Bax interacts with the voltage-dependent anion channel and mediates ethanol-induced apoptosis in rat hepatocytes.
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.
Adachi
Masayuki
M
Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan.
Higuchi
Hajime
H
Miura
Soichiro
S
Azuma
Toshifumi
T
Inokuchi
Sayaka
S
Saito
Hidetsugu
H
Kato
Shinzo
S
Ishii
Hiromasa
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D003432:Cross-Linking Reagents; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004594:Electrophysiology; D000431:Ethanol / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008845:Microinjections; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D018384:Oxidative Stress / Q000502:physiology; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D003432:Cross-Linking Reagents; D007166:Immunosuppressive Agents; D007473:Ion Channels; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D000431:Ethanol; D016572:Cyclosporine; D045304:Cytochromes c; D020169:Caspases