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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Proapoptotic N-truncated BCL-xL protein activates endogenous mitochondrial channels in living synaptic terminals
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Proapoptotic N-truncated BCL-xL protein activates endogenous mitochondrial channels in living synaptic terminals

机译：凋亡前N截短的BCL-xL蛋白激活活突触末端的内源性线粒体通道。

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摘要

Neuronal death is often preceded by functional alterations at nerve terminals. Anti- and proapoptotic BCL-2 family proteins not only regulate the neuronal death pathway but also affect excitability of healthy neurons. We found that exposure of squid stellate ganglia to hypoxia, a death stimulus for neurons, causes a cysteine protease-dependent loss of full-length antiapoptotic BCL-xL, similar to previous findings in mammalian cells. Therefore, to determine the direct effect of the naturally occurring proapoptotic cleavage product of BCL-xL on mitochondria, recombinant N-truncated BCL-xL was applied to mitochondria inside the squid presynaptic terminal and to purified mitochondria isolated from yeast. N-truncated BCL-xL rapidly induced large multi-conductance channels with a maximal conductance significantly larger than those produced by full-length BCL-xL. This activity required the hydrophobic C terminus and the BH3 domain of BCL-xL. Moreover, N-truncated BCL-xL failed to produce any channel activity when applied to plasma membranes, suggesting that a component of the mitochondrial membrane is necessary for its actions. Consistent with this idea, the large channels induced by N-truncated BCL-xL are inhibited by NADH and require the presence of VDAC, a voltage-dependent anion channel present in the outer mitochondrial membrane. These observations suggest that the mitochondrial channels specific to full-length and N-truncated BCL-xL contribute to their opposite effects on synaptic transmission, and are consistent with their opposite effects on the cell death pathway.
机译：神经元死亡通常在神经末梢功能改变之前发生。抗凋亡蛋白BCL-2家族蛋白不仅调节神经元的死亡途径，而且还影响健康神经元的兴奋性。我们发现，鱿鱼星状神经节暴露于缺氧，即神经元的死亡刺激，会导致半胱氨酸蛋白酶依赖性的全长抗凋亡BCL-xL丢失，这与哺乳动物细胞中的先前发现相似。因此，为了确定天然存在的BCL-xL的促凋亡裂解产物对线粒体的直接作用，将重组N截短的BCL-xL应用于鱿鱼突触前末端内的线粒体以及从酵母中分离得到的纯化的线粒体。 N截短的BCL-xL快速诱导出大的多电导通道，其最大电导明显大于全长BCL-xL产生的电导。该活性需要疏水性C末端和BCL-xL的BH3结构域。此外，N截短的BCL-xL应用于质膜时无法产生任何通道活性，这表明线粒体膜的成分对其作用必不可少。与此想法一致，N-截短的BCL-xL诱导的大通道被NADH抑制，并需要存在VDAC（线粒体外膜中存在的电压依赖性阴离子通道）。这些观察结果表明，全长和N截短的BCL-xL特有的线粒体通道对突触传递具有相反的作用，并与它们对细胞死亡途径的相反作用相一致。

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