Li Qince, Su Di, O'Rourke Brian, Pogwizd Steven M, Zhou Lufang
Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Cardiac Rhythm Management Laboratory, University of Alabama at Birmingham, Birmingham, Alabama; and.
Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland.
Am J Physiol Heart Circ Physiol. 2015 Mar 15;308(6):H623-36. doi: 10.1152/ajpheart.00493.2014. Epub 2014 Dec 24.
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.
线粒体与对氧化还原敏感的肌浆网（SR）钙释放[雷诺丁受体（RyRs）]和摄取[钙 - ATP酶（SERCA）]通道紧密相邻。因此，线粒体衍生的活性氧（mdROS）可能在调节心肌细胞钙循环中起关键作用。然而，在病理条件下，mdROS介导的钙失调是否会转化为异常电活动，如果是，其潜在的离子机制是什么，尚未完全阐明。我们假设病理性mdROS通过调节SR钙处理诱导钙升高，这会激活其他钙通道并进一步加剧钙失调，导致异常动作电位（AP）。我们还提出，引发的AP异常形态取决于mdROS诱导时间、线粒体与SR之间的相互作用以及线粒体氧化应激强度。为了验证这些假设，我们建立了一个多尺度豚鼠心肌细胞模型，该模型纳入了兴奋 - 收缩偶联、局部钙控制、线粒体能量学以及ROS诱导的ROS释放。该模型首次包括线粒体 - SR微区以及mdROS对RyR和SERCA活性的调节。模拟结果表明，mdROS爆发通过刺激RyRs和抑制SERCA增加胞质钙，这会激活钠/钙交换器、钙敏感的非特异性阳离子通道以及钙诱导的钙释放，引发异常AP。AP异常形态在很大程度上受mdROS爆发诱导与AP发放之间的时间间隔、mdROS的剂量和扩散以及SR - 线粒体距离的影响。本研究确定了mdROS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疗法时考虑线粒体靶点的重要性。
