biostudies-literatureDenley MCSSwiss National Science Foundation410https://www.ebi.ac.uk/biostudies/studies/S-EPMC11897345biostudies-literatureUnknown8(1)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 mayCommunications biologyMitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria.PMC11897345310030_192505310030_212505175779310030_175779192505212505310030von Meyenn FPenton DPoms MGura MACherkaoui SDenley MCSStraub MSVekeriotaite BBaumgartner MRConte FFroese DSMarcionelli GDelvendahl IfalseMitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria.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 may2025-01-01T00:00:00Z2025 Mar2026-06-02T20:51:38.61Z2025-04-03T23:56:59.577ZS-EPMC118973454006940810.1038/s42003-025-07828-z