FDX1-dependent and independent mechanisms of elesclomol-mediated intracellular copper delivery

Mohammad Zulkifli, Amy N. Spelbring, Yuteng Zhang, Shivatheja Soma, Si Chen, Luxi Li, Trung Le, Vinit Shanbhag, Michael J. Petris, Tai Yen Chen, Martina Ralle, David P. Barondeau, Vishal M. Gohil

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbere2216722120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number10
StatePublished - Mar 7 2023


  • FDX1
  • copper
  • cytochrome c oxidase
  • elesclomol
  • mitochondria

ASJC Scopus subject areas

  • General


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