11:59pm Tuesday 25 February 2020

Unravelled how energy production in brain is regulated

These endocannabinoids not only have the same name as cannabis extracts, but also act on the same receptors in the brain, modulating the communication between neurones. Doctors Ms Nagore Puente and Mr Pedro Grandes, neuroscientists at the Faculty of Medicine and Odontology in the University of the Basque Country – UPV/EHU, have contributed in a crucial manner in research work revealing this scientific phenomenon. The study has managed to identify the principal receptor of cannabinoids in the brain – the CB1 – in the neuronal mitochondria, at a location where its presence was previously not considered possible. Not only this, the research also showed that CB1 plays a key role in the regulation of the principal mitochondrial activity: the production of energy. The finding has been of such significance that an electron microscope photograph of the location of the CB1 in the mitochondria, taken by UPV/EHU researchers, was selected for the front cover of the April issue of Nature Neuroscience, in which the article entitled Mitochondrial CB1 receptors regulate neuronal energy metabolism* was published. “We were highly pleased, proud and happy to see one of our ultramicrophotographs on the front cover of Nature Neuroscience”, commented doctor Grandes.

This research, led by doctor Giovanni Marsicano (Neurocentre Magendie, University of Bordeaux), arose by chance four years ago when it was observed, in the laboratory directed by Pedro Grandes, that the marker for the CB1 receptor appeared systematically in the mitochondria of brain tissue. “It started as a result of a conversation between doctor Marsicano and myself in the corridor during a conference in the USA. Sometimes ideas in science arise like this”, commented the UPV/EHU neuroscientist. At first it was believed that the CB1 marker in mitochondria was false. The confirmation of its actual existence was obtained by UPV/EHU researchers on demonstrating that the mitochondrial CB1 marker was not present in brain tissue of mutant mice that lacked the CB1 receptor. The research went beyond this, the French research team showing that these CB1 receptors in the mitochondria were functional, given that, when the el CB1 was activated by tetrahydrocannabinol (THC) – the main psychoactive substance of cannabis -, the mitochondrial activity dropped and, thereby, the production of energy.

Despite representing only 2% of total body weight, the human brain consumes 20% of the energy produced by the organism. This energy in the brain is supplied by the mitochondria which, moreover, are essential for neuronal activity and survival, thereby mitochondrial malfunctioning can have serious consequences in the brain. In this vein, there is evidence that mitochondrial dysfunction plays a part in the pathogenics of neurological illnesses and age-related disorders – from neurodegenerative diseases to ictus.

The research has shown that the CB1 receptors in mitochondria directly modulate neuronal energy metabolism, thus revealing a new mechanism for these brain signalling receptors. “Advances such as these in knowledge about the cellular and molecular biology of mitochondria are leading to developing new approaches in the prevention and treatment of neurological disorders”, stressed doctor Grandes.

* Mitochondrial CB1 receptors regulate neuronal energy metabolism (Nature Neuroscience, 15, 558–564(2012); doi:10.1038/nn.3053). Giovanni Bénard, Federico Massa, Nagore Puente, Joana Lourenço, Luigi Bellocchio, Edgar Soria-Gómez, Isabel Matias, Anna Delamarre, Mathilde Metna-Laurent, Astrid Cannich, Etienne Hebert-Chatelain, Christophe Mulle, Silvia Ortega-Gutiérrez, Mar Martín-Fontecha, Matthias Klugmann, Stephan Guggenhuber, Beat Lutz, Jürg Gertsch, Francis Chaouloff, María Luz López-Rodríguez, Pedro Grandes, Rodrigue Rossignol & Giovanni Marsicano.



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