title: Functional consequences of the sustained or transient activation by Bax of the mitochondrial permeability transition pore.
abstract: The overexpression of Bax kills cells by a mechanism that depends on induction of the mitochondrial permeability transition (MPT) (Pastorino, J. G., Chen, S.-T., Tafani, M., Snyder, J. W., and Farber, J. L. (1998) J. Biol. Chem. 273, 7770-7775). In the present study, purified, recombinant Bax opened the mitochondrial permeability transition pore (PTP). Depending on its concentration, Bax had two distinct effects. At a concentration of 125 nM, Bax caused the release of the intermembranous proteins cytochrome c and adenylate kinase and the release from the matrix of sequestered calcein, effects prevented by the inhibitor of the PTP cyclosporin A (CSA). At this concentration of Bax, there was no detectable mitochondrial swelling or depolarization. These effects of low Bax concentrations are interpreted as the consequence of transient, non-synchronous activation of the PTP followed by a prompt recovery of mitochondrial integrity. By contrast, Bax concentrations between 250 nM and 1 microM caused a sustained opening of the PTP with consequent persistent mitochondrial swelling and deenergization (the MPT). CSA prevented the MPT induced by Bax. Increasing concentrations of calcium caused a greater proportion of the mitochondria to undergo the MPT in the presence of Bax. Importantly, two known mediators of apoptosis, ceramide and GD3 ganglioside, potentiated the induction by Bax of the MPT. The data imply that Bax mediates the opening of the mitochondrial PTP with the resultant release of cytochrome c from the intermembranous space.
authors.affiliation: Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Pastorino
authors.forename: M
authors.initials: M
authors.lastname: Tafani
authors.forename: R J
authors.initials: RJ
authors.lastname: Rothman
authors.forename: A
authors.initials: A
authors.lastname: Marcinkeviciute
authors.forename: J B
authors.initials: JB
authors.lastname: Hoek
authors.forename: J L
authors.initials: JL
authors.lastname: Farber
authors.forename: A
authors.initials: A
authors.lastname: Marcineviciute
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001278:Atractyloside / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002518:Ceramides / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D005732:Gangliosides / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects*; D007473:Ion Channels; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000187:drug effects*; D008930:Mitochondria, Liver / Q000187:drug effects*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010539:Permeability; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000494:pharmacology*; D051381:Rats; D051028:bcl-2-Associated X Protein
chemical_list: C494828:Bax protein, rat; D002518:Ceramides; D003574:Cytochrome c Group; D005452:Fluoresceins; D005732:Gangliosides; D007473:Ion Channels; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D001278:Atractyloside; C026226:ganglioside, GD3; D016572:Cyclosporine; D000263:Adenylate Kinase; D002118:Calcium; C007740:fluorexon