Academic Journal
Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency
| العنوان: | Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency |
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| المؤلفون: | Granat, Lucy, Ranson, Daniel, Knorr, Debbra, Hamer, Emma, Chakrabarty, Ram Prosad, Mattedi, Francesca, Fort-Aznar, Laura, Hirth, Frank, Sweeney, Sean, Vagnoni, Alessio, Chandel, Navdeep S., Bateman, Joseph |
| المصدر: | Granat , L , Ranson , D , Knorr , D , Hamer , E , Chakrabarty , R P , Mattedi , F , Fort-Aznar , L , Hirth , F , Sweeney , S , Vagnoni , A , Chandel , N S & Bateman , J 2023 , ' Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency ' , PLoS genetics , vol. 19 , no. 7 , e1010793 . https://doi.org/10.1371/journal.pgen.1010793 , https://doi.org/10.1371/journal.pgen.1010793 |
| سنة النشر: | 2023 |
| المجموعة: | King's College, London: Research Portal |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1371/journal.pgen.1010793 |
| الاتاحة: | https://kclpure.kcl.ac.uk/portal/en/publications/e56f87c3-f1df-4c21-9777-93ff9290ee08 https://doi.org/10.1371/journal.pgen.1010793 http://www.scopus.com/inward/record.url?scp=85164473153&partnerID=8YFLogxK |
| Rights: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.2DDF1851 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1371/journal.pgen.1010793 |
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