Oligomeric BAX induces mitochondrial permeability transition and complete cytochrome c release without oxidative stress. 2008

Tsyregma Li, and Tatiana Brustovetsky, and Bruno Antonsson, and Nickolay Brustovetsky
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

In the present study, we investigated the mechanism of cytochrome c release from isolated brain mitochondria induced by recombinant oligomeric BAX (BAX(oligo)). We found that BAX(oligo) caused a complete release of cytochrome c in a concentration- and time-dependent manner. The release was similar to those induced by alamethicin, which causes maximal mitochondrial swelling and eliminates barrier properties of the OMM. BAX(oligo) also produced large amplitude mitochondrial swelling as judged by light scattering assay and transmission electron microscopy. In addition, BAX(oligo) resulted in a strong mitochondrial depolarization. ATP or a combination of cyclosporin A and ADP, inhibitors of the mPT, suppressed BAX(oligo)-induced mitochondrial swelling and depolarization as well as cytochrome c release but did not influence BAX(oligo) insertion into the OMM. Both BAX(oligo)- and alamethicin-induced cytochrome c releases were accompanied by inhibition of ROS generation, which was assessed by measuring mitochondrial H(2)O(2) release with an Amplex Red assay. The mPT inhibitors antagonized suppression of ROS generation caused by BAX(oligo) but not by alamethicin. Thus, BAX(oligo) resulted in a complete cytochrome c release from isolated brain mitochondria in the mPT-dependent manner without involvement of oxidative stress by the mechanism requiring mitochondrial remodeling and permeabilization of the OMM.

UI MeSH Term Description Entries
D008297 Male Males
D008928 Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed) Mitochondrial Contraction,Mitochondrion,Contraction, Mitochondrial,Contractions, Mitochondrial,Mitochondrial Contractions
D010539 Permeability Property of membranes and other structures to permit passage of light, heat, gases, liquids, metabolites, and mineral ions. Permeabilities
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001704 Biopolymers Polymers synthesized by living organisms. They play a role in the formation of macromolecular structures and are synthesized via the covalent linkage of biological molecules, especially AMINO ACIDS; NUCLEOTIDES; and CARBOHYDRATES. Bioplastics,Bioplastic,Biopolymer
D017207 Rats, Sprague-Dawley A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company. Holtzman Rat,Rats, Holtzman,Sprague-Dawley Rat,Rats, Sprague Dawley,Holtzman Rats,Rat, Holtzman,Rat, Sprague-Dawley,Sprague Dawley Rat,Sprague Dawley Rats,Sprague-Dawley Rats
D045304 Cytochromes c Cytochromes of the c type that are found in eukaryotic MITOCHONDRIA. They serve as redox intermediates that accept electrons from MITOCHONDRIAL ELECTRON TRANSPORT COMPLEX III and transfer them to MITOCHONDRIAL ELECTRON TRANSPORT COMPLEX IV. Cytochrome c,Ferricytochrome c,Ferrocytochrome c,Apocytochrome C
D046529 Microscopy, Electron, Transmission Electron microscopy in which the ELECTRONS or their reaction products that pass down through the specimen are imaged below the plane of the specimen. Electron Diffraction Microscopy,Electron Microscopy, Transmission,Microscopy, Electron Diffraction,Transmission Electron Microscopy,Diffraction Microscopy, Electron,Microscopy, Transmission Electron
D051028 bcl-2-Associated X Protein A member of the Bcl-2 protein family and homologous partner of C-BCL-2 PROTO-ONCOGENE PROTEIN. It regulates the release of CYTOCHROME C and APOPTOSIS INDUCING FACTOR from the MITOCHONDRIA. Several isoforms of BCL2-associated X protein occur due to ALTERNATIVE SPLICING of the mRNA for this protein. Bax Protein,Bax-alpha Protein,Bax-omega Protein,Bax-sigma Protein,Bax Apoptosis Regulator Protein,Bax-beta Protein,Bax-delta Protein,bcl2-Associated X Protein,bcl2-Associated X Protein Isoform alpha,bcl2-Associated X Protein Isoform beta,bcl2-Associated X Protein Isoform delta,bcl2-Associated X Protein Isoform omega,bcl2-Associated X Protein Isoform sigma,Bax alpha Protein,Bax beta Protein,Bax delta Protein,Bax omega Protein,Bax sigma Protein,Protein, bcl-2-Associated X,X Protein, bcl-2-Associated,bcl 2 Associated X Protein,bcl2 Associated X Protein,bcl2 Associated X Protein Isoform alpha,bcl2 Associated X Protein Isoform beta,bcl2 Associated X Protein Isoform delta,bcl2 Associated X Protein Isoform omega,bcl2 Associated X Protein Isoform sigma
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus

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