biostudies-literatureZhang ZERC IMITemasek TrustNIHR Imperial Biomedical Research CentreH2020UKRI guarantee funding for Horizon Europe MSCA Postdoctoral FellowshipsBoehringer Ingelheim LtdRoyal SocietyUKRI MRC Research GrantUKRI Future Leaders FellowshipSwiss National Science FoundationPOLG FoundationNVIDIA Academic Hardware Grant ProgramUniversity of Bergen Meltzers HøyskolefondsMedical Research CouncilTFS Research GrantsGerda Meyer Nyquist Legate17721https://www.ebi.ac.uk/biostudies/studies/S-EPMC12822396biostudies-literatureUnknown13(4)Mitochondrial dysfunction and impaired neurogenesis are central to mitochondrial DNA polymerase (POLG)-related disorders, yet therapeutic options remain limited. Here, patient-derived induced pluripotent stem cell (iPSC)-based cortical organoids are used to model POLG-associated neurodegeneration and assess the therapeutic potential of metformin. Single-cell RNA-seq reveals distinct vulnerabilities in dopaminergic, glutamatergic, and GABAergic neuronal subtypes, with dopaminergic neurons exhibiting the most severe loss and mitochondrial transcriptomic deficits. Metformin treatment (250 µm, 2 months) significantly restores neuronal identity, subtype-specific gene expression, and mitochondrial function. Functional assays demonstrate improved mitochondrial membrane potential (TMRE), increasedAdvanced science (Weinheim, Baden-Wurttemberg, Germany)Metformin Restores Mitochondrial Function and Neurogenesis in POLG Patient-Derived Brain Organoids.PMC12822396952172103816102RDA01IEC∖NSFC∖211235103517133MR/V023799/1101005122MR/U506710/1220785MC/PC/21013104291EP/Z002206/1Deng SYang GYangzom TLu NZhang ZXiao XLiang KXfalseMetformin Restores Mitochondrial Function and Neurogenesis in POLG Patient-Derived Brain Organoids.Mitochondrial dysfunction and impaired neurogenesis are central to mitochondrial DNA polymerase (POLG)-related disorders, yet therapeutic options remain limited. Here, patient-derived induced pluripotent stem cell (iPSC)-based cortical organoids are used to model POLG-associated neurodegeneration and assess the therapeutic potential of metformin. Single-cell RNA-seq reveals distinct vulnerabilities in dopaminergic, glutamatergic, and GABAergic neuronal subtypes, with dopaminergic neurons exhibiting the most severe loss and mitochondrial transcriptomic deficits. Metformin treatment (250 µm, 2 months) significantly restores neuronal identity, subtype-specific gene expression, and mitochondrial function. Functional assays demonstrate improved mitochondrial membrane potential (TMRE), increased2026-01-01T00:00:00Z2026 Jan2026-06-06T19:46:43.03Z2026-06-04T03:11:19.373ZS-EPMC128223964135557910.1002/advs.202417721