{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Denley MCS"],"funding":["Swiss National Science Foundation"],"pagination":["410"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11897345"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["8(1)"],"pubmed_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"],"journal":["Communications biology"],"pubmed_title":["Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria."],"pmcid":["PMC11897345"],"funding_grant_id":["310030_192505","310030_212505","175779","310030_175779","192505","212505","310030"],"pubmed_authors":["von Meyenn F","Penton D","Poms M","Gura MA","Cherkaoui S","Denley MCS","Straub MS","Vekeriotaite B","Baumgartner MR","Conte F","Froese DS","Marcionelli G","Delvendahl I"],"additional_accession":[]},"is_claimable":false,"name":"Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria.","description":"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","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Mar","modification":"2026-06-02T20:51:38.61Z","creation":"2025-04-03T23:56:59.577Z"},"accession":"S-EPMC11897345","cross_references":{"pubmed":["40069408"],"doi":["10.1038/s42003-025-07828-z"]}}