Elesclomol restores mitochondrial function in genetic models of copper deficiency
Latimer, Andrew J.
Vicary, Alison C.
Timbalia, Shrishiv A.
Rahn, Jennifer J.
Chan, Sherine S. L.
Leary, Scot C.
Gitlin, Jonathan D.
Gohil, Vishal M.
MetadataShow full item record
Copper is an essential cofactor of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Inherited loss-of-function mutations in several genes encoding proteins required for copper delivery to CcO result in diminished CcO activity and severe pathologic conditions in affected infants. Copper supplementation restores CcO function in patient cells with mutations in two of these genes, COA6 and SCO2, suggesting a potential therapeutic approach. However, direct copper supplementation has not been therapeutically effective in human patients, underscoring the need to identify highly efficient copper transporting pharmacological agents. By using a candidate-based approach, we identified an investigational anticancer drug, elesclomol (ES), that rescues respiratory defects of COA6-deficient yeast cells by increasing mitochondrial copper content and restoring CcO activity. ES also rescues respiratory defects in other yeast mutants of copper metabolism, suggesting a broader applicability. Low nanomolar concentrations of ES reinstate copper-containing subunits of CcO in a zebrafish model of copper deficiency and in a series of copper-deficient mammalian cells, including those derived from a patient with SCO2 mutations. These findings reveal that ES can restore intracellular copper homeostasis by mimicking the function of missing transporters and chaperones of copper, and may have potential in treating human disorders of copper metabolism.
© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Proceedings of the National Academy of Sciences of the United States of America 115 (2018): 8161-8166, doi:10.1073/pnas.1806296115.
Suggested CitationProceedings of the National Academy of Sciences of the United States of America 115 (2018): 8161-8166
The following license files are associated with this item:
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International
Showing items related by title, author, creator and subject.
Sholkovitz, Edward R.; Sedwick, Peter N.; Church, Thomas M. (American Geophysical Union, 2010-10-19)Paytan et al. (2009) argue that the atmospheric deposition of aerosols lead to copper concentrations that are potentially toxic to marine phytoplankton in a large area of tropical and subtropical North Atlantic Ocean. A ...
Conditional knockout of the Menkes disease copper transporter demonstrates its critical role in embryogenesis Wang, Yanfang; Zhu, Sha; Weisman, Gary A.; Gitlin, Jonathan D.; Petris, Michael J. (Public Library of Science, 2012-08-10)The transition metal, copper (Cu), is an enzymatic cofactor required for a wide range of biochemical processes. Its essentiality is demonstrated by Menkes disease, an X-linked copper deficiency disorder characterized by ...
Sunda, William (Massachusetts Institute of Technology and Woods Hole Oceanographic Institution, 1975-04)The purpose of this investigation is to quantify the relationship between cupric ion activity and the toxicity of copper to phytoplankton and further to study the effect on copper toxicity of naturally occurring organic ...