Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase

Abstract

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_Linteracts directly with the β-subunit of the F₁F_O ATP synthase, decreasing an ion leak within the F₁F_O ATPase complex and thereby increasing net transport of H⁺ by F₁F_O during F₁F_O ATPase activity. By patch clamping submitochondrial vesicles enriched in F₁F_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 F₁F_O enzymatic activity. Our findings indicate that increased mitochondrial efficiency contributes to the enhanced synaptic efficacy found in Bcl-x_L-expressing neurons.