Bid, but not Bax, regulates VDAC channels.
During apoptosis, cytochrome c is released from mitochondria into the cytosol, where it participates in caspase activation. Various and often conflicting mechanisms have been proposed to account for the increased permeability of the mitochondrial outer membrane that is responsible for this process. The voltage-dependent anion channel (VDAC) is the major permeability pathway for metabolites in the mitochondrial outer membrane and therefore is a very attractive candidate for cytochrome c translocation. Here, we report that properties of VDAC channels reconstituted into planar phospholipid membranes are unaffected by addition of the pro-apoptotic protein Bax under a variety of conditions. Contrary to other reports (Shimizu, S., Narita, M., and Tsujimoto, Y. (1999) Nature 399, 483-487; Shimizu, S., Ide, T., Yanagida, T., and Tsujimoto, Y. (2000) J. Biol. Chem. 275, 12321-12325; Shimizu, S., Konishi, A., Kodama, T., and Tsujimoto, Y. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 3100-3105), we found no electrophysiologically detectable interaction between VDAC channels isolated from mammalian mitochondria and either monomeric or oligomeric forms of Bax. We conclude that Bax does not induce cytochrome c release by acting on VDAC. In contrast to Bax, another pro-apoptotic protein (Bid) proteolytically cleaved with caspase-8 affected the voltage gating of VDAC by inducing channel closure. We speculate that by decreasing the probability of VDAC opening, Bid reduces metabolite exchange between mitochondria and the cytosol, leading to mitochondrial dysfunction.
Rostovtseva
Tatiana K
TK
Laboratory of Physical and Structural Biology, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA. rostovts@helix.nih.gov
Antonsson
Bruno
B
Suzuki
Motoshi
M
Youle
Richard J
RJ
Colombini
Marco
M
Bezrukov
Sergey M
SM
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism*; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D015640:Ion Channel Gating / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D008930:Mitochondria, Liver / Q000502:physiology*; D018272:Porins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D050994:Voltage-Dependent Anion Channels; D051028:bcl-2-Associated X Protein
D051023:BH3 Interacting Domain Death Agonist Protein; C494828:Bax protein, rat; C494816:Bid protein, rat; D002352:Carrier Proteins; D018272:Porins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050994:Voltage-Dependent Anion Channels; D051028:bcl-2-Associated X Protein; C505528:Casp8 protein, rat; D053181:Caspase 8; D020169:Caspases