Activation of mitochondrial voltage-dependent anion channel by apro-apoptotic BH3-only protein Bim.
Bcl-2 family of proteins regulates apoptosis by controlling mitochondrial membrane permeability. We have previously shown that the voltage-dependent anion channel (VDAC) plays a crucial role in apoptotic changes of the mitochondria and its activity is directly regulated by some Bcl-2 family members, including Bcl-2/Bcl-x(L) and Bax/Bak but not Bid. Here, we showed that in isolated mitochondria, Bim induced loss of membrane potential and cytochrome c release like Bax/Bak, with these changes being inhibited by an anti-VDAC antibody. In addition, microinjection of the anti-VDAC antibody significantly reduced Bim-induced apoptosis. Study using purified proteins indicated that Bim directly interacts with the VDAC. Immunoprecipitation analysis revealed that Bim interacts with the VDAC and the interaction is remarkably enhanced during apoptosis. An experiment using liposomes indicated that Bim enhanced VDAC activity, as did Bax/Bak. Furthermore, Bim (but not tBid) was able to induce apoptotic changes of yeast mitochondria in a VDAC-dependent manner, and also induced the lysis of red blood cells, with this effect being inhibited by the anti-VDAC antibody. These results indicate that Bim has an ability to activate directly the VDAC, which plays an important role in apoptosis of mammalian cells.
Osaka University Medical School and Graduate School of Medicine, Laboratory of Molecular Genetics, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Tomoyasu
T
Sugiyama
Shigeomi
S
Shimizu
Yosuke
Y
Matsuoka
Yoshihiro
Y
Yoneda
Yoshihide
Y
Tsujimoto
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008564:Membrane Potentials / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism*; D018272:Porins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051381:Rats; D050994:Voltage-Dependent Anion Channels
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C000606778:Bcl2l11 protein, rat; D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D018272:Porins; D011518:Proto-Oncogene Proteins; D050994:Voltage-Dependent Anion Channels