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Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans
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 tr...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9098500/ https://www.ncbi.nlm.nih.gov/pubmed/35551180 http://dx.doi.org/10.1038/s41467-022-29972-4 |
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author | Maglioni, Silvia Schiavi, Alfonso Melcher, Marlen Brinkmann, Vanessa Luo, Zhongrui Laromaine, Anna Raimundo, Nuno Meyer, Joel N. Distelmaier, Felix Ventura, Natascia |
author_facet | Maglioni, Silvia Schiavi, Alfonso Melcher, Marlen Brinkmann, Vanessa Luo, Zhongrui Laromaine, Anna Raimundo, Nuno Meyer, Joel N. Distelmaier, Felix Ventura, Natascia |
author_sort | Maglioni, Silvia |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9098500 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-90985002022-05-14 Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans Maglioni, Silvia Schiavi, Alfonso Melcher, Marlen Brinkmann, Vanessa Luo, Zhongrui Laromaine, Anna Raimundo, Nuno Meyer, Joel N. Distelmaier, Felix Ventura, Natascia Nat Commun Article 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. Nature Publishing Group UK 2022-05-12 /pmc/articles/PMC9098500/ /pubmed/35551180 http://dx.doi.org/10.1038/s41467-022-29972-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Maglioni, Silvia Schiavi, Alfonso Melcher, Marlen Brinkmann, Vanessa Luo, Zhongrui Laromaine, Anna Raimundo, Nuno Meyer, Joel N. Distelmaier, Felix Ventura, Natascia Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans |
title | Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans |
title_full | Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans |
title_fullStr | Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans |
title_full_unstemmed | Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans |
title_short | Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans |
title_sort | neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in c. elegans |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9098500/ https://www.ncbi.nlm.nih.gov/pubmed/35551180 http://dx.doi.org/10.1038/s41467-022-29972-4 |
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