Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane.
The diffusion of metabolites across the outer mitochondrial membrane is essential for coupled cellular respiration. The outer membrane of mitochondria isolated from growth factor-deprived cells is impaired in its ability to exchange metabolic anions. When added to mitochondria, recombinant Bcl-x(L) restores metabolite exchange across the outer membrane without inducing the loss of cytochrome c from the intermembrane space. Restoration of outer membrane permeability to anionic metabolites does not occur directly through Bcl-x(L) ion channels. Instead, recombinant Bcl-x(L) maintains the outer mitochondrial membrane channel, VDAC, in an open configuration. Consistent with these findings, when ADP-induced oxidative phosphorylation is limited by exogenous beta-NADH, recombinant Bcl-x(L) can sustain outer mitochondrial membrane permeability to ADP. beta-NADH limits respiration by promoting the closed configuration of VDAC. Together these results demonstrate that following an apoptotic signal, Bcl-x(L) can maintain metabolite exchange across the outer mitochondrial membrane by inhibiting VDAC closure.
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
M G
MG
Vander Heiden
X X
XX
Li
E
E
Gottleib
R B
RB
Hill
C B
CB
Thompson
M
M
Colombini
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D003574:Cytochrome c Group / Q000378:metabolism; D004058:Diffusion; D004594:Electrophysiology; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010539:Permeability; D010725:Phosphocreatine / Q000378:metabolism; D010766:Phosphorylation; D018272:Porins / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D050994:Voltage-Dependent Anion Channels; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; C494813:Bcl2l1 protein, rat; D003574:Cytochrome c Group; D018272:Porins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D050994:Voltage-Dependent Anion Channels; D051020:bcl-X Protein; D010725:Phosphocreatine; D009243:NAD; D000244:Adenosine Diphosphate; D010100:Oxygen