Publication Date:
2022-05-25
Description:
© 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.
Description:
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.
Description:
This work was supported by National Institutes of Health Awards R01GM111672 (to V.M.G.), R01 DK110195 (to B.-E.K.), and DK 44464 (to J.D.G.); Welch Foundation Grant A-1810 (to V.M.G.); and Canadian Institutes of Health Research Operating Grant MOP 133562 (to S.C.L.).
Keywords:
Copper
;
Mitochondria
;
Elesclomol
;
Cytochrome c oxidase
Repository Name:
Woods Hole Open Access Server
Type:
Article
Permalink
