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.
Highlights
Delayed afterdepolarizations (DADs) are abnormal depolarizations during the diastolic phase following an action potential (AP) and could trigger cardiac arrhythmias (Rosen et al, 1984; January and Fozzard, 1988; Katra and Laurita, 2005; Qu et al, 2014; Song et al, 2017)
We investigated the impact of mitochondrial depolarizations on the occurrence of Ca2+ waves and delayed afterdepolarizations (DADs) via mitochondrial permeability transition pores (mPTPs) opening
We used a physiological detailed ventricular myocyte model consisting of a 3D network of coupled Ca2+ release units (CRUs) and mitochondria to investigate the roles of mitochondrial depolarization via mPTP opening in the genesis of DADs
Summary
Delayed afterdepolarizations (DADs) are abnormal depolarizations during the diastolic phase following an action potential (AP) and could trigger cardiac arrhythmias (Rosen et al, 1984; January and Fozzard, 1988; Katra and Laurita, 2005; Qu et al, 2014; Song et al, 2017). DADs are known to be caused by spontaneous calcium (Ca2+) waves (Rosen et al, 1984; Marban et al, 1986; January and Fozzard, 1988), occurring due to spontaneous Ca2+ release from the intracellular Ca2+ store, Mitochondrial Regulation of Delayed Afterdepolarizations sarcoplasmic reticulum (SR), via the ryanodine receptors (RyRs). Exchanger (NCX) and taken back to the SR through sarcoplasmic reticulum Ca2+-ATPase (SERCA) Mitochondria, as another Ca2+ store, are involved in intracellular Ca2+ cycling via mitochondrial Ca2+ uniporter (MCU; Baughman et al, 2011; De Stefani et al, 2011), mitochondrial Na+-Ca2+
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
