Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1F0 ATP synthase

Anti-apoptotic Bcl2 family proteins such as Bcl-x(L) protect cells from death by sequestering apoptotic molecules, but also contribute to normal neuronal function. We find in hippocampal neurons that Bcl-x(L) enhances the efficiency of energy metabolism. Our evidence indicates that Bcl-x(L)interacts directly with the beta-subunit of the F1F0 ATP synthase, decreasing an ion leak within the F1F0 ATPase complex and thereby increasing net transport of H+ by F1F0 during F1F0 ATPase activity. By patch clamping submitochondrial vesicles enriched in F1F0 ATP synthase complexes, we find that, in the presence of ATP, pharmacological or genetic inhibition of Bcl-x(L) activity increases the membrane leak conductance. In addition, recombinant Bcl-x(L) protein directly increases the level of ATPase activity of purified synthase complexes, and inhibition of endogenous Bcl-x(L) decreases the level of F1F0 enzymatic activity. Our findings indicate that increased mitochondrial efficiency contributes to the enhanced synaptic efficacy found in Bcl-x(L)-expressing neurons.