Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria
Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria
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DOI：
10.1073/pnas.95.25.14681
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发表时间：
1998-12-08
影响因子：
11.1
通讯作者：
Tsujimoto, Y
中科院分区：
文献类型：
--
作者：
Narita, M;Shimizu, S;Tsujimoto, Y
细胞色素 c 释放和线粒体通透性转变 (PT)，包括跨膜电位 (Delta psi) 的损失，在细胞凋亡中发挥重要作用。使用分离的线粒体，我们发现重组 Bax 和 Bak（Bcl-2 家族的促凋亡成员）诱导线粒体 Delta psi 损失、肿胀和细胞色素 c 释放。所有这些变化都依赖于 Ca2+，并被环孢菌素 A (CsA) 和 bongkrekic 酸阻止，这两种物质都会关闭 PT 孔（大通道），表明 Bax 和 Bak 诱导的线粒体变化是通过打开这些孔介导的。 Bax 诱导的线粒体变化受到重组 Bcl-x(L) 和转基因衍生的 Bcl-2（Bcl-2 家族的抗凋亡成员）以及寡霉素的抑制，表明 F0F1-ATPase 对 Bax 诱导的线粒体变化可能具有调节作用。促凋亡的 Bax- 和 Bak-BH3（Bcl-2 同源）肽（而非突变型 BH3 肽或缺乏 BH3 的突变型 Bak）诱导线粒体变化，表明 BH3 区域的重要作用。免疫共沉淀研究表明，Bax 和 Bak 与电压依赖性阴离子通道相互作用，该通道是 PT 孔的组成部分。总而言之，这些发现表明促凋亡 Bcl-2 家族蛋白（包括 Bax 和 Bak）通过与 PT 孔相互作用诱导线粒体 PT 和细胞色素 c 释放。
Cytochrome c release and the mitochondrial permeability transition (PT), including loss of the transmembrane potential (Delta psi), play an important role in apoptosis. Using isolated mitochondria, we found that recombinant Bax and Bak, proapoptotic members of the Bcl-2 family, induced mitochondrial Delta psi loss, swelling, and cytochrome c release. All of these changes were dependent on Ca2+ and were prevented by cyclosporin A (CsA) and bongkrekic acid, both of which close the PT pores (megachannels), indicating that Bax- and Bak-induced mitochondrial changes were mediated through the opening of these pores. Bax-induced mitochondrial changes were inhibited by recombinant Bcl-x(L) and transgene-derived Bcl-2, antiapoptotic members of the Bcl-2 family, as well as by oligomycin, suggesting a possible regulatory effect of F0F1-ATPase on Bax-induced mitochondrial changes. Proapoptotic Bax- and Bak-BH3 (Bcl-2 homology) peptides, but not a mutant BH3 peptide nor a mutant Bak lacking BH3, induced the mitochondrial changes, indicating an essential role of the BH3 region. A coimmunoprecipitation study revealed that Bax and Bak interacted with the voltage-dependent anion channel, which is a component of PT pores. Taken together, these findings suggest that proapoptotic Bcl-2 family proteins, including Bax and Bak, induce the mitochondrial PT and cytochrome c release by interacting with the PT pores.