Through direct interaction with the voltage-dependent anion channel (VDAC), proapoptotic members of the Bcl-2 family such as Bax and Bak induce apoptogenic cytochrome c release in isolated mitochondria, whereas BH3-only proteins such as Bid and Bik do not directly target the VDAC to induce cytochrome c release. To investigate the biological significance of the VDAC for apoptosis in mammalian cells, we produced two kinds of anti-VDAC antibodies that inhibited VDAC activity. In isolated mitochondria, these antibodies prevented Bax-induced cytochrome c release and loss of the mitochondrial membrane potential (Δψ), but not Bid-induced cytochrome c release. When microinjected into cells, these anti-VDAC antibodies, but not control antibodies, also prevented Bax-induced cytochrome c release and apoptosis, whereas the antibodies did not prevent Bid-induced apoptosis, indicating that the VDAC is essential for Bax-induced, but not Bid-induced, apoptogenic mitochondrial changes and apoptotic cell death. In addition, microinjection of these anti-VDAC antibodies significantly inhibited etoposide-, paclitaxel-, and staurosporine-induced apoptosis. Furthermore, we used these antibodies to show that Bax- and Bak-induced lysis of red blood cells was also mediated by the VDAC on plasma membrane. Taken together, our data provide evidence that the VDAC plays an essential role in apoptogenic cytochrome c release and apoptosis in mammalian cells. VDAC apoptosis Bcl-2 Bax cytochrome c Footnotes Abbreviations used in this paper: ANT, adenine nucleotide translator; BH, Bcl-2 homology; Δψ, mitochondrial membrane potential; GFP, green fluorescent protein; GPGH, glyceraldehyde 3-phosphate dehydrogenase; NRI, normal rabbit IgG; PT, permeability transition; rGFP, recombinant GFP; VDAC, voltage-dependent anion channel. Submitted: 26 June 2000 Revision requested 13 November 2000 Accepted: 21 November 2000
The Journal of Cell Biology – Rockefeller University Press
Published: Jan 22, 2001
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