A Computational Model of Cytosolic and Mitochondrial [Ca²] in Paced Rat Ventricular Myocytes.

Jae Boum Youm; Seong Woo Choi; Chang Han Jang; Hyoung Kyu Kim; Chae Hun Leem; Nari Kim; Jin Han

We carried out a series of experiment demonstrating the role of mitochondria in the cytosolic and mitochondrial Ca2 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 [Ca2 ] bigger in mitochondria as well as in cytosol. As L-type Ca2 channel has key influence on the amplitude of Ca2 -induced Ca2 release, the relation between stimulus frequency and the amplitude of Ca2 transients was examined under the low density (1/10 of control) of L-type Ca2 channel in model simulation, where the relation was reversed. In experiment, block of Ca2 uniporter on mitochondrial inner membrane significantly reduced the amplitude of mitochondrial Ca2 transients, while it failed to affect the cytosolic Ca2 transients. In computer simulation, the amplitude of cytosolic Ca2 transients was not affected by removal of Ca2 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 [Ca2 ] in cytosol and eventually abolished the Ca2 transients, which was similarly reproduced in computer simulation. The model study suggests that the relative contribution of L-type Ca2 channel to total transsarcolemmal Ca2 flux could determine whether the cytosolic Ca2 transients become bigger or smaller with higher stimulus frequency. The present study also suggests that cytosolic Ca2 affects mitochondrial Ca2 in a beat-to-beat manner, however, removal of Ca2 influx mechanism into mitochondria does not affect the amplitude of cytosolic Ca2 transients.

MITOCHONDRIA; MUSCLE cells; COMPUTER simulation; SIMULATION methods & models; CYTOSOL

Korean Journal of Physiology & Pharmacology, 2011, Vol 15, Issue 4, p217

1226-4512

Academic Journal

10.4196/kjpp.2011.15.4.217