Vander Heiden M G, Li X X, Gottleib E, Hill R B, Thompson C B, Colombini M
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
J Biol Chem. 2001 Jun 1;276(22):19414-9. doi: 10.1074/jbc.M101590200. Epub 2001 Mar 20.
The diffusion of metabolites across the outer mitochondrial membrane is essential for coupled cellular respiration. The outer membrane of mitochondria isolated from growth factor-deprived cells is impaired in its ability to exchange metabolic anions. When added to mitochondria, recombinant Bcl-x(L) restores metabolite exchange across the outer membrane without inducing the loss of cytochrome c from the intermembrane space. Restoration of outer membrane permeability to anionic metabolites does not occur directly through Bcl-x(L) ion channels. Instead, recombinant Bcl-x(L) maintains the outer mitochondrial membrane channel, VDAC, in an open configuration. Consistent with these findings, when ADP-induced oxidative phosphorylation is limited by exogenous beta-NADH, recombinant Bcl-x(L) can sustain outer mitochondrial membrane permeability to ADP. beta-NADH limits respiration by promoting the closed configuration of VDAC. Together these results demonstrate that following an apoptotic signal, Bcl-x(L) can maintain metabolite exchange across the outer mitochondrial membrane by inhibiting VDAC closure.
代谢物跨线粒体外膜的扩散对于细胞呼吸耦合至关重要。从生长因子缺乏的细胞中分离出的线粒体的外膜，其交换代谢阴离子的能力受损。当添加到线粒体中时，重组Bcl-x(L)可恢复跨外膜的代谢物交换，而不会导致细胞色素c从膜间隙丢失。线粒体外膜对阴离子代谢物通透性的恢复并非直接通过Bcl-x(L)离子通道实现。相反，重组Bcl-x(L)使线粒体外膜通道电压依赖性阴离子通道（VDAC）维持在开放构象。与这些发现一致，当外源性β-烟酰胺腺嘌呤二核苷酸（β-NADH）限制ADP诱导的氧化磷酸化时，重组Bcl-x(L)可维持线粒体外膜对ADP的通透性。β-NADH通过促进VDAC的关闭构象来限制呼吸作用。这些结果共同表明，在凋亡信号出现后，Bcl-x(L)可通过抑制VDAC关闭来维持代谢物跨线粒体外膜的交换。
