Elesclomol restores mitochondrial function in genetic models of copper deficiency

Abstract

SignificanceInherited pathogenic mutations in genes required for copper delivery to cytochrome c oxidase (CcO) perturb mitochondrial energy metabolism and result in fatal mitochondrial disease. A prior attempt to treat human patients with these mutations by direct copper supplementation was not successful, possibly because of inefficient copper delivery to the mitochondria. We performed a targeted search to identify compounds that can efficiently transport copper across biological membranes and identified elesclomol (ES), an investigational anticancer drug, as the most efficient copper delivery agent. ES rescues CcO function in yeast, zebrafish, and mammalian models of copper deficiency by increasing cellular and mitochondrial copper content. Thus, our study offers a possibility of repurposing this anticancer drug for the treatment of disorders of copper metabolism.

Exploiting the vulnerable active site of a copper-only superoxide dismutase to disrupt fungal pathogenesis

“…For example, the copper ionophore elesclomol is an effective anticancer agent that causes oxidative damage to cancer cells by delivering toxic concentrations of copper to the mitochondria (81). More recently, however, low levels of elesclomol were seen to rescue copper deficiency in mammalian cells (82). We therefore tested whether PZ can also have both toxic and beneficial properties by addressing whether, at very low doses, it can rescue copper Figure 5.…”

Repurposing elesclomol, an investigational drug for the treatment of copper metabolism disorders

“…Copper(I) released in the mitochondria can react with molecular oxygen generating ROS, which when produced in excess, can cause unmitigated oxidative stress and apoptotic death of cancer cells [14]. While this mechanism of action is consistent with its anticancer activity, it was recently shown that copper(I) released from elesclomol also becomes available for the metalation of CcO [8]. Consistently, low doses of elesclomol were shown to safely but effectively deliver copper to CcO and restore mitochondrial function in genetic models of copper deficiency [8].…”

“…This 'Trojan-horse' fashion delivery of metals by other lipophilic carrier molecules, such as the iron-transporting hinokitiol, has shown promise in restoring iron levels in preclinical animal models [7]. Using this principle, Soma et al, performed a targeted screen with a number of copper-binding pharmacological agents for their ability to restore respiratory growth in a yeast mutant defective in copper delivery to cytochrome c oxidase (CcO), a mitochondrial cuproenzyme [8]. This screen identified elesclomol as the most potent copper-transporting molecule, which rescued CcO function in a number of in vitro and in vivo models of copper deficiency [8,9].…”

What Role Does COA6 Play in Cytochrome C Oxidase Biogenesis: A Metallochaperone or Thiol Oxidoreductase, or Both?

“…Accordingly, treatment of COA6-deficient patient fibroblasts with CuCl 2 revealed partial rescue of the observed COX levels [ 53 ]. Finally, the anticancer drug elesclomol (ES) was proposed to restore COX function by increasing mitochondrial copper content in patient cells with mutations in the COA6 and SCO2 proteins [ 47 , 55 ].…”