Mitochondria-derived ROS bursts disturb Ca²⁺ cycling and induce abnormal automaticity in guinea pig cardiomyocytes: A theoretical study

Mitochondria are in close proximity to the redox-sensitive sarcoplasmic reticulum (SR) Ca²⁺ release [ryanodine receptors (RyRs)] and uptake [Ca²⁺-ATPase (SERCA)] channels. Thus mitochondria-derived reactive oxygen species (mdROS) could play a crucial role in modulating Ca²⁺ cycling in the cardiomyocytes. However, whether mdROS-mediated Ca²⁺ dysregulation translates to abnormal electrical activities under pathological conditions, and if yes what are the underlying ionic mechanisms, have not been fully elucidated. We hypothesize that pathological mdROS induce Ca²⁺ elevation by modulating SR Ca²⁺ handling, which activates other Ca²⁺ channels and further exacerbates Ca²⁺ dysregulation, leading to abnormal action potential (AP). We also propose that the morphologies of elicited AP abnormality rely on the time of mdROS induction, interaction between mitochondria and SR, and intensity of mitochondrial oxidative stress. To test the hypotheses, we developed a multiscale guinea pig cardiomyocyte model that incorporates excitation-contraction coupling, local Ca²⁺ control, mitochondrial energetics, and ROS-induced ROS release. This model, for the first time, includes mitochondria-SR microdomain and modulations of mdROS on RyR and SERCA activities. Simulations show that mdROS bursts increase cytosolic Ca²⁺ by stimulating RyRs and inhibiting SERCA, which activates the Na⁺/Ca²⁺ exchanger, Ca²⁺-sensitive nonspecific cationic channels, and Ca²⁺-induced Ca²⁺ release, eliciting abnormal AP. The morphologies of AP abnormality are largely influenced by the time interval among mdROS burst induction and AP firing, dosage and diffusion of mdROS, and SR-mitochondria distance. This study defines the role of mdROS in Ca²⁺ overload-mediated cardiac arrhythmogenesis and underscores the importance of considering mitochondrial targets in designing new antiarrhythmic therapies.