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Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency
Mutations in subunits of the mitochondrial NADH dehydrogenase cause mitochondrial complex I deficiency, a group of severe neurological diseases that can result in death in infancy. The pathogenesis of complex I deficiency remain poorly understood, and as a result there are currently no available tre...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10348588/ https://www.ncbi.nlm.nih.gov/pubmed/37399212 http://dx.doi.org/10.1371/journal.pgen.1010793 |
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author | Granat, Lucy Knorr, Debbra Y. Ranson, Daniel C. Hamer, Emma L. Chakrabarty, Ram Prosad Mattedi, Francesca Fort-Aznar, Laura Hirth, Frank Sweeney, Sean T. Vagnoni, Alessio Chandel, Navdeep S. Bateman, Joseph M. |
author_facet | Granat, Lucy Knorr, Debbra Y. Ranson, Daniel C. Hamer, Emma L. Chakrabarty, Ram Prosad Mattedi, Francesca Fort-Aznar, Laura Hirth, Frank Sweeney, Sean T. Vagnoni, Alessio Chandel, Navdeep S. Bateman, Joseph M. |
author_sort | Granat, Lucy |
collection | PubMed |
description | Mutations in subunits of the mitochondrial NADH dehydrogenase cause mitochondrial complex I deficiency, a group of severe neurological diseases that can result in death in infancy. The pathogenesis of complex I deficiency remain poorly understood, and as a result there are currently no available treatments. To better understand the underlying mechanisms, we modelled complex I deficiency in Drosophila using knockdown of the mitochondrial complex I subunit ND-75 (NDUFS1) specifically in neurons. Neuronal complex I deficiency causes locomotor defects, seizures and reduced lifespan. At the cellular level, complex I deficiency does not affect ATP levels but leads to mitochondrial morphology defects, reduced endoplasmic reticulum-mitochondria contacts and activation of the endoplasmic reticulum unfolded protein response (UPR) in neurons. Multi-omic analysis shows that complex I deficiency dramatically perturbs mitochondrial metabolism in the brain. We find that expression of the yeast non-proton translocating NADH dehydrogenase NDI1, which reinstates mitochondrial NADH oxidation but not ATP production, restores levels of several key metabolites in the brain in complex I deficiency. Remarkably, NDI1 expression also reinstates endoplasmic reticulum-mitochondria contacts, prevents UPR activation and rescues the behavioural and lifespan phenotypes caused by complex I deficiency. Together, these data show that metabolic disruption due to loss of neuronal NADH dehydrogenase activity cause UPR activation and drive pathogenesis in complex I deficiency. |
format | Online Article Text |
id | pubmed-10348588 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-103485882023-07-15 Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency Granat, Lucy Knorr, Debbra Y. Ranson, Daniel C. Hamer, Emma L. Chakrabarty, Ram Prosad Mattedi, Francesca Fort-Aznar, Laura Hirth, Frank Sweeney, Sean T. Vagnoni, Alessio Chandel, Navdeep S. Bateman, Joseph M. PLoS Genet Research Article Mutations in subunits of the mitochondrial NADH dehydrogenase cause mitochondrial complex I deficiency, a group of severe neurological diseases that can result in death in infancy. The pathogenesis of complex I deficiency remain poorly understood, and as a result there are currently no available treatments. To better understand the underlying mechanisms, we modelled complex I deficiency in Drosophila using knockdown of the mitochondrial complex I subunit ND-75 (NDUFS1) specifically in neurons. Neuronal complex I deficiency causes locomotor defects, seizures and reduced lifespan. At the cellular level, complex I deficiency does not affect ATP levels but leads to mitochondrial morphology defects, reduced endoplasmic reticulum-mitochondria contacts and activation of the endoplasmic reticulum unfolded protein response (UPR) in neurons. Multi-omic analysis shows that complex I deficiency dramatically perturbs mitochondrial metabolism in the brain. We find that expression of the yeast non-proton translocating NADH dehydrogenase NDI1, which reinstates mitochondrial NADH oxidation but not ATP production, restores levels of several key metabolites in the brain in complex I deficiency. Remarkably, NDI1 expression also reinstates endoplasmic reticulum-mitochondria contacts, prevents UPR activation and rescues the behavioural and lifespan phenotypes caused by complex I deficiency. Together, these data show that metabolic disruption due to loss of neuronal NADH dehydrogenase activity cause UPR activation and drive pathogenesis in complex I deficiency. Public Library of Science 2023-07-03 /pmc/articles/PMC10348588/ /pubmed/37399212 http://dx.doi.org/10.1371/journal.pgen.1010793 Text en © 2023 Granat et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Granat, Lucy Knorr, Debbra Y. Ranson, Daniel C. Hamer, Emma L. Chakrabarty, Ram Prosad Mattedi, Francesca Fort-Aznar, Laura Hirth, Frank Sweeney, Sean T. Vagnoni, Alessio Chandel, Navdeep S. Bateman, Joseph M. Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency |
title | Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency |
title_full | Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency |
title_fullStr | Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency |
title_full_unstemmed | Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency |
title_short | Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency |
title_sort | yeast ndi1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex i deficiency |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10348588/ https://www.ncbi.nlm.nih.gov/pubmed/37399212 http://dx.doi.org/10.1371/journal.pgen.1010793 |
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