Modeling the mechanism of metabolic oscillations in ischemic cardiac myocytes.
Oscillations in energy metabolism have been observed in a variety of cells under metabolically deprived conditions such as ischemia. In cardiac ventricular myocytes these metabolic oscillations may cause oscillations in the action potential duration, creating the potential for cardiac arrhythmias during ischemia (O'Rourke, 2000). A mathematical model of the mechanism behind metabolic oscillations is developed here. The model consists of descriptions of the mitochondrial components that regulate mitochondrial membrane potential (Psi), mitochondrial inorganic phosphate concentration, mitochondrial magnesium concentration, and cellular NADH and NAD(+) concentrations. Using parameters from the experimental literature, the model produces physiological values for these both under normoxic (steady state) and ischemic (oscillatory) conditions. The model includes the mitochondrial inner membrane anion channel (IMAC), the centum picosiemen channel (mCS), the phosphate carrier (PIC), and the respiration driven proton pumps. The model suggests that these are the essential components for producing oscillations with mCS essential for the rapid depolarization, PIC for the recovery from depolarization, and IMAC for the slow depolarization between depolarization peaks. A decrease of the inner membrane potential due to ischemia or experimental conditions seems to be a triggering factor for the oscillations. The model simulates the experimental observations that high levels of mitochondrial ADP and ATP abolish the oscillations, as does inhibition of electron transport. The model makes predictions on the influence of pH and magnesium levels on metabolic oscillations.
Saleet Jafri
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Department of Bioinformatics and Computational Biology, George Mason University, Manassas, VA 20110, USA. sjafri@gmu.edu <sjafri@gmu.edu>
Kotulska
Malgorzata
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D001683:Biological Clocks; D003198:Computer Simulation; D004734:Energy Metabolism; D006801:Humans; D008929:Mitochondria, Heart / Q000378:metabolism; D008955:Models, Cardiovascular; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*