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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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-07-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010793&type=printable |
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| _version_ | 1849332040197996544 |
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| author | Lucy Granat Debbra Y Knorr Daniel C Ranson Emma L Hamer Ram Prosad Chakrabarty Francesca Mattedi Laura Fort-Aznar Frank Hirth Sean T Sweeney Alessio Vagnoni Navdeep S Chandel Joseph M Bateman |
| author_facet | Lucy Granat Debbra Y Knorr Daniel C Ranson Emma L Hamer Ram Prosad Chakrabarty Francesca Mattedi Laura Fort-Aznar Frank Hirth Sean T Sweeney Alessio Vagnoni Navdeep S Chandel Joseph M Bateman |
| author_sort | Lucy Granat |
| collection | DOAJ |
| 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 | Article |
| id | doaj-art-720dde159eb94f2e9971e386d99fd3c0 |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2023-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-720dde159eb94f2e9971e386d99fd3c02025-08-20T03:46:20ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042023-07-01197e101079310.1371/journal.pgen.1010793Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency.Lucy GranatDebbra Y KnorrDaniel C RansonEmma L HamerRam Prosad ChakrabartyFrancesca MattediLaura Fort-AznarFrank HirthSean T SweeneyAlessio VagnoniNavdeep S ChandelJoseph M BatemanMutations 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010793&type=printable |
| spellingShingle | Lucy Granat Debbra Y Knorr Daniel C Ranson Emma L Hamer Ram Prosad Chakrabarty Francesca Mattedi Laura Fort-Aznar Frank Hirth Sean T Sweeney Alessio Vagnoni Navdeep S Chandel Joseph M Bateman Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency. PLoS Genetics |
| 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 |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010793&type=printable |
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