Bcl-2 and Bax regulate the channel activity of the mitochondrial adenine nucleotide translocator.
Bcl-2 family protein including anti-apoptotic (Bcl-2) or pro-apoptotic (Bax) members can form ion channels when incorporated into synthetic lipid bilayers. This contrasts with the observation that Bcl-2 stabilizes the mitochondrial membrane barrier function and inhibits the permeability transition pore complex (PTPC). Here we provide experimental data which may explain this apparent paradox. Bax 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 electrophysiological properties differ quantitatively and qualitatively from the channels formed by Bax or ANT alone. The formation of this composite channel can be observed in conditions in which Bax protein alone has no detectable channel activity. Cooperative channel formation by Bax and ANT is stimulated by the ANT ligand atractyloside (Atr) but inhibited by ATP, indicating that it depends on the conformation of ANT. In contrast to the combination of Bax and ANT, ANT does not form active channels when incorporated into membranes with Bcl-2. Rather, ANT and Bcl-2 exhibit mutual inhibition of channel formation. Bcl-2 prevents channel formation by Atr-treated ANT and neutralizes the cooperation between Bax and ANT. Our data are compatible with a ménage à trois model of mitochondrial apoptosis regulation in which ANT, the likely pore forming protein within the PTPC, interacts with Bax or Bcl-2 which influence its pore forming potential in opposing manners.
Brenner
C
C
Centre National de la Recherche Scientifique, UPR420, Villejuif, France.
Cadiou
H
H
Vieira
H L
HL
Zamzami
N
N
Marzo
I
I
Xie
Z
Z
Leber
B
B
Andrews
D
D
Duclohier
H
H
Reed
J C
JC
Kroemer
G
G
D000818:Animals; D001278:Atractyloside / Q000494:pharmacology; D002478:Cells, Cultured; D007473:Ion Channels / Q000502:physiology*; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology*; D000226:Mitochondrial ADP, ATP Translocases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D007473:Ion Channels; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D001278:Atractyloside; D000226:Mitochondrial ADP, ATP Translocases