Mitochondria-derived ROS bursts disturb Ca2+ cycling and induce abnormal automaticity in guinea pig cardiomyocytes: a theoretical study
Mitochondria-derived ROS bursts disturb Ca2+ cycling and induce abnormal automaticity in guinea pig cardiomyocytes: a theoretical study
复制标题
DOI：
10.1152/ajpheart.00493.2014
复制
发表时间：
2015-03-15
影响因子：
4.8
通讯作者：
Zhou, Lufang
中科院分区：
文献类型：
--
作者：
Li, Qince;Su, Di;Zhou, Lufang
线粒体与氧化还原敏感的肌浆网(SR)、钙释放[RyRs(RyRs)]和摄取[Ca2+-ATPase(SERCA)]通道密切相关。因此，线粒体衍生的活性氧物种(MDRO)可能在调节心肌细胞内的钙循环中起着至关重要的作用。然而，在病理条件下，mdROS介导的钙调节异常是否会转化为异常的电活动，如果是，其潜在的离子机制是什么，还没有完全阐明。我们假设病理性MDRO通过调节肌浆网钙离子的处理来诱导钙离子升高，从而激活其他钙通道，进一步加剧钙离子调节失调，导致异常动作电位(AP)。我们还提出，诱发AP异常的形态依赖于MDRO诱导的时间、线粒体与SR之间的相互作用以及线粒体氧化应激的强度。为了验证这些假设，我们建立了一个多尺度的豚鼠心肌细胞模型，该模型结合了兴奋-收缩偶联、局部钙调控、线粒体能量学和ROS诱导的ROS释放。这个模型首次包括了线粒体-SR微域以及MDRO对RyR和SERCA活性的调节。模拟结果表明，MDRO爆发通过刺激RyRs和抑制SERCA而增加胞内钙离子，SERCA激活Na+/Ca~(2+)交换系统、Ca~(2+)敏感的非特异性阳离子通道和Ca~(2+)诱导的Ca~(2+)释放，引起异常AP。MDRO爆发诱导和AP放电之间的时间间隔、MDRO的剂量和扩散以及SR与线粒体的距离对AP的形态异常有很大影响。这项研究明确了MDRO在钙超载介导的心律失常发生中的作用，并强调了在设计新的抗心律失常治疗时考虑线粒体靶点的重要性。
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 mdROSmediated 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.