In:
American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 308, No. 6 ( 2015-03-15), p. H623-H636
Abstract:
Mitochondria are in close proximity to the redox-sensitive sarcoplasmic reticulum (SR) Ca 2+ release [ryanodine receptors (RyRs)] and uptake [Ca 2+ -ATPase (SERCA)] channels. Thus mitochondria-derived reactive oxygen species (mdROS) could play a crucial role in modulating Ca 2+ cycling in the cardiomyocytes. However, whether mdROS-mediated Ca 2+ 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 Ca 2+ elevation by modulating SR Ca 2+ handling, which activates other Ca 2+ channels and further exacerbates Ca 2+ 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 Ca 2+ 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 Ca 2+ by stimulating RyRs and inhibiting SERCA, which activates the Na + /Ca 2+ exchanger, Ca 2+ -sensitive nonspecific cationic channels, and Ca 2+ -induced Ca 2+ 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 Ca 2+ overload-mediated cardiac arrhythmogenesis and underscores the importance of considering mitochondrial targets in designing new antiarrhythmic therapies.
Type of Medium:
Online Resource
ISSN:
0363-6135
,
1522-1539
DOI:
10.1152/ajpheart.00493.2014
Language:
English
Publisher:
American Physiological Society
Publication Date:
2015
detail.hit.zdb_id:
1477308-9
SSG:
12
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