Bcl-x L regulates metabolic efficiency of neurons through interaction with the mitochondrial F₁ 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 indicates that Bcl-x _L interacts directly with the β-subunit of the F₁ F_O ATP synthase, decreasing an ion leak within the F₁ F_O ATPase complex and thereby increasing net transport of H ⁺ by F₁ F_O during F₁ 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 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 F₁ F_O enzymatic activity. Our findings indicate that increased mitochondrial efficiency contributes to the enhanced synaptic efficacy found in Bcl-x L-expressing neurons.