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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,3,7]]},"abstract":"<jats:p>\n                    Recent studies have uncovered the therapeutic potential of elesclomol (ES), a copper-ionophore, for copper deficiency disorders. However, we currently do not understand the mechanism by which copper brought into cells as ES\u2013Cu(II) is released and delivered to cuproenzymes present in different subcellular compartments. Here, we have utilized a combination of genetic, biochemical, and cell-biological approaches to demonstrate that intracellular release of copper from ES occurs inside and outside of mitochondria. The mitochondrial matrix reductase, FDX1, catalyzes the reduction of ES\u2013Cu(II) to Cu(I), releasing it into mitochondria where it is bioavailable for the metalation of mitochondrial cuproenzyme\u2014 cytochrome\n                    <jats:italic>c<\/jats:italic>\n                    oxidase. Consistently, ES fails to rescue cytochrome\n                    <jats:italic>c<\/jats:italic>\n                    oxidase abundance and activity in copper-deficient cells lacking FDX1. In the absence of FDX1, the ES-dependent increase in cellular copper is attenuated but not abolished. Thus, ES-mediated copper delivery to nonmitochondrial cuproproteins continues even in the absence of FDX1, suggesting alternate mechanism(s) of copper release. Importantly, we demonstrate that this mechanism of copper transport by ES is distinct from other clinically used copper-transporting drugs. Our study uncovers a unique mode of intracellular copper delivery by ES and may further aid in repurposing this anticancer drug for copper deficiency disorders.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2216722120","type":"journal-article","created":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T15:17:27Z","timestamp":1677511047000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":176,"title":["FDX1-dependent and independent mechanisms of elesclomol-mediated intracellular copper delivery"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9110-9508","authenticated-orcid":false,"given":"Mohammad","family":"Zulkifli","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biophysics, Texas A&amp;M University, College Station, TX 77843"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy\u00a0N.","family":"Spelbring","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Texas A&amp;M University, College Station, TX 77842"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6180-334X","authenticated-orcid":false,"given":"Yuteng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Houston, Houston, TX 77204"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3853-7503","authenticated-orcid":false,"given":"Shivatheja","family":"Soma","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Texas A&amp;M University, College Station, TX 77843"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si","family":"Chen","sequence":"additional","affiliation":[{"name":"Advanced Photon Source, Argonne National Laboratory, Argonne, IL 60439"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luxi","family":"Li","sequence":"additional","affiliation":[{"name":"Advanced Photon Source, Argonne National Laboratory, Argonne, IL 60439"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3913-8966","authenticated-orcid":false,"given":"Trung","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Texas A&amp;M University, College Station, TX 77842"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinit","family":"Shanbhag","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Life Sciences Center, University of Missouri, Columbia, MO 65211"},{"name":"Department of Ophthalmology, Life Sciences Center, University of Missouri, Columbia, MO 65211"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael\u00a0J.","family":"Petris","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Life Sciences Center, University of Missouri, Columbia, MO 65211"},{"name":"Department of Ophthalmology, Life Sciences Center, University of Missouri, Columbia, MO 65211"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2881-3068","authenticated-orcid":false,"given":"Tai-Yen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Houston, Houston, TX 77204"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7786-0242","authenticated-orcid":false,"given":"Martina","family":"Ralle","sequence":"additional","affiliation":[{"name":"Molecular and Medical Genetics Department, Oregon Health and Sciences University, Portland, OR 97239"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6422-9053","authenticated-orcid":false,"given":"David\u00a0P.","family":"Barondeau","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Texas A&amp;M University, College Station, TX 77842"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9920-2563","authenticated-orcid":false,"given":"Vishal\u00a0M.","family":"Gohil","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Texas A&amp;M University, College Station, TX 77843"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,2,27]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2022.11.001"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-59565-2.00045-9"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/15513"},{"key":"e_1_3_4_4_2","first-page":"1104","article-title":"Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy","volume":"67","author":"Valnot I.","year":"2000","unstructured":"I. 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