Adachi Masayuki, Higuchi Hajime, Miura Soichiro, Azuma Toshifumi, Inokuchi Sayaka, Saito Hidetsugu, Kato Shinzo, Ishii Hiromasa
Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan.
Am J Physiol Gastrointest Liver Physiol. 2004 Sep;287(3):G695-705. doi: 10.1152/ajpgi.00415.2003. Epub 2004 Mar 25.
Acute ethanol exposure induces oxidative stress and apoptosis in primary rat hepatocytes. Previous data indicate that the mitochondrial permeability transition (MPT) is essential for ethanol-induced apoptosis. However, the mechanism by which ethanol induces the MPT remains unclear. In this study, we investigated the role of Bax, a proapoptotic Bcl-2 family protein, in acute ethanol-induced hepatocyte apoptosis. We found that Bax translocates from the cytosol to mitochondria before mitochondrial cytochrome c release. Bax translocation was oxidative stress dependent. Mitochondrial Bax formed a protein complex with the mitochondrial voltage-dependent anion channel (VDAC). Prevention of Bax-VDAC interactions by a microinjection of anti-VDAC antibody effectively prevented hepatocyte apoptosis by ethanol. In conclusion, these data suggest that Bax translocation from the cytosol to mitochondria leads to the subsequent formation of a Bax-VDAC complex that plays a crucial role in acute ethanol-induced hepatocyte apoptosis.
急性乙醇暴露可诱导原代大鼠肝细胞发生氧化应激和凋亡。先前的数据表明，线粒体通透性转换（MPT）对于乙醇诱导的凋亡至关重要。然而，乙醇诱导MPT的机制仍不清楚。在本研究中，我们调查了促凋亡Bcl-2家族蛋白Bax在急性乙醇诱导的肝细胞凋亡中的作用。我们发现，在细胞色素c从线粒体释放之前，Bax从细胞质转位至线粒体。Bax转位依赖于氧化应激。线粒体Bax与线粒体电压依赖性阴离子通道（VDAC）形成蛋白复合物。通过显微注射抗VDAC抗体阻止Bax-VDAC相互作用可有效防止乙醇诱导的肝细胞凋亡。总之，这些数据表明，Bax从细胞质转位至线粒体导致随后形成Bax-VDAC复合物，该复合物在急性乙醇诱导的肝细胞凋亡中起关键作用。
