Copper, an essential cofactor for various enzymes, is absorbed through the intestine and transported to the liver for storage, with a small amount mobilized into the circulation to supply peripheral tissues (see Culotta). The heart is particularly sensitive to copper deficiency, which leads to cardiac hypertrophy and other defects in cardiovascular function. Kim et al. generated transgenic mice that specifically lacked the copper transporter Ctr1 in cardiac tissue (Ctr1hrt/hrt mice) and found that they showed decreased cardiac copper accumulation, compared with wild-type littermates, and severe cardiomyopathy. Similarly, loss of cardiac Ctr1 in 2- or 7-month old mice led to their subsequent development of cardiomyopathy. Unexpectedly, however, Ctr1hrt/hrt mice showed a decrease in liver copper content and an increase in serum copper. Moreover, mice lacking cardiac Ctr1 showed a substantial increase in the abundance of the ATP7A copper-exporting ATPase in liver and intestine. ATP7A, known for its role in absorption of copper from the intestine, had not previously been implicated in hepatic copper handling and, indeed, its abundance in wild-type adult mouse liver was modest. When human umbilical vein endothelial cells or a human epithelial cell–like cell line were treated with serum from Ctr1hrt/hrt mice, they showed an increase in ATP7A abundance, compared to cells treated with serum from control mice, as well as an increase in the abundance of the copper chaperone CCS (suggestive of decreased copper content). The authors thus conclude that cardiac copper deficiency elicits a circulating signal that leads to an increase in the abundance of ATP7A in liver and intestine, thereby enabling increased copper uptake and mobilization into the circulatory system.
B.-E. Kim, M. L. Turski, Y. Nose, M. Casad, H. A. Rockman, D. J. Thiele, Cardiac copper deficiency activates a systemic signaling mechanism that communicates with the copper acquisition and storage organs. Cell Metab. 11, 353–363 (2010). [PubMed]
V. Culotta, Speaking from the heart: Systemic copper signaling. Cell Metab. 11, 343–344 (2010). [PubMed]