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Hypoxia increases activity of the BK-channel in the inner mitochondrial membrane and reduces activity of the permeability transition pore

机译:缺氧增加线粒体内膜中BK通道的活性并降低通透性过渡孔的活性

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Hypoxia can cause severe damage to cells by initiating signaling cascades that lead to cell death. A cellular oxygen sensor, other than the respiratory chain, might exist in sensitive components of these signaling cascades. Recently, we found evidence that mitochondrial ion channels are sensitive to low levels of oxygen. We therefore studied the effects of hypoxia on the mitochondrial BK-channel (mtBK), on the mitochondrial permeability transition pore (PTP), and on their possible interaction. Using single-channel patch-clamp techniques we found that hypoxia inhibited the PTP but substantially increased the mtBK activity of mitoplasts from rat liver and astrocytes. Experiments measuring the mitochondrial membrane potential of intact rat brain mitochondria (using the fluorescence dye safranine O) during hypoxia exhibited an increased Ca2+-retention capacity implying an impaired opening of the PTP. We also found a reduced Ca2+-retention capacity with 100 nM iberiotoxin, a selective inhibitor of BK-channels. We therefore conclude that there is interaction between the mtBK and the PTP in a way that an open mtBK keeps the PTP closed. Thus, the response of mitochondrial ion channels to hypoxia could be interpreted as anti-apoptotic.
机译:缺氧可通过引发导致细胞死亡的信号级联反应而严重破坏细胞。除呼吸链外,细胞氧传感器可能还存在于这些信号级联反应的敏感组件中。最近,我们发现线粒体离子通道对低水平的氧气敏感。因此,我们研究了缺氧对线粒体BK通道(mtBK),线粒体通透性转换孔(PTP)及其可能相互作用的影响。使用单通道膜片钳技术,我们发现缺氧抑制了PTP,但大大提高了大鼠肝脏和星形胶质细胞的原生质体的mtBK活性。在缺氧期间测量完整大鼠脑线粒体(使用荧光染料番红O)的线粒体膜电位的实验显示,Ca2 +保留能力增加,这意味着PTP的开放性受损。我们还发现100 nM的iberiotoxin(BK通道的选择性抑制剂)降低了Ca2 +的保留能力。因此,我们得出结论,以打开的mtBK保持PTP封闭的方式,在mtBK和PTP之间存在交互。因此,线粒体离子通道对缺氧的反应可以解释为抗凋亡。

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