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

• Published in: The Korean journal of physiology & pharmacology Vol. 15; no. 4; pp. 217 - 239
• Main Authors: Youm, Jae-Boum, Choi, Seong-Woo, Jang, Chang-Han, Kim, Hyoung-Kyu, Leem, Chae-Hun, Kim, Na-Ri, Han, Jin
• Format: Journal Article
• Language: Korean
• Published: 대한생리학회-대한약리학회 01.01.2011; The Korean Journal of Physiology & Pharmacology Editorial Office
• Subjects: Mitochondria; Ca 2＋ transient; Rat ventricular myocytes; Computational model; Ca^{2+}$ transient
• ISSN: 1226-4512; 2093-3827

We carried out a series of experiment demonstrating the role of mitochondria in the cytosolic and mitochondrial $Ca^{2+}$ 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 [$Ca^{2+}]$ bigger in mitochondria as well as in cytosol. As L-type $Ca^{2+}$ channel has key influence on the amplitude of $Ca^{2+}$ -induced $Ca^{2+}$ release, the relation between stimulus frequency and the amplitude of $Ca^{2+}$ transients was examined under the low density (1/10 of control) of L-type $Ca^{2+}$ channel in model simulation, where the relation was reversed. In experiment, block of $Ca^{2+}$ uniporter on mitochondrial inner membrane significantly reduced the amplitude of mitochondrial $Ca^{2+}$ transients, while it failed to affect the cytosolic $Ca^{2+}$ transients. In computer simulation, the amplitude of cytosolic $Ca^{2+}$ transients was not affected by removal of $Ca^{2+}$ 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 [$Ca^{2+}$] in cytosol and eventually abolished the $Ca^{2+}$ transients, which was similarly reproduced in computer simulation. The model study suggests that the relative contribution of L-type $Ca^{2+}$ channel to total transsarcolemmal $Ca^{2+}$ flux could determine whether the cytosolic $Ca^{2+}$ transients become bigger or smaller with higher stimulus frequency. The present study also suggests that cytosolic $Ca^{2+}$ affects mitochondrial $Ca^{2+}$ in a beat-to-beat manner, however, removal of $Ca^{2+}$ influx mechanism into mitochondria does not affect the amplitude of cytosolic $Ca^{2+}$ transients.