdown and lactate production at the onset of ischemia and supports the concept of localization of glycolysis to a subdomain of the cytosol. redox state; computer simulation; cytosol; mitochondria; metabolic channeling THE PRIMARY EFFECT of myocardial ischemia is impaired oxidative phosphorylation due to decreased oxygen delivery to the mitochondria (68). Reduced aerobic ATP production stimulates glycogen breakdown and ATP formation from glycolysis in the cytosol and results in lactate accumulation in the tissue (52, 68). Various metabolites related to energy transfer (e.g., NADH-NAD ϩ and ADP-ATP) act as modulators of key reactions in the cytosol and mitochondria but have different concentrations in these cellular domains. For example, under aerobic conditions, 5-10% of total ATP (10, 62) and 90% of the NAD ϩ and NADH (61) are in the mitochondria. On the basis of this evidence, it is inappropriate to assume the same concentrations of these metabolites in the cytosol and mitochondria when studying mechanisms controlling glycolysis and lactate metabolism from normal to ischemic conditions. Furthermore, it has been observed that key glycolytic enzymes are bound together in specific intracellular structures to form a multienzyme complex near the sarcolemma and sarcoplasmic reticulum (8,19,42). Because the glycolytic enzymes are not freely distributed, glycolysis can be considered localized in a subdomain within the cytosol.Unfortunately, at present, it is not feasible to measure dynamic changes in the fluxes and concentrations of key cytosolic and mitochondrial species in the transition from normal to ischemic conditions with current experimental techniques. As an alternate approach to conducting e...

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