{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T14:27:21Z","timestamp":1791901641121,"version":"4.3.4"},"reference-count":70,"publisher":"National Academy of Sciences","issue":"16","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"publisher","award":["M2020184"],"award-info":[{"award-number":["M2020184"]}],"id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021856","name":"Ministero dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["PRIN2020 grant 2020XBCMHJ"],"award-info":[{"award-number":["PRIN2020 grant 2020XBCMHJ"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["TGM22MT01"],"award-info":[{"award-number":["TGM22MT01"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,4,21]]},"abstract":"<jats:p>\n                    Stargardt disease type 1 (STGD1) is the most common hereditary macular degeneration. It is caused by mutations in\n                    <jats:italic toggle=\"yes\">ABCA4<\/jats:italic>\n                    , which result in the progressive degeneration of the retinal pigment epithelium (RPE), ultimately leading to photoreceptor loss. Despite extensive efforts, STGD1 currently lacks effective treatments. Here, we first identified mitochondrial defects in the photoreceptors of\n                    <jats:italic toggle=\"yes\">\n                      Abca4\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice and STGD1 patient-derived retinal organoids. Specifically, we found reduced mitochondrial content, defective cristae morphology, and downregulation of OPA1, a critical regulator of mitochondrial integrity, demonstrating that photoreceptor defects in STGD1 also have a cell-autonomous origin, besides the RPE dysfunction. Importantly, we also demonstrated that correcting this pathological phenotype through the modulation of microRNAs 181a and b (miR-181a\/b), key regulators of mitochondrial function, ameliorates the STGD1 phenotype. Indeed, genetic inactivation and adeno-associated viral vector-mediated silencing of miR-181a\/b in STGD1 models restored OPA1 levels, improved mitochondrial phenotype, and reduced lipofuscin accumulation in the RPE. Our study demonstrates that mitochondrial dysfunction in photoreceptors is an important contributor to STGD1 pathology, opening promising therapeutic avenues for this disorder.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2504764123","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T17:36:48Z","timestamp":1776274608000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Uncovering mitochondrial defects in photoreceptors opens therapeutic opportunities for Stargardt disease"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0481-1997","authenticated-orcid":false,"given":"Simona","family":"Brillante","sequence":"first","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]},{"name":"Institute for Genetic and Biomedical Research, National Research Council","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariagrazia","family":"Volpe","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]},{"name":"Institute for Genetic and Biomedical Research, National Research Council","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3367-8899","authenticated-orcid":false,"given":"Anna","family":"Diana","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Negueruela","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3252-2789","authenticated-orcid":false,"given":"Marta","family":"Molinari","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]},{"name":"European School of Molecular Medicine","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Saurino","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]},{"name":"European School of Molecular Medicine","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6381-5664","authenticated-orcid":false,"given":"Eva","family":"Cipollaro","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Polishchuk","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4073-8259","authenticated-orcid":false,"given":"Erika","family":"Tenderini","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8833-6112","authenticated-orcid":false,"given":"Carla","family":"Damiano","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]},{"name":"Department of Translational Medical Sciences, University of Naples Federico II","place":["Naples, Italy"]},{"name":"Santobono-Pausilipon, Laboratori di Ricerca e Biobanca","place":["Naples, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Tornabene","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7698-1955","authenticated-orcid":false,"given":"Roman","family":"Polishchuk","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Parenti","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]},{"name":"Department of Translational Medical Sciences, University of Naples Federico II","place":["Naples, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonietta","family":"Tarallo","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]},{"name":"Department of Translational Medical Sciences, University of Naples Federico II","place":["Naples, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandro","family":"Banfi","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]},{"name":"Medical Genetics, Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d","place":["Naples, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3134-2973","authenticated-orcid":false,"given":"Ivana","family":"Trapani","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]},{"name":"Department of Advanced Biomedical Sciences, University of Naples Federico II","place":["Naples, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Carrella","sequence":"additional","affiliation":[{"name":"Biology and Evolution of Marine Organisms Department, Stazione Zoologica Anton Dohrn","place":["Naples, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2325-0913","authenticated-orcid":false,"given":"Alessia","family":"Indrieri","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine","place":["Pozzuoli, Italy"]},{"name":"Institute for Genetic and Biomedical Research, National Research Council","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2016-308823"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-004-1079-4"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80602-9"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1802519115"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.07-1470"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddh048"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2022.10.001"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.21037\/aes-20-81"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.64.12.33"},{"key":"e_1_3_4_10_2","first-page":"495","article-title":"Stargardt macular dystrophy and therapeutic approaches","volume":"108","author":"Fujinami K.","year":"2023","unstructured":"K. Fujinami , Stargardt macular dystrophy and therapeutic approaches. Br. J. Ophthalmol. 108, 495\u2013505 (2023).","journal-title":"Br. J. Ophthalmol."},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2023.126"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv386"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2020-316225"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2018.04.037"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61376-3"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/ceo.13917"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2017.03.006"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.588234"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-65482-3"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.653522"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2020.100858"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/238463"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2005.01.007"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.36184"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4835(03)00023-X"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1523061113"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.142254"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201708734"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202215941"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21228468"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2021.101944"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.08.032"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.06.025"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2019104105"},{"key":"e_1_3_4_35_2","first-page":"1179","article-title":"An analysis of allelic variation in the ABCA4 gene","volume":"42","author":"Webster A. R.","year":"2001","unstructured":"A. R. Webster , An analysis of allelic variation in the ABCA4 gene. Invest. Ophthalmol. Vis. Sci. 42, 1179\u20131189 (2001).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22717"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21062092"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.9786"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2011.09.001"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22041801"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.12-11490"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.5215"},{"key":"e_1_3_4_43_2","first-page":"1685","article-title":"Delayed dark-adaptation and lipofuscin accumulation in abcr+\/- mice: Implications for involvement of ABCR in age-related macular degeneration","volume":"42","author":"Mata N. L.","year":"2001","unstructured":"N. L. Mata , Delayed dark-adaptation and lipofuscin accumulation in abcr+\/- mice: Implications for involvement of ABCR in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 42, 1685\u20131690 (2001).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm3041302"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01327-07"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2018.027"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-79651-x"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2016.16"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2008.05864.x"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/s10020-021-00341-z"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.09-3741"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3240935"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M309881200"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.12242"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1568-1637(03)00028-X"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000003491"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.61.6.42"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1802724115"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-021-00466-z"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38292-0"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0421-21.2021"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.29733"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2024.109829"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13578-024-01243-3"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2024.113"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adt9354"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.13-11688"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.06.012"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.02.021"},{"key":"e_1_3_4_70_2","unstructured":"S. Negueruela Gene expression profile from single cell level of retinal cells from optic cup of injected Abca4KO mice with miR-181a\/b sponge therapeutic. BioStudies. https:\/\/www.ebi.ac.uk\/biostudies\/ArrayExpress\/studies\/E-MTAB-15988. Accessed 6 April 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2504764123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T17:37:04Z","timestamp":1776274624000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2504764123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,15]]},"references-count":70,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2026,4,21]]}},"alternative-id":["10.1073\/pnas.2504764123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2504764123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,15]]},"assertion":[{"value":"2025-03-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2504764123"}}