THE REGULATION OF THE INTESTINAL COPPER EXPORTER IS COORDINATED WITH SYSTEMIC COPPER HOMEOSTASIS

Abstract

Copper (Cu) plays key catalytic and regulatory roles in biochemical reactions essential for normal growth, development, and health. Defects in Cu metabolism cause Menkes and Wilson’s disease, myeloneuropathy, and cardiovascular disease and are associated with other pathophysiological states. Consequently, it is critical to understand the mechanisms by which organisms control the acquisition, distribution, and utilization of Cu. While it is well established that the enterocyte is a key regulatory point for Cu absorption into the body, how the intestine responds to systemic Cu requirements is poorly understood. Here, we demonstrate that fine-tuned Cu homeostasis is required for normal growth and development in C. elegans. Moreover, we show that CUA-1, the ATP7A/B homolog in worms, localizes to lysosome-like organelles (gut granules) in the intestine under Cu-overload conditions for Cu detoxification, while Cu-deficiency results in a redistribution of CUA-1 to basolateral membranes for Cu efflux to peripheral tissues. Defects in gut granule biogenesis exhibit result in abnormal Cu sequestration and increased susceptibility to toxic Cu levels. Our studies establish that CUA-1 is a key intestinal Cu exporter, and that its trafficking is regulated in response to systemic Cu status in worms. In addition, while the Cu transporter ATP7A plays a major role in both intestinal Cu mobilization to the periphery and prevention of Cu over-accumulation, it is unclear how regulation of ATP7A contributes to Cu homeostasis in response to systemic Cu fluctuation in mammals. Here we show, using Cu-deficient mouse models, that steady-state levels of ATP7A are lower in peripheral tissues (including the heart, spleen, and liver) under Cu deficiency and that subcutaneous administration of Cu to these animals restore normal ATP7A levels in these tissues. Importantly, ATP7A in the intestine is regulated in the opposite manner - low systemic Cu increases ATP7A while subcutaneous Cu administration decreases ATP7A suggesting that intestine-specific non-autonomous regulation of ATP7A abundance may serve as a key homeostatic control for Cu export into the circulation. Altogether, our results implicate CUA-1/ATP7A Cu exporter in the intestine as a key modulator for organismal Cu homeostasis in metazoans.