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Mitochondrial CB1 receptors regulate neuronal energy metabolism

Nature Neuroscience volume 15, pages 558–564 (2012)Cite this article

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Abstract

The mammalian brain is one of the organs with the highest energy demands, and mitochondria are key determinants of its functions. Here we show that the type-1 cannabinoid receptor (CB1) is present at the membranes of mouse neuronal mitochondria (mtCB1), where it directly controls cellular respiration and energy production. Through activation of mtCB1 receptors, exogenous cannabinoids and in situ endocannabinoids decreased cyclic AMP concentration, protein kinase A activity, complex I enzymatic activity and respiration in neuronal mitochondria. In addition, intracellular CB1 receptors and mitochondrial mechanisms contributed to endocannabinoid-dependent depolarization-induced suppression of inhibition in the hippocampus. Thus, mtCB1 receptors directly modulate neuronal energy metabolism, revealing a new mechanism of action of G protein–coupled receptor signaling in the brain.

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Figure 1: CB1 receptors in neuronal mitochondria.
Figure 2: Mt-CB1 is present in both GABAergic and glutamatergic CA1 hippocampal neurons.
Figure 3: Direct regulation of mitochondrial activity by mtCB1 receptors in the brain.
Figure 4: MtCB1 receptors are activated by THC, and mitochondria contain biologically active endocannabinoids.
Figure 5: Hemopressin and HU-biot do not penetrate cells and cannot alter cellular respiration in intact cells.
Figure 6: Intracellular CB1 receptors contribute to depolarization-induced DSI.
Figure 7: Inhibition of mitochondrial activity potentiates DSI.

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  • 27 March 2012

    In the version of this article initially published online, the description of the procedure given in the Online Methods for synthesis of fluorescent hemopressin, taken from a different protocol not used in this work, was incorrect. The entire paragraph has been replaced. The error has been corrected in the PDF and HTML versions of this article.

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Acknowledgements

We thank D. Gonzales, N. Aubailly and all the personnel of the Animal Facility of the NeuroCentre Magendie for mouse care and genotyping; all the members of G.M.'s laboratory for discussions; and A. Bacci, D. Cota, M. Guzman, U. Pagotto, P.V. Piazza and C. Wotjak for critically reading the manuscript. Supported by AVENIR/INSERM (G.M.), INSERM–Agence Nationale de la Recherche (Retour Post-Doc ANR-09RDPOC-006-01 (G.B.), European Union 7th Framework Program (REPROBESITY, HEALTH-F2-2008-223713, G.M. and B.L.), European Research Council (ENDOFOOD, ERC-2010-StG-260515, G.M.), Fondation pour la Recherche Medicale (G.M. and M.M.-L.), Region Aquitaine (G.M.), Fyssen Foundation (E.S.-G.), University of Bordeaux (J.L.), Red de Trastornos Adictivos, Instituto de Salud Carlos III (RD07/0001/2001, P.G.), Basque Country Government (GIC07/70-IT-432-07, P.G.), University of the Basque Country UPV/EHU (UFI11/41, P.G.), Comunidad de Madrid (S2010/BMD-2353, M.L.L.-R.), MICINN (SAF2009-07065, P.G.; SAF2010-22198-C02-01, M.L.L.-R.), Ramon y Cajal program (S.O.-G.), Deutsche Forschungsgemeinschaft (FOR926, B.L.) and CONACyT (E.S.-G.).

Author information

Author notes

  1. Joana Lourenço

    Present address: Present address: European Brain Research Institute, “Rita Levi-Montalcini” Foundation, Rome, Italy.,

  2. Giovanni Bénard and Federico Massa: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, Endocannabinoids and Neuroadaptation, U862, Bordeaux, France.,

    Giovanni Bénard, Federico Massa, Joana Lourenço, Luigi Bellocchio, Edgar Soria-Gómez, Isabel Matias, Anna Delamarre, Mathilde Metna-Laurent, Astrid Cannich, Etienne Hebert-Chatelain, Francis Chaouloff & Giovanni Marsicano

  2. Université de Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), EA 4576, Bordeaux, France.,

    Giovanni Bénard & Rodrigue Rossignol

  3. Université de Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U862, Bordeaux, France.,

    Giovanni Bénard, Federico Massa, Joana Lourenço, Luigi Bellocchio, Edgar Soria-Gómez, Isabel Matias, Anna Delamarre, Mathilde Metna-Laurent, Astrid Cannich, Etienne Hebert-Chatelain, Christophe Mulle, Francis Chaouloff, Rodrigue Rossignol & Giovanni Marsicano

  4. Department of Neurosciences, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain

    Nagore Puente & Pedro Grandes

  5. Laboratoire Physiologie Cellulaire de la Synapse, Centre National de la Recherche Scientifique UMR 5091, Bordeaux, France

    Joana Lourenço & Christophe Mulle

  6. Department of Organic Chemistry, Complutense University, Madrid, Spain

    Silvia Ortega-Gutiérrez, Mar Martín-Fontecha & María Luz López-Rodríguez

  7. Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany

    Matthias Klugmann, Stephan Guggenhuber & Beat Lutz

  8. Department of Physiology, Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia

    Matthias Klugmann

  9. Institute of Biochemistry and Molecular Medicine, Bern, Switzerland

    Jürg Gertsch

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Contributions

N.P., J.L. and L.B. equally contributed to experiments. P.G. and R.R. equally supervised different parts of this work. G.B., P.G., R.R. and G.M. designed the study. G.B. performed the biochemical experiments. F.M., J.L. and C.M. performed the electrophysiological studies. N.P. performed the anatomical studies. L.B. and E.S.-G. performed in vivo studies and stereotactic injections of viruses. A.D., M.M.-L., E.H.-C. and A.C. participated in biochemical experiments. I.M. measured endocannabinoids and endocannabinoid-degrading enzymatic activities. S.O.-G., M.M.-F. and M.L.L.-R. synthesized and biochemically characterized HU-biot and measured intracellular hemopressin and AM251. J.G. generated fluorescent hemopressin and performed in vitro studies on cell penetration. M.K., S.G. and B.L. provided the viruses for local re-expression of CB1 receptors. F.C. supervised part of the work. P.G. supervised the anatomical studies. R.R. supervised biochemical experiments. G.M. conceived and supervised the whole study and wrote the manuscript. All authors edited the manuscript.

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Correspondence to Giovanni Marsicano.

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Bénard, G., Massa, F., Puente, N. et al. Mitochondrial CB1 receptors regulate neuronal energy metabolism. Nat Neurosci 15, 558–564 (2012). https://doi.org/10.1038/nn.3053

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