The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
21 Mar 2024
21 Mar 2024
Historique:
received:
25
03
2023
accepted:
15
02
2024
medline:
22
3
2024
pubmed:
22
3
2024
entrez:
22
3
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38514619
doi: 10.1038/s41467-024-46146-6
pii: 10.1038/s41467-024-46146-6
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2487Subventions
Organisme : Fondation pour la Recherche Médicale (Foundation for Medical Research in France)
ID : AJE20141031276
Organisme : Fondation pour la Recherche Médicale (Foundation for Medical Research in France)
ID : SPF202110014126
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : ERC-STG-678302-NEUROMET
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-11-LABX-0042
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-11-IDEX-0007
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-10-INBS-0009
Organisme : Novo Nordisk Fonden (Novo Nordisk Foundation)
ID : NNF18CC0034900
Informations de copyright
© 2024. The Author(s).
Références
Lewis, T. L., Courchet, J. & Polleux, F. Cell biology in neuroscience: cellular and molecular mechanisms underlying axon formation, growth, and branching. J. Cell Biol. 202, 837–848 (2013).
pubmed: 24043699
pmcid: 3776347
doi: 10.1083/jcb.201305098
Kalil, K. & Dent, E. W. Branch management: mechanisms of axon branching in the developing vertebrate CNS. Nat. Rev. Neurosci. 15, 7–18 (2014).
pubmed: 24356070
pmcid: 4063290
doi: 10.1038/nrn3650
Dent, E. W. & Kalil, K. Axon branching requires interactions between dynamic microtubules and actin filaments. J. Neurosci. 21, 9757–9769 (2001).
pubmed: 11739584
pmcid: 6763027
doi: 10.1523/JNEUROSCI.21-24-09757.2001
Dent, E. W., Callaway, J. L., Szebenyi, G., Baas, P. W. & Kalil, K. Reorganization and movement of microtubules in axonal growth cones and developing interstitial branches. J. Neurosci. 19, 8894–8908 (1999).
pubmed: 10516309
pmcid: 6782770
doi: 10.1523/JNEUROSCI.19-20-08894.1999
Brosig, A. et al. The axonal membrane protein PRG2 Inhibits PTEN and directs growth to branches. Cell Rep. 29, 2028–2040.e8 (2019).
pubmed: 31722215
pmcid: 6856728
doi: 10.1016/j.celrep.2019.10.039
Spillane, M., Ketschek, A., Merianda, T. T., Twiss, J. L. & Gallo, G. Mitochondria coordinate sites of axon branching through localized intra-axonal protein synthesis. Cell Rep. 5, 1564–1575 (2013).
pubmed: 24332852
pmcid: 3947524
doi: 10.1016/j.celrep.2013.11.022
Sun, T., Qiao, H., Pan, P.-Y., Chen, Y. & Sheng, Z.-H. Motile axonal mitochondria contribute to the variability of presynaptic strength. Cell Rep. 4, 413–419 (2013).
pubmed: 23891000
pmcid: 3757511
doi: 10.1016/j.celrep.2013.06.040
Matsumoto, N. et al. Intermitochondrial signaling regulates the uniform distribution of stationary mitochondria in axons. Mol. Cell Neurosci. 119, 103704 (2022).
pubmed: 35131465
doi: 10.1016/j.mcn.2022.103704
Li, S., Xiong, G.-J., Huang, N. & Sheng, Z.-H. The cross-talk of energy sensing and mitochondrial anchoring sustains synaptic efficacy by maintaining presynaptic metabolism. Nat. Metab. 2, 1077–1095 (2020).
pubmed: 33020662
pmcid: 7572785
doi: 10.1038/s42255-020-00289-0
Williams, T., Courchet, J., Viollet, B., Brenman, J. E. & Polleux, F. AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress. Proc. Natl. Acad. Sci. USA 108, 5849–5854 (2011).
pubmed: 21436046
pmcid: 3078367
doi: 10.1073/pnas.1013660108
Courchet, J. et al. Terminal axon branching is regulated by the LKB1-NUAK1 kinase pathway via presynaptic mitochondrial capture. Cell 153, 1510–1525 (2013).
pubmed: 23791179
pmcid: 3729210
doi: 10.1016/j.cell.2013.05.021
Iossifov, I. et al. De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285–299 (2012).
pubmed: 22542183
pmcid: 3619976
doi: 10.1016/j.neuron.2012.04.009
Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014).
pubmed: 25363768
pmcid: 4313871
doi: 10.1038/nature13908
Alemany, S. et al. New suggestive genetic loci and biological pathways for attention function in adult attention-deficit/hyperactivity disorder. Am. J. Med. Genetic. Part B Neuropsychiatr. Genet. https://doi.org/10.1002/ajmg.b.32341 (2015).
Johnson, M. R. et al. Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease. Nat. Neurosci. 19, 223–232 (2016).
pubmed: 26691832
doi: 10.1038/nn.4205
Vojinovic, D. et al. Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume. Nat. Commun. 9, 3945 (2018).
pubmed: 30258056
pmcid: 6158214
doi: 10.1038/s41467-018-06234-w
Courchet, V. et al. Haploinsufficiency of autism spectrum disorder candidate gene NUAK1 impairs cortical development and behavior in mice. Nat. Commun. 9, 4289 (2018).
pubmed: 30327473
pmcid: 6191442
doi: 10.1038/s41467-018-06584-5
Zagórska, A. et al. New roles for the LKB1-NUAK pathway in controlling myosin phosphatase complexes and cell adhesion. Sci. Signal. 3, ra25–ra25 (2010).
pubmed: 20354225
doi: 10.1126/scisignal.2000616
Cossa, G. et al. Localized inhibition of protein phosphatase 1 by NUAK1 promotes spliceosome activity and reveals a MYC-sensitive feedback control of transcription. Mol. Cell 77, 1322–1339.e11 (2020).
pubmed: 32006464
pmcid: 7086158
doi: 10.1016/j.molcel.2020.01.008
Liu, L. et al. Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Nature 483, 608–612 (2012).
pubmed: 22460906
doi: 10.1038/nature10927
Escalona, E., Muñoz, M., Pincheira, R., Elorza, Á. A. & Castro, A. F. Cytosolic NUAK1 enhances ATP production by maintaining proper glycolysis and mitochondrial function in cancer cells. Front. Oncol. 10, 1123 (2020).
pubmed: 32754444
pmcid: 7367139
doi: 10.3389/fonc.2020.01123
Bulina, M. E. et al. Chromophore-assisted light inactivation (CALI) using the phototoxic fluorescent protein KillerRed. Nat. Protoc. 1, 947–953 (2006).
pubmed: 17406328
doi: 10.1038/nprot.2006.89
Bulina, M. E. et al. A genetically encoded photosensitizer. Nat. Biotechnol. 24, 95–99 (2006).
pubmed: 16369538
doi: 10.1038/nbt1175
Zhang, S. et al. Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly. Nat. Commun. 11, 1312 (2020).
pubmed: 32161263
pmcid: 7066179
doi: 10.1038/s41467-020-14999-2
Liang, C. et al. Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis. Cell Rep. 40, 111204 (2022).
pubmed: 35977508
doi: 10.1016/j.celrep.2022.111204
Tantama, M., Martínez-François, J. R., Mongeon, R. & Yellen, G. Imaging energy status in live cells with a fluorescent biosensor of the intracellular ATP-to-ADP ratio. Nat. Commun. 4, 2550 (2013).
pubmed: 24096541
doi: 10.1038/ncomms3550
Pathak, D. et al. The role of mitochondrially derived ATP in synaptic vesicle recycling. J. Biol. Chem. 290, 22325–22336 (2015).
pubmed: 26126824
pmcid: 4566209
doi: 10.1074/jbc.M115.656405
Goebbels, S. et al. Genetic targeting of principal neurons in neocortex and hippocampus of NEX-Cre mice. Genesis 44, 611–621 (2006).
pubmed: 17146780
doi: 10.1002/dvg.20256
Tao, K., Matsuki, N. & Koyama, R. AMP-activated protein kinase mediates activity-dependent axon branching by recruiting mitochondria to axon. Dev. Neurobiol. 74, 557–573 (2014).
pubmed: 24218086
doi: 10.1002/dneu.22149
Meyer-Dilhet, G. & Courchet, J. In utero cortical electroporation of plasmids in the mouse embryo. STAR Protoc. 1, 100027 (2020).
pubmed: 32685931
pmcid: 7357676
doi: 10.1016/j.xpro.2020.100027
Steinberg, G. R. & Carling, D. AMP-activated protein kinase: the current landscape for drug development. Nat. Rev. Drug Discov. 18, 527–551 (2019).
pubmed: 30867601
doi: 10.1038/s41573-019-0019-2
Guigas, B. et al. Beyond AICA riboside: in search of new specific AMP‐activated protein kinase activators. Iubmb Life 61, 18–26 (2009).
pubmed: 18798311
pmcid: 2845387
doi: 10.1002/iub.135
Collodet, C. et al. AMPK promotes induction of the tumor suppressor FLCN through activation of TFEB independently of mTOR. FASEB J. 33, 12374–12391 (2019).
pubmed: 31404503
pmcid: 6902666
doi: 10.1096/fj.201900841R
Fisher, J. S. et al. Muscle contractions, AICAR, and insulin cause phosphorylation of an AMPK-related kinase. Am. J. Physiol. Endocrinol. Metab. 289, E986–E992 (2005).
pubmed: 16030062
doi: 10.1152/ajpendo.00335.2004
Lizcano, J. M. et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 23, 833–843 (2004).
pubmed: 14976552
pmcid: 381014
doi: 10.1038/sj.emboj.7600110
Sainath, R., Ketschek, A., Grandi, L. & Gallo, G. CSPGs inhibit axon branching by impairing mitochondria-dependent regulation of actin dynamics and axonal translation. Dev. Neurobiol. 77, 454–473 (2017).
pubmed: 27429169
doi: 10.1002/dneu.22420
Dickey, A. S. & Strack, S. PKA/AKAP1 and PP2A/Bβ2 regulate neuronal morphogenesis via Drp1 phosphorylation and mitochondrial bioenergetics.J. Neurosci. 31, 15716–15726 (2011).
pubmed: 22049414
pmcid: 3328351
doi: 10.1523/JNEUROSCI.3159-11.2011
Vos, M. et al. Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency. Science 336, 1306–1310 (2012).
pubmed: 22582012
doi: 10.1126/science.1218632
Oruganty-Das, A., Ng, T., Udagawa, T., Goh, E. L. K. & Richter, J. D. Translational control of mitochondrial energy production mediates neuron morphogenesis. Cell Metab. 16, 789–800 (2012).
pubmed: 23217258
pmcid: 3597101
doi: 10.1016/j.cmet.2012.11.002
Gunnewiek, T. M. K. et al. m.3243A > G-induced mitochondrial dysfunction impairs human neuronal development and reduces neuronal network activity and synchronicity. Cell Rep. 31, 107538 (2020).
doi: 10.1016/j.celrep.2020.107538
Lewis, T. L., Kwon, S.-K., Lee, A., Shaw, R. & Polleux, F. MFF-dependent mitochondrial fission regulates presynaptic release and axon branching by limiting axonal mitochondria size. Nat. Commun. 9, 5008 (2018).
pubmed: 30479337
pmcid: 6258764
doi: 10.1038/s41467-018-07416-2
Fernandez, A. et al. Mitochondrial dysfunction leads to cortical under-connectivity and cognitive impairment. Neuron 102, 1127–1142.e3 (2019).
pubmed: 31079872
pmcid: 6668992
doi: 10.1016/j.neuron.2019.04.013
Meyer, M. P. & Smith, S. J. Evidence from in vivo imaging that synaptogenesis guides the growth and branching of axonal arbors by two distinct mechanisms. J Neurosci. 26, 3604–3614 (2006).
pubmed: 16571769
pmcid: 6673851
doi: 10.1523/JNEUROSCI.0223-06.2006
Ruthazer, E. S., Li, J. & Cline, H. T. Stabilization of axon branch dynamics by synaptic maturation. J. Neurosci. 26, 3594–3603 (2006).
pubmed: 16571768
pmcid: 6673865
doi: 10.1523/JNEUROSCI.0069-06.2006
Javaherian, A. & Cline, H. T. Coordinated motor neuron axon growth and neuromuscular synaptogenesis are promoted by CPG15 in vivo. Neuron 45, 505–512 (2005).
pubmed: 15721237
doi: 10.1016/j.neuron.2004.12.051
Wong, H. H.-W. et al. RNA docking and local translation regulate site-specific axon remodeling in vivo. Neuron 95, 852–868.e8 (2017).
pubmed: 28781168
pmcid: 5563073
doi: 10.1016/j.neuron.2017.07.016
Lilley, B. N., Pan, Y. A. & Sanes, J. R. SAD kinases sculpt axonal arbors of sensory neurons through long- and short-term responses to neurotrophin signals. Neuron 79, 39–53 (2013).
pubmed: 23790753
pmcid: 3725037
doi: 10.1016/j.neuron.2013.05.017
Vos, M., Lauwers, E. & Verstreken, P. Synaptic mitochondria in synaptic transmission and organization of vesicle pools in health and disease.Front. Synap. Neurosci. 2, 139 (2010).
Attwell, D. & Laughlin, S. B. An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow Metab. 21, 1133–1145 (2001).
pubmed: 11598490
doi: 10.1097/00004647-200110000-00001
Rangaraju, V., Calloway, N. & Ryan, T. A. Activity-driven local ATP synthesis is required for synaptic function. Cell 156, 825–835 (2014).
pubmed: 24529383
pmcid: 3955179
doi: 10.1016/j.cell.2013.12.042
Ashrafi, G., Juan-Sanz, J., de, Farrell, R. J. & Ryan, T. A. Molecular tuning of the axonal mitochondrial Ca2+ Uniporter ensures metabolic flexibility of neurotransmission. Neuron 105, 678–687.e5 (2020).
pubmed: 31862210
doi: 10.1016/j.neuron.2019.11.020
Vaccaro, V., Devine, M. J., Higgs, N. F. & Kittler, J. T. Miro1-dependent mitochondrial positioning drives the rescaling of presynaptic Ca2+ signals during homeostatic plasticity. EMBO Rep. 18, 231–240 (2017).
pubmed: 28039205
doi: 10.15252/embr.201642710
Villegas, R. et al. Calcium release from intra-axonal endoplasmic reticulum leads to axon degeneration through mitochondrial dysfunction. J. Neurosci. 34, 7179–7189 (2014).
pubmed: 24849352
pmcid: 4028495
doi: 10.1523/JNEUROSCI.4784-13.2014
Kwon, S.-K. et al. LKB1 regulates mitochondria-dependent presynaptic calcium clearance and neurotransmitter release properties at excitatory synapses along cortical axons. PLoS Biol. 14, e1002516 (2016).
pubmed: 27429220
pmcid: 4948842
doi: 10.1371/journal.pbio.1002516
Hirabayashi, Y. et al. ER-mitochondria tethering by PDZD8 regulates Ca(2+) dynamics in mammalian neurons. Science 358, 623–630 (2017).
pubmed: 29097544
pmcid: 5818999
doi: 10.1126/science.aan6009
Martínez-Reyes, I. & Chandel, N. S. Mitochondrial TCA cycle metabolites control physiology and disease. Nat. Commun. 11, 102 (2020).
pubmed: 31900386
pmcid: 6941980
doi: 10.1038/s41467-019-13668-3
Hutchins, B. I. & Kalil, K. Differential outgrowth of axons and their branches is regulated by localized calcium transients. J. Neurosci. 28, 143–153 (2008).
pubmed: 18171932
pmcid: 2474798
doi: 10.1523/JNEUROSCI.4548-07.2008
Llorente-Folch, I. et al. Calcium-regulation of mitochondrial respiration maintains ATP homeostasis and requires ARALAR/AGC1-malate aspartate shuttle in intact cortical neurons. J. Neurosci. 33, 13957–71–13971a (2013).
pubmed: 23986233
pmcid: 6618512
doi: 10.1523/JNEUROSCI.0929-13.2013
Ulisse, V. et al. Regulation of axonal morphogenesis by the mitochondrial protein Efhd1. Life Sci. Alliance 3, e202000753 (2020).
Vaarmann, A. et al. Mitochondrial biogenesis is required for axonal growth. Development 143, 1981–1992 (2016).
pubmed: 27122166
Dzamko, N. et al. AMPK beta1 deletion reduces appetite, preventing obesity and hepatic insulin resistance. J. Biol. Chem. 285, 115–122 (2009).
pubmed: 19892703
pmcid: 2804155
doi: 10.1074/jbc.M109.056762
Sakamoto, K., Göransson, O., Hardie, D. G. & Alessi, D. R. Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR. Am. J. Physiol. Endocrinol. Metab. 287, E310–E317 (2004).
pubmed: 15068958
doi: 10.1152/ajpendo.00074.2004
Ahwazi, D. et al. Investigation of the specificity and mechanism of action of the ULK1/AMPK inhibitor SBI-0206965. Biochem. J. 478, 2977–2997 (2021).
pubmed: 34259310
doi: 10.1042/BCJ20210284
Vogt, J., Traynor, R. & Sapkota, G. P. The specificities of small molecule inhibitors of the TGFß and BMP pathways. Cell Signal. 23, 1831–1842 (2011).
pubmed: 21740966
doi: 10.1016/j.cellsig.2011.06.019
Zheng, X. & Xiang, M. Mitochondrion‐located peptides and their pleiotropic physiological functions. FEBS J. 289, 6919–6935 (2022).
pubmed: 35599630
doi: 10.1111/febs.16532
Miller, B. et al. Mitochondrial DNA variation in Alzheimer’s disease reveals a unique microprotein called SHMOOSE. Mol. Psychiatr. 1–14 https://doi.org/10.1038/s41380-022-01769-3 (2022).
Miller, B., Kim, S.-J., Kumagai, H., Yen, K. & Cohen, P. Mitochondria-derived peptides in aging and healthspan. J. Clin. Investig. 132, e158449 (2022).
pubmed: 35499074
pmcid: 9057581
doi: 10.1172/JCI158449
Chalkia, D. et al. Association between mitochondrial DNA haplogroup variation and autism spectrum disorders. Jama Psychiatry 74, 1161 (2017).
pubmed: 28832883
pmcid: 5710217
doi: 10.1001/jamapsychiatry.2017.2604
Wang, Y., Picard, M. & Gu, Z. Genetic evidence for elevated pathogenicity of mitochondrial DNA heteroplasmy in autism spectrum disorder. Plos Genet. 12, e1006391 (2016).
pubmed: 27792786
pmcid: 5085253
doi: 10.1371/journal.pgen.1006391
Murtaza, N. et al. Neuron-specific protein network mapping of autism risk genes identifies shared biological mechanisms and disease-relevant pathologies. Cell Rep. 41, 111678 (2022).
pubmed: 36417873
doi: 10.1016/j.celrep.2022.111678
Cabungcal, J.-H. et al. Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia. Neuron 83, 1073–1084 (2014).
pubmed: 25132466
pmcid: 4418441
doi: 10.1016/j.neuron.2014.07.028
Zanelli, S. A., Solenski, N. J., Rosenthal, R. E. & Fiskum, G. Mechanisms of ischemic neuroprotection by acetyl-L-carnitine. Annal. N. Y. Acad. Sci. 1053, 153–161 (2005).
Tefera, T. W. & Borges, K. Metabolic dysfunctions in amyotrophic lateral sclerosis pathogenesis and potential metabolic treatments. Front. Neurosci. 10, 611 (2016).
pubmed: 28119559
Chiechio, S., Canonico, P. L. & Grilli, M. l-Acetylcarnitine: a mechanistically distinctive and potentially rapid-acting antidepressant drug. Int. J. Mol. Sci. 19, 11 (2017).
Filiou, M. D. & Sandi, C. Anxiety and brain mitochondria: a bidirectional crosstalk. Trends Neurosci. 42, 573–588 (2019).
pubmed: 31362874
doi: 10.1016/j.tins.2019.07.002
Cherix, A. et al. Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine. eLife 9, e50631 (2020).