Integrated 3D Simulation of Cardiomyocyte Revealed the Distinct Functional Characteristics between Subsarcolemmal and Interfibrillar Mitochondria

Abstract

It has been reported that two subpopulations of mitochondria exist in cardiomyocyte: subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). However, their functional characteristics have yet to be clarified, due to the experimental difficulties in differential isolation and assessment techniques. We have already developed a 3-D computational model of cardiomyocyte with subcellular structure integrating electrophysiology, metabolism, and mechanics. In this study, this model was further improved to include the intracellular gradient of oxygen and myoglobin distribution to test the hypothesis that the difference in location within the cell can introduce significant changes in mitochondrial metabolism. For this purpose, all mitochondria in the model were made to have the same membrane permeability and enzymatic activities. When compared the responses of [Ca2+], TCA activity, [NADH] and mitochondrial inner membrane potential to an abrupt changes in pacing frequency (0.25 Hz to 2 Hz) between SSM and IFM, IFM reached higher plateau levels in all of these parameters. These differences seemed to be related to the intracellular gradient in [Ca2+]. We also examined the effect of reduction in [O2]. Under normal condition intracellular [O2] is much higher than the half saturation concentration for oxidative phosphorylation even for the IFM located in the core region of the cell. However under limited extracellular [O2] environment, [NADH] and inner membrane potential gradually decreased in IFM compared to SSM reflecting the intracellular [O2] gradient from the cell surface to the core. Although further validations are required, the current simulation results suggested that only the difference in intracellular location can cause the different functional characteristics of mitochondrial metabolism in cardiomyocytes.