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

Author

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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
    Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208)

  • 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
    CECS/AFM, I-STEM, 28 rue Henri Desbruères)

  • 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)

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.

Suggested Citation

  • Marine Lanfranchi & Sozerko Yandiev & Géraldine Meyer-Dilhet & Salma Ellouze & Martijn Kerkhofs & Raphael Dos Reis & Audrey Garcia & Camille Blondet & Alizée Amar & Anita Kneppers & Hélène Polvèche & , 2024. "The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46146-6
    DOI: 10.1038/s41467-024-46146-6
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