Mitochondria-Derived Ros Disturb Ca2+ Cycling and Evoke Abnormal Action Potentials in Guinea-Pig Ventricular Myocytes: A Theoretical Study

Abstract

Abnormal Ca2+ handling often results in contractile dysfunction and ventricular arrhythmias, the leading causes of sudden cardiac death. However, in spite of extensive efforts, the molecular mechanisms underlying disturbance of Ca2+ cycling are not completely understood, hindering the development of effective antiarrhythmic therapies. Accompanying dysfunctional Ca2+ handling, increased mitochondrial reactive oxygen species (ROS) production is also observed in the diseased heart. Since mitochondria are in close proximity to the redox-sensitive sarcoplasmic reticulum (SR) Ca2+ release channels (ryanodine receptors, RyRs) and the SR Ca2+ ATPase (SERCA), mitochondria-derived ROS could play a crucial role in modulating Ca2+ cycling under pathological conditions. Previous work has shown that mitochondrial depolarization and ROS-induced ROS release significantly enhance spontaneous SR Ca2+ release (Ca2+ spark frequency) in resting myocytes, but the role of mitochondria-derived ROS on Ca2+ dynamics and action potentials in paced cardiac myocytes has not been examined. We hypothesize that the pathological mitochondrial ROS burst forms a ROS microdomain between mitochondria and SR, altering the proximal SR Ca2+ handling channels and consequently leading to disturbed Ca2+ cycling and abnormal electrical activity. To test this hypothesis, we developed a new multiscale myocyte model that incorporates mitochondria and local Ca2+ control, and links RyRs and SERCA to the ROS environment surrounding the SR. The simulations show that the mitochondria-derived ROS burst stimulates RyRs and inhibits SERCA, inducing a cytosolic Ca2+ ([Ca2+]i) transient. This extra [Ca2+]i transient activates the Na+/Ca2+ exchanger and Ca2+-sensitive nonspecific cationic channels, forming a transient inward current (Iti) that evokes early or delayed afterdepolarizations. This study defines the role of mitochondria-derived ROS in Ca2+ overload-mediated ventricular arrhythmias, and underscores the importance of considering mitochondrial targets in designing new antiarrhythmic drugs in the context of sudden cardiac death.