A Spatiotemporal Ventricular Myocyte Model Incorporating Mitochondrial Calcium Cycling.

Biophys J

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; Department of Biomathematics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. Electronic address:

Published: December 2019

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

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990377PMC
http://dx.doi.org/10.1016/j.bpj.2019.09.005DOI Listing

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