Elesclomol restores mitochondrial function in genetic models of copper deficiency

Soma, S., Latimer, A.J., Chun, H., Vicary, A.C., Timbalia, S.A., Boulet, A., Rahn, J.J., Chan, S.S.L., Leary, S.C., Kim, B.E., Gitlin, J.D., Gohil, V.M.
Proceedings of the National Academy of Sciences of the United States of America   115(32): 8161-8166 (Journal)
Registered Authors
Chan, Sherine, Gitlin, Jonathan D., Latimer, Andrew, Rahn, Jennifer
copper, cytochrome c oxidase, elesclomol, mitochondria
MeSH Terms
  • Animals
  • Antineoplastic Agents/pharmacology*
  • Antineoplastic Agents/therapeutic use
  • Biological Transport/genetics
  • Carrier Proteins/genetics
  • Cell Line
  • Coenzymes/deficiency
  • Copper/deficiency*
  • Copper/therapeutic use
  • Dietary Supplements
  • Disease Models, Animal
  • Drug Repositioning
  • Drugs, Investigational/pharmacology*
  • Drugs, Investigational/therapeutic use
  • Electron Transport Complex IV/metabolism*
  • Fibroblasts
  • Humans
  • Hydrazines/pharmacology*
  • Hydrazines/therapeutic use
  • Membrane Transport Proteins/genetics
  • Metabolism, Inborn Errors/drug therapy
  • Metabolism, Inborn Errors/genetics
  • Metabolism, Inborn Errors/metabolism
  • Mitochondria/drug effects*
  • Mitochondria/metabolism
  • Mitochondrial Proteins/genetics
  • Mutagenesis, Site-Directed
  • Mutation
  • Rats
  • Saccharomyces cerevisiae
  • Zebrafish
  • Zebrafish Proteins/genetics
30038027 Full text @ Proc. Natl. Acad. Sci. USA
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.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes