LAUSR

Significance Genetic defects in copper transport to cuproenzymes result in infantile disorders for which no effective therapies are currently available. Recent studies have uncovered the therapeutic potential of elesclomol, a copper-transporting drug, in the treatment of copper deficiency disorders. To realize the full potential of this drug, it is necessary to gain a mechanistic understanding of how elesclomol makes copper available to different cellular cuproenzymes. Here, we demonstrate that copper is released from elesclomol within mitochondria via FDX1, and outside of mitochondria in an FDX1-independent manner to make copper available to mitochondrial and nonmitochondrial cuproenzymes, respectively. These modes of copper release are distinct from other currently used copper-transporting drugs and may explain the high potency of elesclomol in rectifying copper deficiency.