Mitochondrial depolarization promotes calcium alternans: Mechanistic insights from a ventricular myocyte model

Mitochondria are vital organelles inside the cell and contribute to intracellular calcium (Ca(2+)) dynamics directly and indirectly via calcium exchange, ATP generation, and production of reactive oxygen species (ROS). Arrhythmogenic Ca(2+) alternans in cardiac myocytes has been observed in experiments under abnormal mitochondrial depolarization. However, complex signaling pathways and Ca(2+) cycling between mitochondria and cytosol make it difficult in experiments to reveal the underlying mechanisms of Ca(2+) alternans under abnormal mitochondrial depolarization. In this study, we use a newly developed spatiotemporal ventricular myocyte computer model that integrates mitochondrial Ca(2+) cycling and complex signaling pathways to investigate the mechanisms of Ca(2+) alternans during mitochondrial depolarization. We find that elevation of ROS in response to mitochondrial depolarization plays a critical role in promoting Ca(2+) alternans. Further examination reveals that the redox effect of ROS on ryanodine receptors and sarco/endoplasmic reticulum Ca(2+)-ATPase synergistically promote alternans. Upregulation of mitochondrial Ca(2+) uniporter promotes Ca(2+) alternans via Ca(2+)-dependent mitochondrial permeability transition pore opening. Due to their relatively slow kinetics, oxidized Ca(2+)/calmodulin-dependent protein kinase II activation and ATP do not play significant roles acutely in the genesis of Ca(2+) alternans after mitochondrial depolarization, but their roles can be significant in the long term, mainly through their effects on sarco/endoplasmic reticulum Ca(2+)-ATPase activity. In conclusion, mitochondrial depolarization promotes Ca(2+) alternans acutely via the redox effect of ROS and chronically by ATP reduction. It suppresses Ca(2+) alternans chronically through oxidized Ca(2+)/calmodulin-dependent protein kinase II activation.