UCLA

Intracellular calcium (Ca²⁺) cycling dynamics in cardiac myocytes are spatiotemporally generated by stochastic events arising from a spatially distributed network of coupled Ca²⁺ release units that interact with an intertwined mitochondrial network. In this study, we developed a spatiotemporal ventricular myocyte model that integrates mitochondria-related Ca²⁺ cycling components into our previously developed ventricular myocyte model consisting of a three-dimensional Ca²⁺ release unit network. Mathematical formulations of mitochondrial membrane potential, mitochondrial Ca²⁺ cycling, mitochondrial permeability transition pore stochastic opening and closing, intracellular reactive oxygen species signaling, and oxidized Ca²⁺/calmodulin-dependent protein kinase II signaling were incorporated into the model. We then used the model to simulate the effects of mitochondrial depolarization on mitochondrial Ca²⁺ cycling, Ca²⁺ spark frequency, and Ca²⁺ amplitude, which agree well with experimental data. We also simulated the effects of the strength of mitochondrial Ca²⁺ uniporters and their spatial localization on intracellular Ca²⁺ cycling properties, which substantially affected diastolic and systolic Ca²⁺ levels in the mitochondria but exhibited only a small effect on sarcoplasmic reticulum and cytosolic Ca²⁺ levels under normal conditions. We show that mitochondrial depolarization can cause Ca²⁺ waves and Ca²⁺ alternans, which agrees with previous experimental observations. We propose that this new, to our knowledge, spatiotemporal ventricular myocyte model, incorporating properties of mitochondrial Ca²⁺ cycling and reactive-oxygen-species-dependent signaling, will be useful for investigating the effects of mitochondria on intracellular Ca²⁺ cycling and action potential dynamics in ventricular myocytes.