title: Bax and Bcl-xL independently regulate apoptotic changes of yeast mitochondria that require VDAC but not adenine nucleotide translocator.
abstract: Mitochondria play an essential role in apoptosis by releasing apoptogenic molecules such as cytochrome c and AIF, and some caspases, which are all regulated by Bcl-2 family proteins. Pro-apoptotic Bax and Bak have been shown to induce cytochrome c release and loss of membrane potential (Deltapsi) leading to AIF release in the isolated mitochondria. We have previously shown that Bax and Bak open the voltage-dependent anion channel (VDAC) allowing cytochrome c to pass through the channel, and Bcl-xL closes the channel. However, it has been reported that it is adenine nucleotide translocator (ANT) with which Bax/Bcl-xL interacts that modulate the channel activity. Here, we investigated the role of ANT and VDAC in the changes of isolated mitochondria triggered by Bax and by chemicals that induce permeability transition (PT). In rat and yeast mitochondria, Bax did not affect the ADP/ATP exchange activity of ANT. VDAC-deficient but not ANT-deficient yeast mitochondria showed resistance to cytochrome c release, Deltapsi loss, and swelling caused by Bax and PT inducers. Bcl-xL showed similar inhibition of all these changes in ANT-deficient and wild type yeast mitochondria. Furthermore, Bax induces cytochrome c release in wild type yeast cells but not VDAC1-deficient yeast cells. These data indicate that VDAC, but not ANT, is essential for apoptotic mitochondrial changes. The data also indicate that Bcl-xL and Bax possess an ability to regulate mitochondrial membrane permeability independently of other Bcl-2 family members.
authors.affiliation: Department of Medical Genetics, Osaka University Graduate School of Medicine, Biomedical Research Center, 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: Shinohara
authors.forename: Y
authors.initials: Y
authors.lastname: Tsujimoto
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D003574:Cytochrome c Group / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism*; D018272:Porins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D050995:Voltage-Dependent Anion Channel 1; D050994:Voltage-Dependent Anion Channels; D015003:Yeasts / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D003574:Cytochrome c Group; D018272:Porins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C494764:Vdac1 protein, rat; D050994:Voltage-Dependent Anion Channels; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D000431:Ethanol; D000255:Adenosine Triphosphate; D000226:Mitochondrial ADP, ATP Translocases; D050995:Voltage-Dependent Anion Channel 1