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Here, patient\u2010derived induced pluripotent stem cell (iPSC)\u2010based cortical organoids are used to model\n                    <jats:italic>POLG<\/jats:italic>\n                    \u2010associated neurodegeneration and assess the therapeutic potential of metformin. Single\u2010cell RNA\u2010seq 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\u00a0\u00b5\n                    <jats:sc>m<\/jats:sc>\n                    , 2\u00a0months) significantly restores neuronal identity, subtype\u2010specific gene expression, and mitochondrial function. Functional assays demonstrate improved mitochondrial membrane potential (TMRE), increased mitochondrial mass (MTG, MTDR), and reduced oxidative stress (MitoSOX, BAX\/cleaved caspase 3). Notably, mitochondrial DNA (mtDNA)\u00a0copy number and the expression of mitochondrial replisome proteins (\n                    <jats:italic>POLG<\/jats:italic>\n                    ,\n                    <jats:italic>POLG<\/jats:italic>\n                    2) are upregulated, indicating enhanced mitochondrial genome maintenance. Calcium measurement confirms improved neuronal excitability. Untargeted metabolomics further reveals metformin\u2010induced metabolic reprogramming, including enrichment of the tricarboxylic acid (TCA) cycle, amino acid metabolism, and redox\u2010related pathways. Together, these findings demonstrate that metformin enhances mitochondrial integrity and neural function across multiple neuronal subtypes and offer mechanistic insights into its potential as a treatment for\n                    <jats:italic>POLG<\/jats:italic>\n                    \u2010related disorders.\n                  <\/jats:p>","DOI":"10.1002\/advs.202417721","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T09:32:50Z","timestamp":1765186370000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Metformin Restores Mitochondrial Function and Neurogenesis in\n                    <i>POLG<\/i>\n                    Patient\u2010Derived Brain Organoids"],"prefix":"10.1002","volume":"13","author":[{"given":"Zhuoyuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Biomedicine (IBM) University of Bergen Bergen 5009 Norway"},{"name":"State Key Laboratory of Oral Diseases National Clinical Research Center for Oral Diseases West China School of Stomatology Sichuan University Chengdu 610041 China"},{"name":"Department of Head and Neck Cancer Surgery West China Hospital of Stomatology Sichuan University Chengdu 610041 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsering","family":"Yangzom","sequence":"additional","affiliation":[{"name":"Department of Biomedicine (IBM) University of Bergen Bergen 5009 Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Biomedicine (IBM) University of Bergen Bergen 5009 Norway"},{"name":"NorVita Med AS Bergen 5161 Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenglong","family":"Deng","sequence":"additional","affiliation":[{"name":"Bioengineering Department and Imperial\u2010X, Imperial College London, London W12 7SL, UK\/6. National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK\/7. Cardiovascular Research Centre, Royal Brompton Hospital, London SW3 6NP, UK\/8. School of Biomedical Engineering &amp; Imaging Sciences, King's College London, London WC2R 2LS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianglu","family":"Xiao","sequence":"additional","affiliation":[{"name":"Bioengineering Department and Imperial\u2010X, Imperial College London, London W12 7SL, UK\/6. National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK\/7. Cardiovascular Research Centre, Royal Brompton Hospital, London SW3 6NP, UK\/8. School of Biomedical Engineering &amp; Imaging Sciences, King's College London, London WC2R 2LS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Yang","sequence":"additional","affiliation":[{"name":"Bioengineering Department and Imperial\u2010X, Imperial College London, London W12 7SL, UK\/6. National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK\/7. Cardiovascular Research Centre, Royal Brompton Hospital, London SW3 6NP, UK\/8. School of Biomedical Engineering &amp; Imaging Sciences, King's College London, London WC2R 2LS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3586-4218","authenticated-orcid":false,"given":"Kristina Xiao","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Biomedicine (IBM) University of Bergen Bergen 5009 Norway"},{"name":"NorVita Med AS Bergen 5161 Norway"},{"name":"Bergen Center of Medical Stem Cell Research Institute of Medicine and Dentistry University of Bergen Bergen 5009 Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr040463d"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1081\/CNV-120002155"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.06.010"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl088"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0060010"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12517"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2016.06.037"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2013.11.006"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature22047"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-016-0082-7"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-181240"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00255.2006"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2022.106114"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202307136"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.200504"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.09.027"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202012146"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl097"},{"key":"e_1_2_10_19_1","volume":"11","author":"Chen A.","year":"2025","journal-title":"bioRxiv"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.737304"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35574-x"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-017-2199-y"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3415"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2022.11.002"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.09.034"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2000.80.1.315"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2020.102784"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.06.034"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1097\/WNR.0000000000001014"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells14141064"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph16121714"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aba8271"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00400"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2016.01.010"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1159\/000360101"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-017-4342-z"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04629-3"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab931"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1382-0"},{"key":"e_1_2_10_41_1","first-page":"2825","volume":"12","author":"Pedregosa F.","year":"2011","journal-title":"J. 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