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

Silvia Maglioni, Alfonso Schiavi, Marlen Melcher, Vanessa Brinkmann, Zhongrui Luo, Anna Laromaine, Nuno Raimundo, Joel N. Meyer, Felix Distelmaier and Natascia Ventura ()
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Silvia Maglioni: IUF-Leibniz Research Institute for Environmental Medicine
Alfonso Schiavi: IUF-Leibniz Research Institute for Environmental Medicine
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

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29972-4

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