Elesclomol elevates cellular and mitochondrial iron levels by delivering copper to the iron import machinery

Copper (Cu) and iron (Fe) are redox-active metals that serve as cofactors for many essential cellular enzymes. Disruption in the intracellular homeostasis of these metals results in debili-tating and frequently fatal human disorders, such as Menkes disease and Friedreich's ataxia. Recently, we reported that an investigational anticancer drug, elesclomol (ES), can deliver Cu to critical mitochondrial cuproenzymes and has the potential to be repurposed for the treatment of Cu deficiency disorders. Here, we sought to determine the specificity of ES and the ES-Cu complex in delivering Cu to cuproenzymes in different intracellular compartments. Using a combination of yeast genetics, subcellular fractionation, and inductively coupled plasma-mass spectrometry-based metal measurements, we showed that ES and ES-Cu treatment results in an increase in cellular and mitochondrial Fe content, along with the expected increase in Cu. Using yeast mutants of Cu and Fe transporters, we demonstrate that ES-based elevation in cellular Fe levels is independent of the major cellular Cu importer but is depen-dent on the Fe importer Ftr1 and its partner Fet3, a multi -copper oxidase. As Fet3 is metalated in the Golgi lumen, we sought to uncover the mechanism by which Fet3 receives Cu from ES. Using yeast knockouts of genes involved in Cu delivery to Fet3, we determined that ES can bypass Atx1, a metallochaperone involved in Cu delivery to the Golgi mem-brane Cu pump, Ccc2, but not Ccc2 itself. Taken together, our study provides a mechanism by which ES distributes Cu in cells and impacts cellular and mitochondrial Fe homeostasis.

Automated summary

Copper and iron are essential cofactors for cellular enzymes, and disruption in their homeostasis can lead to severe human disorders. A study found that the investigational anticancer drug ES can deliver copper to mitochondrial cuproenzymes, potentially treating copper deficiency disorders. The study also revealed that ES treatment increases cellular and mitochondrial iron content, independent of the major cellular copper importer but dependent on the iron importer Ftr1 and its partner Fet3. The mechanism by which ES distributes copper in cells and influences iron homeostasis was further investigated.