Synchronized whole cell oscillations in mitochondrial metabolism triggered by a local release of reactive oxygen species in cardiac myocytes
Synchronized whole cell oscillations in mitochondrial metabolism triggered by a local release of reactive oxygen species in cardiac myocytes
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DOI：
10.1074/jbc.m302673200
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发表时间：
2003-11-07
影响因子：
4.8
通讯作者：
O'Rourke, B
中科院分区：
文献类型：
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作者：
Aon, MA;Cortassa, S;O'Rourke, B
活性氧(ROS)和/或钙超载可引发线粒体内膜电位(DeltaPsi(M))的去极化和细胞损伤。关于少数线粒体中DeltaPsi(M)的丢失如何影响细胞的整体功能，人们知之甚少。在这里，我们利用双光子显微镜的窄焦激发体积来观察局部线粒体去极化对豚鼠心室肌细胞的影响。值得注意的是，单个局部激光闪光在延迟约40s后，在超过70%的线粒体群体中触发了DeltaPsi(M)、NADH和ROS的同步和自我维持的振荡。只有在线粒体产生的ROS超过特定的阈值水平后，振荡才会启动，并且不涉及经典的通透性转换孔或细胞内钙超载。几种呼吸抑制剂或一种超氧化物歧化酶模拟物可以消除这种同步的转变。阴离子通道抑制剂增强了基质ROS在闪光区的积累，但阻止了向心肌细胞其余部分的传播，这表明内膜，超氧化物通透性，阴离子通道开放，以响应自由基。线粒体能量学的跃迁与肌膜K-ATP电流的激活紧密耦合，导致动作电位时程的振荡，从而可能导致缺血再灌注损伤时的灾难性心律失常。
Reactive oxygen species (ROS) and/or Ca2+ overload can trigger depolarization of mitochondrial inner membrane potential (DeltaPsi(m)) and cell injury. Little is known about how loss of DeltaPsi(m) in a small number of mitochondria might influence the overall function of the cell. Here we employ the narrow focal excitation volume of the two-photon microscope to examine the effect of local mitochondrial depolarization in guinea pig ventricular myocytes. Remarkably, a single local laser flash triggered synchronized and self-sustained oscillations in DeltaPsi(m), NADH, and ROS after a delay of similar to40s, in more than 70% of the mitochondrial population. Oscillations were initiated only after a specific threshold level of mitochondrially produced ROS was exceeded, and did not involve the classical permeability transition pore or intracellular Ca2+ overload. The synchronized transitions were abolished by several respiratory inhibitors or a superoxide dismutase mimetic. Anion channel inhibitors potentiated matrix ROS accumulation in the flashed region, but blocked propagation to the rest of the myocyte, suggesting that an inner membrane, super-oxide-permeable, anion channel opens in response to free radicals. The transitions in mitochondrial energetics were tightly coupled to activation of sarcolemmal K-ATP currents, causing oscillations in action potential duration, and thus might contribute to catastrophic arrhythmias during ischemia-reperfusion injury.