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

Abstract

Anti-apoptotic Bcl2 family proteins such as Bcl-xL protect cells from death by sequestering apoptotic molecules, but also contribute to normal neuronal function. We find in hippocampal neurons that Bcl-xL enhances the efficiency of energy metabolism. Our evidence indicates that Bcl-xLinteracts directly with the β-subunit of the F1FO ATP synthase, decreasing an ion leak within the F1FO ATPase complex and thereby increasing net transport of H+ by F1FO during F1FO ATPase activity. By patch clamping submitochondrial vesicles enriched in F1FO ATP synthase complexes, we find that, in the presence of ATP, pharmacological or genetic inhibition of Bcl-xL activity increases the membrane leak conductance. In addition, recombinant Bcl-xL protein directly increases the level of ATPase activity of purified synthase complexes, and inhibition of endogenous Bcl-xL decreases the level of F1FO enzymatic activity. Our findings indicate that increased mitochondrial efficiency contributes to the enhanced synaptic efficacy found in Bcl-xL-expressing neurons. ATP production by mitochondria requires the efficient flow of protons through the F1FO ATP-synthase complex. Jonas and colleagues show that Bcl-xL interacts with the F1FO complex in the mitochondrial matrix and increases the efficiency of this enzyme by decreasing proton leak.