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

Qince Li, Di Su, Brian O’Rourke, Steven M. Pogwizd, Lufang Zhou

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)H623-H636
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume308
Issue number6
DOIs
StatePublished - Mar 15 2015

Keywords

  • Arrhythmias
  • Computational modeling
  • Mitochondria
  • ROS-induced Ca release
  • Reactive oxygen species
  • Ryanodine receptors

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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