Jonas Elizabeth A, Hardwick J Marie, Kaczmarek Leonard K
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Antioxid Redox Signal. 2005 Sep-Oct;7(9-10):1092-100. doi: 10.1089/ars.2005.7.1092.
Changes in mitochondrial architecture and permeability facilitate programmed cell death. The BCL-2 family protein BAX is implicated in the formation of large "death channels" in outer mitochondrial membranes. We found that BAX-induced channels on mitochondria may have alternative functions. By patch clamping mitochondrial membranes inside the presynaptic terminal of the living squid giant synapse, we made direct measurements of channel activity produced by BAX application. Only infrequently did BAX application result in large conductance channels similar to those produced by a proapoptotic BCL-xL fragment or by application of a BH3-only peptide. Instead, the majority of outer mitochondrial channels induced by BAX had much smaller conductances than those found previously for the proapoptotic protein. Injection of BAX into the presynaptic terminal did not abolish synaptic transmission, contrary to previous findings with the proapoptotic fragment of BCL-xL. Instead, injection of BAX caused an increase in neurotransmitter release, as has also been found for the full-length antiapoptotic BCL-xL protein. We suggest that BAX can act to enhance synaptic efficacy in a normal physiological setting. Furthermore, the occasional large openings may reflect the function of "activated" BAX either to facilitate cell death or to play a physiological role in decreasing synaptic activity.
线粒体结构和通透性的变化有助于程序性细胞死亡。BCL-2家族蛋白BAX与线粒体外膜中大型“死亡通道”的形成有关。我们发现，BAX诱导的线粒体通道可能具有其他功能。通过膜片钳技术对活乌贼巨大突触突触前终末内的线粒体膜进行检测，我们直接测量了应用BAX后产生的通道活性。应用BAX很少产生类似于促凋亡BCL-xL片段或应用仅含BH3结构域的肽所产生的大电导通道。相反，BAX诱导的大多数线粒体外通道的电导比先前发现的促凋亡蛋白的电导小得多。与先前关于BCL-xL促凋亡片段的研究结果相反，将BAX注入突触前终末并没有消除突触传递。相反，注入BAX导致神经递质释放增加，这在全长抗凋亡BCL-xL蛋白中也有发现。我们认为，在正常生理环境中，BAX可以增强突触效能。此外，偶尔出现的大开口可能反映出“激活的”BAX在促进细胞死亡或在降低突触活性方面发挥生理作用的功能。
