Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects*
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Caspases / metabolism
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Cell Membrane Permeability / drug effects
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Cross-Linking Reagents
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Cyclosporine / pharmacology
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Cytochromes c / metabolism
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Electrophysiology
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Ethanol / pharmacology*
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Hepatocytes / drug effects*
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Hepatocytes / physiology*
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Immunoblotting
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Immunohistochemistry
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Immunosuppressive Agents / pharmacology
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In Vitro Techniques
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Ion Channel Gating / drug effects
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Ion Channel Gating / physiology*
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Ion Channels / drug effects
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Ion Channels / physiology*
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Male
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Microinjections
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Mitochondria, Liver / drug effects
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Mitochondria, Liver / enzymology
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Oxidative Stress / physiology
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Precipitin Tests
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-bcl-2*
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Rats
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Rats, Wistar
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Reactive Oxygen Species / metabolism
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bcl-2-Associated X Protein
Substances
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Bax protein, rat
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Cross-Linking Reagents
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Immunosuppressive Agents
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Ion Channels
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Reactive Oxygen Species
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bcl-2-Associated X Protein
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Ethanol
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Cyclosporine
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Cytochromes c
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Caspases