A mitochondrial oscillator dependent on reactive oxygen species
A mitochondrial oscillator dependent on reactive oxygen species
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DOI：
10.1529/biophysj.104.041749
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发表时间：
2004-09-01
影响因子：
3.4
通讯作者：
O'Rourke, B
中科院分区：
文献类型：
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作者：
Cortassa, S;Aon, MA;O'Rourke, B
我们描述了一个独特的线粒体振荡器，依赖于氧化磷酸化，活性氧（ROS），和线粒体内膜离子通道。最近在分离的心肌细胞中描述了线粒体膜电位（DeltaPsi（m））、NADH和ROS产生的全细胞同步振荡，并且我们假设通过内膜阴离子通道的超氧阴离子流出和细胞内ROS清除能力之间的平衡在振荡机制中起关键作用。在这里，我们正式测试的假设，使用线粒体能量学和Ca 2+处理，包括线粒体活性氧的生产，细胞质活性氧清除，和活性氧激活内膜阴离子通量的计算模型。数学模型再现了DeltaPsi（m），NADH和ROS中观察到的振荡的周期和相位。此外，我们通过实验验证模型预测，振荡器的周期可以通过改变ROS清除剂的浓度或氧化磷酸化的速率来调制，并且谷胱甘肽池的氧化还原状态振荡。除了它在代谢应激期间的细胞功能障碍中的作用之外，振荡器的周期可以显示为跨越很宽的范围，从毫秒到小时，这表明它也可能是生理计时和/或氧化还原信号的机制。
We describe a unique mitochondrial oscillator that depends on oxidative phosphorylation, reactive oxygen species (ROS), and mitochondrial inner membrane ion channels. Cell-wide synchronized oscillations in mitochondrial membrane potential (DeltaPsi(m)), NADH, and ROS production have been recently described in isolated cardiomyocytes, and we have hypothesized that the balance between superoxide anion efflux through inner membrane anion channels and the intracellular ROS scavenging capacity play a key role in the oscillatory mechanism. Here, we formally test the hypothesis using a computational model of mitochondrial energetics and Ca2+ handling including mitochondrial ROS production, cytoplasmic ROS scavenging, and ROS activation of inner membrane anion flux. The mathematical model reproduces the period and phase of the observed oscillations in DeltaPsi(m), NADH, and ROS. Moreover, we experimentally verify model predictions that the period of the oscillator can be modulated by altering the concentration of ROS scavengers or the rate of oxidative phosphorylation, and that the redox state of the glutathione pool oscillates. In addition to its role in cellular dysfunction during metabolic stress, the period of the oscillator can be shown to span a wide range, from milliseconds to hours, suggesting that it may also be a mechanism for physiological timekeeping and/or redox signaling.