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Arrhythmogenic Ca<jats:sup>2+<\/jats:sup>alternans in cardiac myocytes has been observed in experiments under abnormal mitochondrial depolarization. However, complex signaling pathways and Ca<jats:sup>2+<\/jats:sup>cycling between mitochondria and cytosol make it difficult in experiments to reveal the underlying mechanisms of Ca<jats:sup>2+<\/jats:sup>alternans under abnormal mitochondrial depolarization. In this study, we use a newly developed spatiotemporal ventricular myocyte computer model that integrates mitochondrial Ca<jats:sup>2+<\/jats:sup>cycling and complex signaling pathways to investigate the mechanisms of Ca<jats:sup>2+<\/jats:sup>alternans during mitochondrial depolarization. We find that elevation of ROS in response to mitochondrial depolarization plays a critical role in promoting Ca<jats:sup>2+<\/jats:sup>alternans. Further examination reveals that the redox effect of ROS on ryanodine receptors and sarco\/endoplasmic reticulum Ca<jats:sup>2+<\/jats:sup>-ATPase synergistically promote alternans. Upregulation of mitochondrial Ca<jats:sup>2+<\/jats:sup>uniporter promotes Ca<jats:sup>2+<\/jats:sup>alternans via Ca<jats:sup>2+<\/jats:sup>-dependent mitochondrial permeability transition pore opening. Due to their relatively slow kinetics, oxidized Ca<jats:sup>2+<\/jats:sup>\/calmodulin-dependent protein kinase II activation and ATP do not play significant roles acutely in the genesis of Ca<jats:sup>2+<\/jats:sup>alternans after mitochondrial depolarization, but their roles can be significant in the long term, mainly through their effects on sarco\/endoplasmic reticulum Ca<jats:sup>2+<\/jats:sup>-ATPase activity. In conclusion, mitochondrial depolarization promotes Ca<jats:sup>2+<\/jats:sup>alternans acutely via the redox effect of ROS and chronically by ATP reduction. It suppresses Ca<jats:sup>2+<\/jats:sup>alternans chronically through oxidized Ca<jats:sup>2+<\/jats:sup>\/calmodulin-dependent protein kinase II activation.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008624","type":"journal-article","created":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T18:54:36Z","timestamp":1611600876000},"page":"e1008624","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Mitochondrial depolarization promotes calcium alternans: Mechanistic insights from a ventricular myocyte 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