The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis

Copper plays a fundamental role in the biochemistry of all aerobic organism s. The delivery of this metal to specific intracellular targets is mediated by metallochaperones. To elucidate the role of the metallochaperone Atox1, we analyzed mice with a disruption of the Atox1 locus. Atox1(-/-) mice fai led to thrive immediately after birth, with 45% of pups dying before weanin g. surviving animals exhibited growth failure, skin laxity, hypopigmentatio n, and seizures because of perinatal copper deficiency. Maternal Atox1 defi ciency markedly increased the severity of Atox1(-/-) phenotype, resulting i n increased perinatal mortality as well as severe growth retardation and co ngenital malformations among surviving Atox1(-/-) progeny. Furthermore, Ato x1-deficient cells accumulated high levels of intracellular copper, and met abolic studies indicated that this defect was because of impaired cellular copper efflux. Taken together, these data reveal a direct role for Atox1 in trafficking of intracellular copper to the secretory pathway of mammalian cells and demonstrate that this metallochaperone plays a critical role in p erinatal copper homeostasis.