Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria
Abstract Methylmalonic aciduria (MMA) is an inborn error of metabolism resulting in loss of function of the enzyme methylmalonyl-CoA mutase (MMUT). Despite acute and persistent neurological symptoms, the pathogenesis of MMA in the central nervous system is poorly understood, which has contributed to...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-03-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07828-z |
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| author | Matthew C. S. Denley Monique S. Straub Giulio Marcionelli Miriam A. Güra David Penton Igor Delvendahl Martin Poms Beata Vekeriotaite Sarah Cherkaoui Federica Conte Ferdinand von Meyenn D. Sean Froese Matthias R. Baumgartner |
| author_facet | Matthew C. S. Denley Monique S. Straub Giulio Marcionelli Miriam A. Güra David Penton Igor Delvendahl Martin Poms Beata Vekeriotaite Sarah Cherkaoui Federica Conte Ferdinand von Meyenn D. Sean Froese Matthias R. Baumgartner |
| author_sort | Matthew C. S. Denley |
| collection | DOAJ |
| description | Abstract Methylmalonic aciduria (MMA) is an inborn error of metabolism resulting in loss of function of the enzyme methylmalonyl-CoA mutase (MMUT). Despite acute and persistent neurological symptoms, the pathogenesis of MMA in the central nervous system is poorly understood, which has contributed to a dearth of effective brain specific treatments. Here we utilised patient-derived induced pluripotent stem cells and in vitro differentiation to generate a human neuronal model of MMA. We reveal strong evidence of mitochondrial dysfunction caused by deficiency of MMUT in patient neurons. By employing patch-clamp electrophysiology, targeted metabolomics, and bulk transcriptomics, we expose an altered state of excitability, which is exacerbated by application of dimethyl-2-oxoglutarate, and we suggest may be connected to metabolic rewiring. Our work provides first evidence of mitochondrial driven neuronal dysfunction in MMA, which through our comprehensive characterisation of this paradigmatic model, enables first steps to identifying effective therapies. |
| format | Article |
| id | doaj-art-7f871f05079143c5bbd2ea99f36194dd |
| institution | DOAJ |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-7f871f05079143c5bbd2ea99f36194dd2025-08-20T03:01:45ZengNature PortfolioCommunications Biology2399-36422025-03-018111710.1038/s42003-025-07828-zMitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduriaMatthew C. S. Denley0Monique S. Straub1Giulio Marcionelli2Miriam A. Güra3David Penton4Igor Delvendahl5Martin Poms6Beata Vekeriotaite7Sarah Cherkaoui8Federica Conte9Ferdinand von Meyenn10D. Sean Froese11Matthias R. Baumgartner12Division of Metabolism and Children’s Research Center, University Children’s Hospital Zurich, University of ZurichDivision of Metabolism and Children’s Research Center, University Children’s Hospital Zurich, University of ZurichDivision of Metabolism and Children’s Research Center, University Children’s Hospital Zurich, University of ZurichDivision of Metabolism and Children’s Research Center, University Children’s Hospital Zurich, University of ZurichElectrophysiology Core Facility, University of ZurichDepartment of Molecular Life Sciences, University of ZurichClinical Chemistry and Biochemistry and Children’s Research Center, University Children’s Hospital Zurich, University of ZurichLaboratory of Nutrition and Metabolic Epigenetics, Institute for Food, Nutrition and Health, Department of Health Sciences and Technology, ETH ZurichPediatric Cancer Metabolism Laboratory, Children’s Research Center, University Children’s Hospital Zurich, University of ZurichDepartment of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud, University Medical CenterLaboratory of Nutrition and Metabolic Epigenetics, Institute for Food, Nutrition and Health, Department of Health Sciences and Technology, ETH ZurichDivision of Metabolism and Children’s Research Center, University Children’s Hospital Zurich, University of ZurichDivision of Metabolism and Children’s Research Center, University Children’s Hospital Zurich, University of ZurichAbstract Methylmalonic aciduria (MMA) is an inborn error of metabolism resulting in loss of function of the enzyme methylmalonyl-CoA mutase (MMUT). Despite acute and persistent neurological symptoms, the pathogenesis of MMA in the central nervous system is poorly understood, which has contributed to a dearth of effective brain specific treatments. Here we utilised patient-derived induced pluripotent stem cells and in vitro differentiation to generate a human neuronal model of MMA. We reveal strong evidence of mitochondrial dysfunction caused by deficiency of MMUT in patient neurons. By employing patch-clamp electrophysiology, targeted metabolomics, and bulk transcriptomics, we expose an altered state of excitability, which is exacerbated by application of dimethyl-2-oxoglutarate, and we suggest may be connected to metabolic rewiring. Our work provides first evidence of mitochondrial driven neuronal dysfunction in MMA, which through our comprehensive characterisation of this paradigmatic model, enables first steps to identifying effective therapies.https://doi.org/10.1038/s42003-025-07828-z |
| spellingShingle | Matthew C. S. Denley Monique S. Straub Giulio Marcionelli Miriam A. Güra David Penton Igor Delvendahl Martin Poms Beata Vekeriotaite Sarah Cherkaoui Federica Conte Ferdinand von Meyenn D. Sean Froese Matthias R. Baumgartner Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria Communications Biology |
| title | Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria |
| title_full | Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria |
| title_fullStr | Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria |
| title_full_unstemmed | Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria |
| title_short | Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria |
| title_sort | mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria |
| url | https://doi.org/10.1038/s42003-025-07828-z |
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