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
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.