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KCI등재 학술저널

A Computational Model of Cytosolic and Mitochondrial [Ca<SUP>2+</SUP>] in Paced Rat Ventricular Myocytes

A Computational Model of Cytosolic and Mitochondrial [Ca<SUP>2+</SUP>] in Paced Rat Ventricular Myocytes

We carried out a series of experiment demonstrating the role of mitochondria in the cytosolic and mitochondrial Ca<sup>2+</sup> transients and compared the results with those from computer simulation. In rat ventricular myocytes, increasing the rate of stimulation (1∼3 Hz) made both the diastolic and systolic [Ca<sup>2+</sup>] bigger in mitochondria as well as in cytosol. As L-type Ca<sup>2+</sup> channel has key influence on the amplitude of Ca<sup>2+</sup>-induced Ca<sup>2+</sup> release, the relation between stimulus frequency and the amplitude of Ca<sup>2+</sup> transients was examined under the low density (1/10 of control) of L-type Ca<sup>2+</sup> channel in model simulation, where the relation was reversed. In experiment, block of Ca<sup>2+</sup> uniporter on mitochondrial inner membrane significantly reduced the amplitude of mitochondrial Ca<sup>2+</sup> transients, while it failed to affect the cytosolic Ca<sup>2+</sup> transients. In computer simulation, the amplitude of cytosolic Ca<sup>2+</sup> transients was not affected by removal of Ca<sup>2+</sup> uniporter. The application of carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) known as a protonophore on mitochondrial membrane to rat ventricular myocytes gradually increased the diastolic [Ca<sup>2+</sup>] in cytosol and eventually abolished the Ca<sup>2+</sup> transients, which was similarly reproduced in computer simulation. The model study suggests that the relative contribution of L-type Ca<sup>2+</sup> channel to total transsarcolemmal Ca<sup>2+</sup> flux could determine whether the cytosolic Ca<sup>2+</sup> transients become bigger or smaller with higher stimulus frequency. The present study also suggests that cytosolic Ca<sup>2+</sup> affects mitochondrial Ca<sup>2+</sup> in a beat-to-beat manner, however, removal of Ca<sup>2+</sup> influx mechanism into mitochondria does not affect the amplitude of cytosolic Ca<sup>2+</sup> transients.

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