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

Nature Cell Biology volume 13, pages 1224–1233 (2011)Cite this article

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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.

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  • 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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Author notes

  1. Kambiz N. Alavian, Hongmei Li and Leon Collis: These authors contributed equally to the work

Authors and Affiliations

  1. Department of Internal Medicine, Yale University, New Haven, Connecticut 06520, USA

    Kambiz N. Alavian, Hongmei Li, Lu Zeng, Silvio Sacchetti, Emma Lazrove, Panah Nabili, Benjamin Flaherty & Elizabeth A. Jonas

  2. Biocurrents Research Center, Marine Biological Laboratory, Woods Hole, Massachusetts 02543, USA

    Leon Collis, Shanta M. Messerli & Peter J. S. Smith

  3. Department of Oncology and Neuroscience and Aging Research Center, University G.D’Annunzio of Chieti-Pescara, I-66013 Chieti, Italy

    Laura Bonanni

  4. Department of Neuroscience and Imaging, and Ce.S.I. Aging Research Center, Universitá G.D'Annunzio of Chieti-Pescara, I-66013 Chieti, Italy

    Silvio Sacchetti & Maria A. Mariggio

  5. Department of Cell Biology, Yale University, New Haven, Connecticut 06520, USA

    Morven Graham & Christoph Rahner

  6. Department of Pharmacology and Molecular Sciences, Johns Hopkins, Baltimore, Maryland 21205, USA

    Yingbei Chen & J. Marie Hardwick

  7. Behavioural Neuroscience and Center for Neuroscience Research, University at Albany, New York 12222, USA

    Ewan McNay

  8. Gemin X Pharmaceuticals, Montréal, Quebec H2X 2H7, Canada

    Gordon C. Shore

  9. Institute for Life Sciences, University of Southampton, SO17 1BJ, UK

    Peter J. S. Smith

  10. Department of Molecular Microbiology and Immunology, Johns Hopkins, Baltimore, Maryland 21205, USA

    J. Marie Hardwick

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Contributions

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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