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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
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.
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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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