@article{4bc26fb7bbd44bf584f13a387e7beee2,
title = "FDX1-dependent and independent mechanisms of elesclomol-mediated intracellular copper delivery",
abstract = "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–Cu(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–Cu(II) to Cu(I), releasing it into mitochondria where it is bioavailable for the metalation of mitochondrial cuproenzyme— cytochrome c oxidase. Consistently, ES fails to rescue cytochrome c 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.",
keywords = "FDX1, copper, cytochrome c oxidase, elesclomol, mitochondria",
author = "Mohammad Zulkifli and Spelbring, {Amy N.} and Yuteng Zhang and Shivatheja Soma and Si Chen and Luxi Li and Trung Le and Vinit Shanbhag and Petris, {Michael J.} and Chen, {Tai Yen} and Martina Ralle and Barondeau, {David P.} and Gohil, {Vishal M.}",
note = "Funding Information: ACKNOWLEDGMENTS.We thank Dr.John Markley for providing the FDX1 plasmid, Deepika Das for the FDX1 purification protocol, and Dr. Byung-Eun Kim for providing H9c2Ctr1−/−cells.We alsothank Adriana Okonkwo for assistance with cell culture experiments and Vishav Sharma for help with ChemDraw. Research reported in this publication was supported by the National Institute of General Medical Sciences of the NIH awards R01GM143630 and R01GM111672 to V.M.G., R21GM129592 to M.R., R35GM133505 to T.-Y.C., R01GM096100 to Funding Information: D.P.B. and National Institute of Diabetes and Digestive and Kidney Diseases award DK131190 and National Cancer Institute award CA262664 to M.J.P.The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Use of the Advanced Photon Source part of the Argonne National Laboratory is supported by the Department of Energy, Office of Basic Energy Sciences, under contract no. DEAC02-06CH11357. The authors have research support to disclose: The corresponding author{\textquoteright}s university (Texas A&M) has entered into a licensing agreement with Engrail Therapeutics for the development of elesclomol:copper as a therapeutic agent for the disorders of copper metabolism. Publisher Copyright: Copyright {\textcopyright} 2023 the Author(s).",
year = "2023",
month = mar,
day = "7",
doi = "10.1073/pnas.2216722120",
language = "English (US)",
volume = "120",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "10",
}