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Cited by 25Axon Guidance and Neuronal SignalingNeuroscience and Neuropharmacology ResearchNeurogenesis and neuroplasticity mechanisms

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

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Lanfranchi, Marine, Yandiev, Sozerko, Meyer-Dilhet, Géraldine, Ellouze, Salma, Kerkhofs, Martijn, Dos Reis, Raphael, Garcia, Audrey, Blondet, Camille +12 more·2024·Nature Communications
DOI 10.1038/s41467-024-46146-6PMC PMC10958033
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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.

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  • Proper balance between motile and stationary mitochondria is crucial for maintaining high ATP levels required for proper axonal growth and branching.

    “Several studies over the last years suggest that a proper balance between motile and stationary mitochondria is crucial for maintaining the high ATP levels required for proper axonal growth and branching105,106.”

    From CYFIP1 governs the development of cortical axons by modulating calcium availability (2025) · cites this paper as [106]

    The Results section on mitochondrial recruitment (page unavailable) reports that local mitochondrial inactivation lowered the axonal ATP:ADP ratio and impaired branch growth and stabilization. It does not establish that a particular balance of motile and stationary mitochondria maintains high ATP levels for both axonal growth and branching; the Discussion also cautions that ATP alone is unlikely to suffice for branch stabilization. (LLM, conf=0.87)

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Authors
Lanfranchi, M., Yandiev, S., Meyer-Dilhet, G., Ellouze, S., Kerkhofs, M., Dos Reis, R., Garcia, A., Blondet, C., Amar, A., Kneppers, A., Polvèche, H., Plassard, D., Foretz, M., Viollet, B., Sakamoto, K., Mounier, R., Bourgeois, C. F., Raineteau, O., Goillot, E., & Courchet, J.
Affiliations
  • Lyon 1 Université (FR)
  • Centre National de la Recherche Scientifique (FR)
  • University of Copenhagen (DK)
Corresponding author
Courchet, Julien
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-03-21
Volume
15
Issue
1
Pages
2487-2487
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-46146-6
PMC
PMC10958033
OpenAlex
W4393055434
Cited by
25
References
5
Citations by year
2026: 6 · 2025: 16 · 2024: 2 · 2020: 1
FWCI
4.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • HAL (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Agence Nationale de la Recherche (ANR-10-INBS-0009, ANR-11-IDEX-0007, ANR-11-IDEX, ANR-11-LABX-0042, ANR-10, 11 IDEX - 0007)
  • Fondation pour la Recherche Médicale (SPF202110014126, AJE20141031276)
  • Novo Nordisk (NNF18CC0034900)
  • Novo Nordisk Fonden (NNF 18 CC0034900)
  • H2020 European Research Council (678302)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
NUAK1, axon branching, cortical neurons, mitochondrial metabolism, mitochondrial trafficking, synaptic boutons, AMPK-related kinases, autism spectrum disorder, collateral branches
MeSH terms
AMP-Activated Protein Kinase Kinases, Animals, Axons, Mitochondria, Neurons, Protein Kinases, Repressor Proteins, Mice, AMP-Activated Protein Kinases

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