title: Distinct functional roles of cardiac mitochondrial subpopulations revealed by a 3D simulation model.
abstract: Experimental characterization of two cardiac mitochondrial subpopulations, namely, subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM), has been hampered by technical difficulties, and an alternative approach is eagerly awaited. We previously developed a three-dimensional computational cardiomyocyte model that integrates electrophysiology, metabolism, and mechanics with subcellular structure. In this study, we further developed our model to include intracellular oxygen diffusion, and determined whether mitochondrial localization or intrinsic properties cause functional variations. For this purpose, we created two models: one with equal SSM and IFM properties and one with IFM having higher activity levels. Using these two models to compare the SSM and IFM responses of [Ca(2+)], tricarboxylic acid cycle activity, [NADH], and mitochondrial inner membrane potential to abrupt changes in pacing frequency (0.25-2 Hz), we found that the reported functional differences between these subpopulations appear to be mostly related to local [Ca(2+)] heterogeneity, and variations in intrinsic properties only serve to augment these differences. We also examined the effect of hypoxia on mitochondrial function. Under normoxic conditions, intracellular oxygen is much higher throughout the cell than the half-saturation concentration for oxidative phosphorylation. However, under limited oxygen supply, oxygen is mostly exhausted in SSM, leaving the core region in an anoxic condition. Reflecting this heterogeneous oxygen environment, the inner membrane potential continues to decrease in IFM, whereas it is maintained to nearly normal levels in SSM, thereby ensuring ATP supply to this region. Our simulation results provide clues to understanding the origin of functional variations in two cardiac mitochondrial subpopulations and their differential roles in maintaining cardiomyocyte function as a whole.
authors.affiliation: Department of Mechanical Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan. Electronic address: hatano@fml.t.u-tokyo.ac.jp.
authors.forename: Asuka
authors.initials: A
authors.lastname: Hatano
authors.affiliation: Department of Human and Engineered Environmental Studies, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Okada
authors.affiliation: Department of Human and Engineered Environmental Studies, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Washio
authors.affiliation: Department of Human and Engineered Environmental Studies, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hisada
authors.affiliation: Department of Human and Engineered Environmental Studies, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
authors.forename: Seiryo
authors.initials: S
authors.lastname: Sugiura
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002463:Cell Membrane Permeability; D004058:Diffusion; D008929:Mitochondria, Heart / Q000378:metabolism*; D008954:Models, Biological; D009200:Myocardial Contraction; D009243:NAD / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D051381:Rats
chemical_list: D009243:NAD; D010100:Oxygen