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

A Corrigendum to this article was published on 02 November 2011

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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.

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Figure 1: Cellular ATP levels are altered by Bcl-xL overexpression or depletion in hippocampal neurons.
Figure 2: Bcl-xL alters oxygen uptake by neurons.
Figure 3: Bcl-xL is expressed in the mitochondrial inner membrane and interacts with ATP synthase.
Figure 4: Bcl-xL protein regulates ATPase activity.
Figure 5: ATP-sensitive H+ ion sequestration into F1FO ATPase vesicles (SMVs) is attenuated by Bcl-xL inhibitors, and by oligomycin and FCCP.
Figure 6: Pharmacological inhibition or depletion of Bcl-xL reverses leak closure in patch-clamp recordings of isolated ATP F1FO ATPase vesicles.

Change history

  • 27 September 2011

    In the version of this article initially published online and in print, the affiliation denoted by number 4 was incorrect.

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Acknowledgements

We thank L. K. Kaczmarek for scientific discussion and review of the manuscript. We thank C. Kinnally and N. Danial for the gift of Bax, Bak (DKO) MEFs and Institut de Recherches Servier, Croissy sur Seine, France for ABT-737. This work was supported by NIH NS064967 (E.A.J.) and NS37402 (J.M.H.).

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K.N.A. and E.A.J. conceived the project, carried out most of the experiments, analysed the data and prepared the manuscript. H.L. and L.C. contributed experiments to Figs 1 and 2. L.B. contributed experiments to Fig. 6. L.Z., S.S. and M.A.M. contributed to Fig. 4. E.L. and P.N. contributed to Fig. 3. B.F. helped with Fig. 6. M.G. and C.R. contributed experiments to Fig. 3 and Supplementary Fig. S2. S.M.M. and E.M. contributed to Fig. 1. Y.C. and G.C.S. contributed to discussion. P.J.S.S. provided experimental design and discussion for Figs 1 and 2. J.M.H. designed Bcl-xL immunolocalization experiments, and contributed intellectually as well as in manuscript preparation.

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Correspondence to Elizabeth A. Jonas.

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G.C. Shore is a shareholder in Gemin X Pharmaceuticals Inc.

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Alavian, K., Li, H., Collis, L. et al. Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase. Nat Cell Biol 13, 1224–1233 (2011). https://doi.org/10.1038/ncb2330

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