The effect of bioenergetic impairment of cytosolic processes in spatio-temporal Ca2+ dynamics in a three-dimensional cardiomyocyte model

Abstract

The heart consumes large amounts of energy with each beat. Mitochondria are the source of over 95% of this energy in the form of ATP and rely on increased Ca2+ uptake to stimulate production in times of increased work. Ca2+ uptake into the mitochondria primarily occurs within microdomains. Structural remodeling associated with heart failure may disrupt these microdomains leading to impaired mitochondrial Ca2+ uptake and energetic impairment. To investigate the effect of structural changes on single cell behavior, a model describing mitochondrial dynamics and energetics production is modified and incorporated into a recently developed three-dimensional model of spatio-temporal calcium handling, which preserves microdomain structure and incorporates stochastic processes in Ca2+ handling protein kinetics. Modifications to the mitochondria model included a reformulation of mitochondrial Ca2+ uniporter uptake, making it suitable for concentrations in microdomains. With this model we demonstrate the importance of an ordered structure within the cell for normal function. Changes in the arrangement of mitochondria can have a pronounced effect on intracellular Ca2+ dynamics through their energetic regulation of SERCA, leading to spatially heterogeneous sarcoplasmic reticulum uptake and loading.