Key result
A new spatiotemporal ventricular myocyte model demonstrated that mitochondrial depolarization can cause Ca2+ waves and Ca2+ alternans, agreeing with experimental observations.
A newly developed spatiotemporal ventricular myocyte model successfully simulates the effects of mitochondrial depolarization on intracellular calcium cycling, providing a tool for investigating mitochondrial impacts on action potential dynamics.
Mitochondrial depolarization may promote Ca2+ instability in myocytes; extends in silico tools but leaves open in vivo and clinical relevance.
Intracellular calcium (Ca 2+ ) cycling dynamics in cardiac myocytes are spatiotemporally generated by stochastic events arising from a spatially distributed network of coupled Ca 2+ release units (CRUs) that interact with an intertwined mitochondrial network. In this study, we developed a spatiotemporal ventricular myocyte model that integrates mitochondria-related Ca 2+ cycling components into our previously developed ventricular myocyte model consisting of a 3-dimensional CRU network. Mathematical formulations of mitochondrial membrane potential, mitochondrial Ca 2+ cycling, mitochondrial permeability transition pore (MPTP) stochastic opening and closing, intracellular reactive oxygen species (ROS) signaling, and oxidized Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) signaling were incorporated into the model. We then used the model to simulate the effects of mitochondrial depolarization on mitochondrial Ca 2+ cycling, Ca 2+ spark frequency and amplitude, which agree well with experimental data. We also simulated the effects of the strength of mitochondrial Ca 2+ uniporters and their spatial localization on intracellular Ca 2+ cycling properties, which substantially affected diastolic and systolic Ca 2+ levels in the mitochondria but exhibited only a small effect on sarcoplasmic reticulum and cytosolic Ca 2+ levels under normal conditions. We show that mitochondrial depolarization can cause Ca 2+ waves and Ca 2+ alternans, which agrees with previous experimental observations. We propose that this new spatiotemporal ventricular myocyte model, incorporating properties of mitochondrial Ca 2+ cycling and ROS-dependent signaling, will be useful for investigating the effects of mitochondria on intracellular Ca 2+ cycling and action potential dynamics in ventricular myocytes.
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Song et al. (2019) studied this question. Spatiotemporal ventricular myocyte model was evaluated on Effects of mitochondrial depolarization on mitochondrial Ca2+ cycling, Ca2+ spark frequency and amplitude. A new spatiotemporal ventricular myocyte model demonstrated that mitochondrial depolarization can cause Ca2+ waves and Ca2+ alternans, agreeing with experimental observations.
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