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.

Insights on the impact of mitochondrial organisation on bioenergetics in high-resolution computational models of cardiac cell architecture

“…We have studied the diffusion of phosphagens within the cell cross section using new, spatially detailed finite element models. Although finite element (FE) based computational models have been used to study the energy landscape in cardiac myocytes previously [10][11][12][13], these models defined idealised geometric domains (crystalline mitochondria or rectangular grid-like arrangements) and did not account for the mitochondrial clustering and non-uniform distribution that we observe in our data (Fig 1.). The simulations and analyses in our study were conducted using three cross-section images that were selected from different positions within a 3D serial block-face scanning electron microscopy (SBF-SEM) dataset of a single control cardiomyocyte (Fig 1).…”

“…The phosphocreatine shuttle enables rapid transport of inorganic phosphate from the vicinity of mitochondria to the vicinity of myofibrils, where it is used for muscle contraction in the form of ATP. Models such as [10][11][12][13], have only studied the role that phosphocreatine shuttle plays in the context of a uniform or crystalline distribution of mitochondria. To the authors' knowledge no spatially realistic computational model has yet examined how oxygen supply and distribution across the cell cross section (or lack thereof in hypoxic conditions) might also interact with the phosphocreatine shuttle mechanism to facilitate uniform supply of ATP.…”

Exploring the mitochondrial microRNA import pathway through Polynucleotide Phosphorylase (PNPase)

“…Our laboratory and others have shown that the assault to the transcript can occur in both the cytosol and mitochondria within the cardiomyocyte [44,50]. Cardiac mitochondrial subpopulations have previously been shown to have distinct functional differences [37,47,49,87]. Our laboratory has shown that during type 1 diabetes mellitus, mitochondria located between the myofibrils, interfibrillar mitochondria (IFM), are negatively impacted to a greater extent, while the mitochondria residing directly below the sarcolemmal membrane, subsarcolemmal mitochondria (SSM), are predominantly affected during type 2 diabetes mellitus [8–10,22–25,50,88].…”

Three‐dimensional electron microscopy techniques for unravelling mitochondrial dysfunction in heart failure and identification of new pharmacological targets

“…Significantly, TEM studies have revealed that cristae morphology varies between cardiac mitochondrial populations; SSM are reported to have a lamelliform cristae (Shimada et al, ; Riva et al, ; Hollander et al, ), whereas IFM and PNM are thought to mostly have tubular cristae (Riva et al, ). Moreover, several groups have proposed that there are functional differences between each population; for example, IFM are shown to have higher respiration rates and ATP production, which may be an adaptation/optimization for facilitating muscle contraction (Schwarzer et al, ; Hatano et al, ). Crochemore et al .…”