title: Proapoptotic BH3-only Bcl-2 family members induce cytochrome c release, but not mitochondrial membrane potential loss, and do not directly modulate voltage-dependent anion channel activity.
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.
authors.affiliation: Osaka University Graduate School of Medicine, Biomedical Research Center, Department of Medical Genetics, CREST of Japan Science and Technology Corporation (JST), 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Shimizu
authors.forename: Y
authors.initials: Y
authors.lastname: Tsujimoto
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D002460:Cell Line; D003574:Cytochrome c Group / Q000378:metabolism*; D004558:Electric Stimulation; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D008565:Membrane Proteins; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D024101:Mitochondrial Proteins; D010539:Permeability / Q000187:drug effects; D018272:Porins / Q000187:drug effects* / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D050994:Voltage-Dependent Anion Channels; D051028:bcl-2-Associated X Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C096820:BIK protein, human; C494828:Bax protein, rat; C494816:Bid protein, rat; D002352:Carrier Proteins; D003574:Cytochrome c Group; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018272:Porins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D050994:Voltage-Dependent Anion Channels; D051028:bcl-2-Associated X Protein