title: Activation of the permeability transition pore by Bax via inhibition of the mitochondrial BK channel.
abstract: Mitochondria are crucially involved in the intrinsic pathway of apoptosis. Upon induction of apoptosis, proapoptotic proteins of the Bcl-2 family, in particular Bax and Bak, transfer the death signal to the organelle. The outcome is release of proapoptotic factors, such as cytochrome c, and mitochondrial changes, such as depolarization. Details of the mechanism by which Bax mediates mitochondrial alterations, however, are unknown. Using the single-channel patch-clamp method, we studied mitoplasts (vesicles of inner membrane) from rat astrocyte and liver mitochondria and intact murine glioma mitochondria to determine the action of proapoptotic Bax and antiapoptotic Bcl-xL on the mitochondrial Ca(2+)-activated channel (mtBK) and the permeability transition pore (mtPTP). Bax (1 nM) inhibited the open probability of the mtBK, whereas Bcl-xL or control proteins had no effect. Incubating mitochondria with iberiotoxin, an inhibitor of mtBK, induced the release of cytochrome c. Bcl-xL inhibited the effects of Bax on mtBK. Furthermore, in patch-clamp studies Bcl-xL inhibited the mtPTP itself, whereas Bax had no direct effect on the mtPTP. We conclude that Bax exerts its proapototic effect by inhibiting mitochondrial K(+) channels, whereas Bcl-xL exerts its antiapoptotic effect by inhibiting the effects of Bax on mitochondrial potassium channels and by direct inhibition of the mtPTP.
authors.affiliation: Department of Neurology, Otto von Guericke University, Magdeburg, Germany.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cheng
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.forename: Detlef
authors.initials: D
authors.lastname: Siemen
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000166:cytology / Q000502:physiology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010455:Peptides; D024681:Potassium Channels, Calcium-Activated; D011993:Recombinant Fusion Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C064719:iberiotoxin; D045304:Cytochromes c