The anti-apoptotic BCL-2 family protein, Bcl-xL, is highly expressed in the brain. Beside its anti-apoptotic function, Bcl-xL may contribute to activity-dependent normal functioning of neurons. In this study, using a set of gain and loss of function experiments, we find that, in hippocampal neurons, Bcl-xL enhances the efficiency of neuronal energy metabolism by increasing total cellular ATP levels, while decreasing cellular oxygen use. This effect is due to the presence of Bcl-xL in the mitochondrial inner membrane, co-localized with the (F1F0) ATP synthase, shown by immunocytochemistry and immune-electron microscopy. The interaction causes a decrease in leak of H+ ions across the mitochondrial inner membrane. The decreased leak is correlated with an increase in coupling of oxidative phosphorylation. In contrast, inhibition of Bcl-xL by pharmacological or genetic means increases a leak conductance measured by patch clamping the membrane of submitochondrial particles enriched in ATP synthase complexes (SMVs). Leaky SMVs demonstrate attenuated ability to sequester H+ during ATP hydrolysis. Additionally, Bcl-xL protein directly increases ATPase activity of the purified synthase complexes, while inhibition of endogenous Bcl-xL decreases synthase activity. The exact site of the leak is being determined by cross-linking studies and by patch clamping individual protein components of the ATP synthase reconstituted into artificial lipid vesicles. Improved mitochondrial metabolic efficiency of neurons accompanying changes in leak level may result in long lasting changes in synaptic efficacy in both physiological and pathological conditions.
