{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:23:32Z","timestamp":1789392212960,"version":"build-2803163510"},"reference-count":76,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,11,23]],"date-time":"2025-11-23T00:00:00Z","timestamp":1763856000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,23]],"date-time":"2025-11-23T00:00:00Z","timestamp":1763856000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100010724","name":"Health Systems Research Institute","doi-asserted-by":"publisher","award":["62\u2010030"],"award-info":[{"award-number":["62\u2010030"]}],"id":[{"id":"10.13039\/501100010724","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013238","name":"Faculty of Medicine Siriraj Hospital, Mahidol University","doi-asserted-by":"publisher","award":["IO R016531048"],"award-info":[{"award-number":["IO R016531048"]}],"id":[{"id":"10.13039\/501100013238","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008966","name":"Thailand Toray Science Foundation","doi-asserted-by":"publisher","award":["12\/2019"],"award-info":[{"award-number":["12\/2019"]}],"id":[{"id":"10.13039\/100008966","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["FEBS Open Bio"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:p>Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder caused by mitochondrial DNA mutations in complex I of the respiratory chain, leading to impaired ATP production, mitochondrial fragmentation, and oxidative stress that contribute to vision loss. This study investigated the potential repurposing of metformin, a widely used antidiabetic drug, in fibroblasts from LHON patients carrying the m.11778G&gt;A mutation. Fibroblasts from LHON patients and healthy individuals were treated with metformin, and mitochondrial function was assessed using high\u2010content imaging, biochemical assays, immunoblotting, immunofluorescence, and Seahorse analysis. Metformin reduced mitochondrial fragmentation, increased network length, stabilized mitochondrial membrane potential, enhanced ATP production, and lowered ROS accumulation under oxidative stress. Metformin significantly increased mitophagy and autophagic flux, as shown by LC3B puncta quantification with and without chloroquine, and activated AMPK signaling through increased AMPK\u03b11\/2 phosphorylation and AMPK\u03b21 Ser182 phosphorylation. In addition, metformin promoted PGC\u20101\u03b1 nuclear translocation, indicating stimulation of mitochondrial biogenesis, while maintaining mtDNA copy number and supporting oxidative phosphorylation. These findings suggest that metformin, at clinically relevant concentrations, enhances mitochondrial health and function in LHON fibroblasts, supporting its potential as an affordable and safe therapeutic option to mitigate vision loss in LHON.<\/jats:p>","DOI":"10.1002\/2211-5463.70165","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T07:52:51Z","timestamp":1763970771000},"page":"885-905","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Metformin promotes mitochondrial integrity through\n                    <scp>AMPK<\/scp>\n                    \u2010signaling in Leber's hereditary optic neuropathy"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7863-6936","authenticated-orcid":false,"given":"Chatnapa","family":"Panusatid","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine Siriraj Hospital Mahidol University  Bangkok Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9277-0687","authenticated-orcid":false,"given":"Rapasviranda","family":"Soiyangsuk","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine Siriraj Hospital Mahidol University  Bangkok Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7109-7578","authenticated-orcid":false,"given":"Maneeluck","family":"Tanadjindarat","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine Siriraj Hospital Mahidol University  Bangkok Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7308-3853","authenticated-orcid":false,"given":"Chayanon","family":"Peerapittayamongkol","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine Siriraj Hospital Mahidol University  Bangkok Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M006476200"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.39.3.162"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/02713683.2020.1736307"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1215233"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601963"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a011072"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1217113109"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2012.81"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199630050-00003"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1530\/JME-12-0007"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsif.2017.0774"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI13505"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2021.0019"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.14141"},{"key":"e_1_2_10_16_1","first-page":"1056","article-title":"Metformin restores the mitochondrial network and reverses mitochondrial dysfunction in down syndrome cells","volume":"26","author":"Izzo A","year":"2017","journal-title":"Hum Mol Genet"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04431-8"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-014-9632-2"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.04.017"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4684-7200-4_4"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00769635"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2006-7-10-r100"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mex.2022.101685"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2018.04.005"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-510X(99)00087-8"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0106779"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2008.06.013"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2012.10.035"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2009.10.003"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M503062200"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.9.3671"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(62)90189-4"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1156906"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.064"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/543758"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18091865"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2019.101393"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.2337\/db16-0915"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1196371"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X16671528"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2016.00299"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a015008"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00538.2010"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2007.00357.x"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-2697(02)00539-0"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresrev.2010.11.004"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-009-0477-x"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.114958"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/2524174"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2019.01.021"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20140620"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.09.070"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2017.08.018"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-011-2340-0"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.832707"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101626"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200544070-00004"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-015-0323-x"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2020.09.001"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.01.003"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11808"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10856"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.93936"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0222-4"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00753"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2122287119"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1021\/mp300429e"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2013.06.044"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1076\/0271-3683(200003)2031-9FT195"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10863-014-9571-y"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2011.10.012"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr170"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr180"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14834"},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.5115\/acb.20.320"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2023.05.019"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12974"}],"container-title":["FEBS Open Bio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/2211-5463.70165","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/2211-5463.70165","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/2211-5463.70165","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T14:19:50Z","timestamp":1778941190000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1002\/2211-5463.70165"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,23]]},"references-count":76,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1002\/2211-5463.70165"],"URL":"https:\/\/doi.org\/10.1002\/2211-5463.70165","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1002\/2211-5463.70165\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/2211-5463.70165\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/2211-5463.70165\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/2211-5463.70165\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/2211-5463.70165\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/2211-5463.70165\/v2\/decision1","asserted-by":"object"}]},"ISSN":["2211-5463","2211-5463"],"issn-type":[{"value":"2211-5463","type":"print"},{"value":"2211-5463","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,23]]},"assertion":[{"value":"2024-12-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}