Cytochrome bc1 regulates the mitochondrial permeability transition by two distinct pathways
Cytochrome bc1 regulates the mitochondrial permeability transition by two distinct pathways
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DOI：
10.1074/jbc.m408882200
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发表时间：
2004-11-26
影响因子：
4.8
通讯作者：
Whiteman, M
中科院分区：
文献类型：
--
作者：
Armstrong, JS;Yang, HY;Whiteman, M
线粒体通透性转换（MPT）孔是线粒体内膜上的钙敏感通道，在细胞死亡中起着至关重要的作用。在这里，我们表明，细胞色素bc（1）调节MPT在离体大鼠肝线粒体和CEM和HL 60细胞通过两个独立的途径。谷氨酰胺耗竭通过增加细胞色素bc1产生的活性氧（ROS）的产生来激活MPT。细胞色素bc 1中的活性氧产生机制涉及酶复合物的“Rieske”铁硫蛋白亚基的运动，因为通过药理学阻断铁硫蛋白运动来抑制细胞色素bc 1完全消除了活性氧的产生、MPT激活和细胞死亡。MPT的经典抑制剂环孢素A对MPT活化没有保护作用。与此相反，钙激活，环孢素A调节的MPT在大鼠肝线粒体也被阻断细胞色素bc1的抑制剂。这些结果表明，通过细胞色素bc1的电子通量调节两个不同的途径MPT，一个不受调节，涉及线粒体ROS和其他调节和激活钙。
The mitochondrial permeability transition (MPT) pore is a calcium-sensitive channel in the mitochondrial inner membrane that plays a crucial role in cell death. Here we show that cytochrome bc(1) regulates the MPT in isolated rat liver mitochondria and in CEM and HL60 cells by two independent pathways. Glutathione depletion activated the MPT via increased production of reactive oxygen species (ROS) generated by cytochrome bc1. The ROS producing mechanism in cytochrome bc1 involves movement of the "Rieske" iron-sulfur protein subunit of the enzyme complex, because inhibition of cytochrome bc1 by pharmacologically blocking iron-sulfur protein movement completely abolished ROS production, MPT activation, and cell death. The classical inhibitor of the MPT, cyclosporine A, had no protective effect against MPT activation. In contrast, the calcium-activated, cyclosporine A-regulated MPT in rat liver mitochondria was also blocked with inhibitors of cytochrome bc1. These results indicate that electron flux through cytochrome bc1 regulates two distinct pathways to the MPT, one unregulated and involving mitochondrial ROS and the other regulated and activated by calcium.