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Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans

Author

Listed:
  • Silvia Maglioni

    (IUF-Leibniz Research Institute for Environmental Medicine)

  • Alfonso Schiavi

    (IUF-Leibniz Research Institute for Environmental Medicine
    Heinrich Heine University)

  • Marlen Melcher

    (University Children’s Hospital, Heinrich Heine University)

  • Vanessa Brinkmann

    (IUF-Leibniz Research Institute for Environmental Medicine)

  • Zhongrui Luo

    (Institut de Ciència de Materials de Barcelona, ICMAB-CSIC. Campus UAB)

  • Anna Laromaine

    (Institut de Ciència de Materials de Barcelona, ICMAB-CSIC. Campus UAB)

  • Nuno Raimundo

    (Penn State College of Medicine)

  • Joel N. Meyer

    (Duke University)

  • Felix Distelmaier

    (University Children’s Hospital, Heinrich Heine University)

  • Natascia Ventura

    (IUF-Leibniz Research Institute for Environmental Medicine
    Heinrich Heine University)

Abstract

Complex-I-deficiency represents the most frequent pathogenetic cause of human mitochondriopathies. Therapeutic options for these neurodevelopmental life-threating disorders do not exist, partly due to the scarcity of appropriate model systems to study them. Caenorhabditis elegans is a genetically tractable model organism widely used to investigate neuronal pathologies. Here, we generate C. elegans models for mitochondriopathies and show that depletion of complex I subunits recapitulates biochemical, cellular and neurodevelopmental aspects of the human diseases. We exploit two models, nuo-5/NDUFS1- and lpd-5/NDUFS4-depleted animals, for a suppressor screening that identifies lutein for its ability to rescue animals’ neurodevelopmental deficits. We uncover overexpression of synaptic neuroligin as an evolutionarily conserved consequence of mitochondrial dysfunction, which we find to mediate an early cholinergic defect in C. elegans. We show lutein exerts its beneficial effects by restoring neuroligin expression independently from its antioxidant activity, thus pointing to a possible novel pathogenetic target for the human disease.

Suggested Citation

  • Silvia Maglioni & Alfonso Schiavi & Marlen Melcher & Vanessa Brinkmann & Zhongrui Luo & Anna Laromaine & Nuno Raimundo & Joel N. Meyer & Felix Distelmaier & Natascia Ventura, 2022. "Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29972-4
    DOI: 10.1038/s41467-022-29972-4
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    References listed on IDEAS

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    1. Christopher F. Bennett & Helen Vander Wende & Marissa Simko & Shannon Klum & Sarah Barfield & Haeri Choi & Victor V. Pineda & Matt Kaeberlein, 2014. "Activation of the mitochondrial unfolded protein response does not predict longevity in Caenorhabditis elegans," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
    2. Ying Liu & Buck S. Samuel & Peter C. Breen & Gary Ruvkun, 2014. "Caenorhabditis elegans pathways that surveil and defend mitochondria," Nature, Nature, vol. 508(7496), pages 406-410, April.
    3. Louis R. Lapierre & C. Daniel De Magalhaes Filho & Philip R. McQuary & Chu-Chiao Chu & Orane Visvikis & Jessica T. Chang & Sara Gelino & Binnan Ong & Andrew E. Davis & Javier E. Irazoqui & Andrew Dill, 2013. "The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans," Nature Communications, Nature, vol. 4(1), pages 1-8, October.
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