Iron Metabolism in a Rodent Model of Menkes Disease (Brindled Mice)

The Menkes copper‐transporting ATPase (Atp7a) is induced in the rodent duodenum during iron deficiency. To understand its role in intestinal iron metabolism, we thus initiated an investigation in Atp7a mutant mice (Brindled). As mutant mice die perinatally of severe copper deficiency, IP copper injections were administered at 7 and 9 days‐of‐age. Mice developed normally thereafter and were similar in size and activity level to wt littermates. Subsequently, mice were deprived of dietary iron for 3 wks and iron and copper homeostasis was studied. Several important observations arose from these analyses, including: 1) mutant mice on control diet were copper deficient and anemic with no changes in iron status; 2) mutant mice on iron‐deficient diet were iron and copper deficient and more significantly anemic; 3) the transcriptional response to iron deficiency in enterocytes was seen only in mutant mice on low Fe diet, suggesting that the HIF2α‐mediated induction of iron and copper homeostasis‐related genes is triggered by iron levels and not hypoxia per se ; and 4) Brindled mice had increased hepatic copper levels during iron deprivation, leading to a concomitant increase in serum ferroxidase activity, while no such changes were noted in control or low Fe wt mice. This study has thus revealed novel aspects of the iron‐copper connection and is the first to investigate iron homeostasis in a model of genetic copper deficiency. Grant Funding Source : NIH