{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:41:35Z","timestamp":1791232895350,"version":"4.1.0"},"reference-count":11,"publisher":"National Academy of Sciences","issue":"25","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM152102"],"award-info":[{"award-number":["R35GM152102"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA262664"],"award-info":[{"award-number":["R01CA262664"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK131190"],"award-info":[{"award-number":["R01DK131190"]}],"id":[{"id":"10.13039\/100000062","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":[[2026,6,23]]},"abstract":"<jats:p>\n                    Copper (Cu) is an essential cofactor for cytochrome\n                    <jats:italic toggle=\"yes\">c<\/jats:italic>\n                    oxidase (CcO), a mitochondrial respiratory chain enzyme that is metalated in the intermembrane space (IMS) primarily using Cu derived from the mitochondrial matrix pool. While Cu import into the matrix depends on the inner membrane carrier SLC25A3, the route by which matrix Cu is exported to the IMS for insertion into CcO has remained a major, unresolved step in intramitochondrial Cu trafficking. Here, we leveraged our recent discovery that the Cu ionophore elesclomol (ES) releases Cu directly into the mitochondrial matrix to show that SLC25A3 is required for exporting Cu to the IMS for CcO metalation. Loss of SLC25A3 decreases mitochondrial Cu content and CcO activity as expected. Strikingly, bypassing the loss of SLC25A3 with ES-mediated Cu delivery to the matrix fails to restore CcO function; rather, it drives toxic Cu retention and triggers cuproptosis, revealing that SLC25A3-facilitated Cu export is the limiting determinant of CcO metalation. Heterologous expression in\n                    <jats:italic toggle=\"yes\">Lactococcus lactis<\/jats:italic>\n                    confirms that SLC25A3 can mediate Cu export. These results suggest that SLC25A3 is the long-sought mitochondrial Cu exporter with a dual role in enabling CcO metalation and gating susceptibility to cuproptosis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2612098123","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T16:08:59Z","timestamp":1781712539000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":5,"title":["SLC25A3 exports mitochondrial copper to metalate cytochrome\n                    <i>c<\/i>\n                    oxidase and prevent cuproptosis"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9110-9508","authenticated-orcid":false,"given":"Mohammad","family":"Zulkifli","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01f5ytq51","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Biophysics, MS 3474, Texas A&M University","place":["College Station"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ifrah","family":"Farid","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01f5ytq51","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Biophysics, MS 3474, Texas A&M University","place":["College Station"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E.","family":"Oldfather","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02v80fc35","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biological Sciences, Auburn University","place":["Auburn"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6188-7421","authenticated-orcid":false,"given":"Vinit C.","family":"Shanbhag","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02ymw8z06","id-type":"ROR","asserted-by":"publisher"}],"name":"Departments of Biochemistry and Ophthalmology, Bond Life Sciences Center, University of Missouri","place":["Columbia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8488-7822","authenticated-orcid":false,"given":"Scot C.","family":"Leary","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/010x8gc63","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan","place":["Saskatoon, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4162-1674","authenticated-orcid":false,"given":"Michael J.","family":"Petris","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02ymw8z06","id-type":"ROR","asserted-by":"publisher"}],"name":"Departments of Biochemistry and Ophthalmology, Bond Life Sciences Center, University of Missouri","place":["Columbia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Cobine","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02v80fc35","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biological Sciences, Auburn University","place":["Auburn"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9920-2563","authenticated-orcid":false,"given":"Vishal M.","family":"Gohil","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01f5ytq51","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Biophysics, MS 3474, Texas A&M University","place":["College Station"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2022.11.001"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.000265"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M606839200"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2020.118867"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2216722120"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1806296115"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz8899"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.64690"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb00997.x"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf0529"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2011.10.011"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2612098123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T16:09:23Z","timestamp":1781712563000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2612098123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,17]]},"references-count":11,"journal-issue":{"issue":"25","published-print":{"date-parts":[[2026,6,23]]}},"alternative-id":["10.1073\/pnas.2612098123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2612098123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,17]]},"assertion":[{"value":"2026-04-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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