Department of Medicine (Cardiology), David Geffen School of Medicine at University of California, Los Angeles, California, USA.
Biophys J. 2010 Apr 21;98(8):1428-38. doi: 10.1016/j.bpj.2009.12.4300.
Periodic cellwide depolarizations of mitochondrial membrane potential (PsiM) which are triggered by reactive oxygen species (ROS) and propagated by ROS-induced ROS release (RIRR) have been postulated to contribute to cardiac arrhythmogenesis and injury during ischemia/reperfusion. Two different modes of RIRR have been described: PsiM oscillations involving ROS-sensitive mitochondrial inner membrane anion channels (IMAC), and slow depolarization waves related to mitochondrial permeability transition pore (MPTP) opening. In this study, we developed a computational model of mitochondria exhibiting both IMAC-mediated RIRR and MPTP-mediated RIRR, diffusively coupled in a spatially extended network, to study the spatiotemporal dynamics of RIRR on PsiM. Our major findings are: 1), as the rate of ROS production increases, mitochondria can exhibit either oscillatory dynamics facilitated by IMAC opening, or bistable dynamics facilitated by MPTP opening; 2), in a diffusively-coupled mitochondrial network, the oscillatory dynamics of IMAC-mediated RIRR results in rapidly propagating (approximately 25 microm/s) cellwide PsiM oscillations, whereas the bistable dynamics of MPTP-mediated RIRR results in slow (0.1-2 microm/s) PsiM depolarization waves; and 3), the slow velocity of the MPTP-mediated depolarization wave is related to competition between ROS scavenging systems and ROS diffusion. Our observations provide mechanistic insights into the spatiotemporal dynamics underlying RIRR-induced PsiM oscillations and waves observed experimentally in cardiac myocytes.
周期性的线粒体膜电位去极化（PsiM），由活性氧（ROS）触发并通过 ROS 诱导的 ROS 释放（RIRR）传播，被认为有助于缺血/再灌注期间的心脏心律失常和损伤。已经描述了两种不同的 RIRR 模式：涉及 ROS 敏感的线粒体内膜阴离子通道（IMAC）的 PsiM 振荡，以及与线粒体通透性转换孔（MPTP）开放相关的缓慢去极化波。在这项研究中，我们开发了一个展示 IMAC 介导的 RIRR 和 MPTP 介导的 RIRR 的线粒体计算模型，这些模型在空间扩展的网络中扩散耦合，以研究 RIRR 在 PsiM 上的时空动力学。我们的主要发现是：1），随着 ROS 产生速率的增加，线粒体可以表现出由 IMAC 打开促进的振荡动力学，或由 MPTP 打开促进的双稳态动力学；2），在扩散耦合的线粒体网络中，IMAC 介导的 RIRR 的振荡动力学导致快速传播（约 25 微米/秒）的细胞 PsiM 振荡，而 MPTP 介导的 RIRR 的双稳态动力学导致缓慢（0.1-2 微米/秒）的 PsiM 去极化波；3），MPTP 介导的去极化波的缓慢速度与 ROS 清除系统和 ROS 扩散之间的竞争有关。我们的观察结果为实验中观察到的 RIRR 诱导的 PsiM 振荡和波的时空动力学提供了机制见解。
