The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions

Marine Lanfranchi, Sozerko Yandiev, Géraldine Meyer-Dilhet, Salma Ellouze, Martijn Kerkhofs, Raphael Dos Reis, Audrey Garcia, Camille Blondet, Alizée Amar, Anita Kneppers, Hélène Polvèche, Damien Plassard, Marc Foretz, Benoit Viollet, Kei Sakamoto, Rémi Mounier, Cyril F. Bourgeois, Olivier Raineteau, Evelyne Goillot and Julien Courchet ()
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Marine Lanfranchi: Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène
Sozerko Yandiev: Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène
Géraldine Meyer-Dilhet: Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène
Salma Ellouze: Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène
Martijn Kerkhofs: Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène
Raphael Dos Reis: Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène
Audrey Garcia: Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène
Camille Blondet: Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène
Alizée Amar: Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène
Anita Kneppers: Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène
Hélène Polvèche: Ecole Normale Superieure de Lyon, CNRS, UMR 5239, Inserm, U1293, Universite Claude Bernard Lyon 1
Damien Plassard: GenomEast Platform, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg
Marc Foretz: Université Paris Cité, CNRS, Inserm, Institut Cochin
Benoit Viollet: Université Paris Cité, CNRS, Inserm, Institut Cochin
Kei Sakamoto: University of Copenhagen
Rémi Mounier: Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène
Cyril F. Bourgeois: Ecole Normale Superieure de Lyon, CNRS, UMR 5239, Inserm, U1293, Universite Claude Bernard Lyon 1
Olivier Raineteau: Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208
Evelyne Goillot: Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène
Julien Courchet: Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract The cellular mechanisms underlying axonal morphogenesis are essential to the formation of functional neuronal networks. We previously identified the autism-linked kinase NUAK1 as a central regulator of axon branching through the control of mitochondria trafficking. However, (1) the relationship between mitochondrial position, function and axon branching and (2) the downstream effectors whereby NUAK1 regulates axon branching remain unknown. Here, we report that mitochondria recruitment to synaptic boutons supports collateral branches stabilization rather than formation in mouse cortical neurons. NUAK1 deficiency significantly impairs mitochondrial metabolism and axonal ATP concentration, and upregulation of mitochondrial function is sufficient to rescue axonal branching in NUAK1 null neurons in vitro and in vivo. Finally, we found that NUAK1 regulates axon branching through the mitochondria-targeted microprotein BRAWNIN. Our results demonstrate that NUAK1 exerts a dual function during axon branching through its ability to control mitochondrial distribution and metabolic activity.

Date: 2024
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DOI: 10.1038/s41467-024-46146-6

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