Bcl-2 and Bax regulate the channel activity of the mitochondrial adenine nucleotide translocator

Citation
C. Brenner et al., Bcl-2 and Bax regulate the channel activity of the mitochondrial adenine nucleotide translocator, ONCOGENE, 19(3), 2000, pp. 329-336
Citations number
40
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
ONCOGENE
ISSN journal
09509232 → ACNP
Volume
19
Issue
3
Year of publication
2000
Pages
329 - 336
Database
ISI
SICI code
0950-9232(20000120)19:3<329:BABRTC>2.0.ZU;2-E
Abstract
Bcl-2 family protein including anti-apoptotic (Bcl-2) or pro-apoptotic (Bax ) members can form ion channels when incorporated into synthetic lipid bila yers. This contrasts with the observation that Bcl-2 stabilizes the mitocho ndrial membrane barrier function and inhibits the permeability transition p ore complex (PTPC), Here we provide experimental data which may explain thi s apparent paradox. Bar and adenine nucleotide translocator (ANT), the most abundant inner mitochondrial membrane protein, can interact in artificial lipid bilayers to yield an efficient composite channel whose electrophysiol ogical properties differ quantitatively and qualitatively from the channels formed by Bar or ANT alone. The formation of this composite channel can be observed in conditions in which Bar protein alone has no detectable channe l activity, Cooperative channel formation by Bar and ANT is stimulated by t he ANT ligand atractyloside (Atr) but inhibited by ATP, indicating that it depends on the conformation of ANT, In contrast to the combination of Bar a nd ANT, ANT does not form active channels when incorporated into membranes with Bcl-2, Rather, ANT and Bcl-2 exhibit mutual inhibition of channel form ation. Bcl-2 prevents channel formation by Atr-treated ANT and neutralizes the cooperation between Bar and ANT. Our data are compatible with a menage a trois model of mitochondrial apoptosis regulation in which ANT, the likel y pore forming protein within the PTPC, interacts with Bar or Bcl-2 which i nfluence its pore forming potential in opposing manners.