Abstract
Through direct interaction with the voltage-dependent anion channel (VDAC), proapoptotic Bcl-2 family members such as Bax and Bak induce apoptogenic mitochondrial cytochrome c release and membrane potential (Deltapsi) loss in isolated mitochondria. Using isolated mitochondria, we showed that Bid and Bik, BH3-only proteins from the Bcl-2 family, induced cytochrome c release but not Deltapsi loss. Unlike Bax/Bak, the cytochrome c release induced by Bid/Bik was Ca(2+)-independent, cyclosporin A-insensitive, and respiration-independent. Furthermore, in contrast to Bax/Bak, Bid/Bik neither interacted with VDAC nor directly affected the VDAC activity in liposomes. Consistently, Bid/Bik induced apoptosis without Deltapsi loss, whereas Bax induced apoptosis with Deltapsi loss. These findings indicated the involvement of a different mechanism in BH3-only, protein-induced apoptogenic cytochrome c release.
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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Apoptosis / physiology
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Apoptosis Regulatory Proteins
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BH3 Interacting Domain Death Agonist Protein
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Carrier Proteins / genetics
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Carrier Proteins / pharmacology
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Carrier Proteins / physiology
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Cell Line
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Cytochrome c Group / metabolism*
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Electric Stimulation
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Humans
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Intracellular Membranes / drug effects
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Intracellular Membranes / physiology
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Ion Channels / drug effects
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Ion Channels / metabolism
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Male
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Membrane Potentials / drug effects*
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Membrane Proteins*
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Mitochondria, Liver / drug effects*
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Mitochondria, Liver / enzymology
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Mitochondria, Liver / physiology
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Mitochondrial Proteins
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Permeability / drug effects
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Porins / drug effects*
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Porins / metabolism
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Proteins / genetics
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Proteins / pharmacology
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Proteins / physiology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / pharmacology*
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Proto-Oncogene Proteins c-bcl-2 / physiology
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Rats
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Rats, Inbred Strains
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / physiology
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Recombinant Proteins / pharmacology
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Voltage-Dependent Anion Channels
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bcl-2-Associated X Protein
Substances
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Apoptosis Regulatory Proteins
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BAX protein, human
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BH3 Interacting Domain Death Agonist Protein
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BID protein, human
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BIK protein, human
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Bax protein, rat
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Bid protein, rat
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Carrier Proteins
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Cytochrome c Group
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Ion Channels
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Membrane Proteins
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Mitochondrial Proteins
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Porins
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Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Fusion Proteins
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Recombinant Proteins
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Voltage-Dependent Anion Channels
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bcl-2-Associated X Protein