AUTHOR=Pandey Vikas , Xie Lai-Hua , Qu Zhilin , Song Zhen TITLE=Mitochondrial Contributions in the Genesis of Delayed Afterdepolarizations in Ventricular Myocytes JOURNAL=Frontiers in Physiology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2021.744023 DOI=10.3389/fphys.2021.744023 ISSN=1664-042X ABSTRACT=

Mitochondria fulfill the cell’s energy demand and affect the intracellular calcium (Ca2+) dynamics via direct Ca2+ exchange, the redox effect of reactive oxygen species (ROS) on Ca2+ handling proteins, and other signaling pathways. Recent experimental evidence indicates that mitochondrial depolarization promotes arrhythmogenic delayed afterdepolarizations (DADs) in cardiac myocytes. However, the nonlinear interactions among the Ca2+ signaling pathways, ROS, and oxidized Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathways make it difficult to reveal the mechanisms. Here, we use a recently developed spatiotemporal ventricular myocyte computer model, which consists of a 3-dimensional network of Ca2+ release units (CRUs) intertwined with mitochondria and integrates mitochondrial Ca2+ signaling and other complex signaling pathways, to study the mitochondrial regulation of DADs. With a systematic investigation of the synergistic or competing factors that affect the occurrence of Ca2+ waves and DADs during mitochondrial depolarization, we find that the direct redox effect of ROS on ryanodine receptors (RyRs) plays a critical role in promoting Ca2+ waves and DADs under the acute effect of mitochondrial depolarization. Furthermore, the upregulation of mitochondrial Ca2+ uniporter can promote DADs through Ca2+-dependent opening of mitochondrial permeability transition pores (mPTPs). Also, due to much slower dynamics than Ca2+ cycling and ROS, oxidized CaMKII activation and the cytosolic ATP do not appear to significantly impact the genesis of DADs during the acute phase of mitochondrial depolarization. However, under chronic conditions, ATP depletion suppresses and enhanced CaMKII activation promotes Ca2+ waves and DADs.