Bcl-x(L) regulates metabolic efficiency of neurons through interaction with the mitochondrial F(1)F(O) 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 suggests that Bcl-x(L) interacts directly with the beta subunit of the F(1)F(O) ATP synthase, decreasing an ion leak within the F(1)F(O) ATPase complex and thereby increasing net transport of H(+) by F(1)F(O) during F(1)F(O) ATPase activity. By patch clamping submitochondrial vesicles enriched in F(1)F(O) ATP synthase complexes, we find that, in the presence of ATP, pharmacological or genetic inhibition of Bcl-x(L) increases the membrane leak conductance. In addition, recombinant Bcl-x(L) protein directly increases ATPase activity of purified synthase complexes, while inhibition of endogenous Bcl-x(L) decreases F(1)F(O) enzymatic activity. Our findings suggest that increased mitochondrial efficiency contributes to the enhanced synaptic efficacy found in Bcl-x(L) expressing neurons.