Copper therapy reduces intravascular hemolysis and derepresses ferroportin in mice with mosaic mutation ( Atp7a mo-ms ): An implication for copper-mediated regulation of the Slc40a1 gene expression

Abstract

Mosaic mutant mice displaying functional dysfunction of Atp7a copper transporter (the Menkes ATPase) are an established animal model of Menkes disease and constitute a convenient tool for investigating connections between copper and iron metabolisms. This model allows to explore changes in iron metabolism in suckling mutant mice suffering from systemic copper deficiency as well as in young and adult ones undergone copper therapy, which reduces lethal effect of the Atp7a gene mutation. Our recent study demonstrated that 14-day-old mosaic mutant males display blood cell abnormalities associated with intravascular hemolysis, and show disturbances in the functioning of the hepcidin-ferroportin regulatory axis, which controls systemic iron homeostasis. We thus aimed to check whether copper supplementation recovers mutants from hemolytic insult and rebalance systemic iron regulation. Copper supplementation of 14-day-old mosaic mutants resulted in the reestablishment of hematological status, attenuation of hepicidin and concomitant induction of the iron exporter ferroportin/Slc40a1 expression in the liver, down-regulated in untreated mutants. Interestingly, treatment of wild-type males with copper, induced hepcidin-independent up-regulation of ferroportin protein level in hepatic macrophages in both young and adult (6-month-old) animals. Stimulatory effect of copper on ferroportin mRNA and protein levels was confirmed in bone marrow-derived macrophages isolated from both wild-type and mosaic mutant males. Our study indicates that copper is an important player in the regulation of the Slc40a1 gene expression.

Role of the kidneys in the redistribution of heme-derived iron during neonatal hemolysis in mice

“…In many hemolytic disorders, excessive hemolysis may overwhelm endogenous plasma haptoglobin/hemopexin and other scavenging mechanisms as well as heme degradation pathways in hepatic, splenic and bone marrow macrophages. Human 9 and animal 10,11 studies have clearly shown that under severe hemolytic conditions, the kidneys participate in the management of heme and non-heme iron released from disrupted RBCs. There is growing evidence that renal tubular cells can adapt to exposure to high levels of heme by inducing HO1 and ferritin 9,10 .…”

Exacerbation of Neonatal Hemolysis and Impaired Renal Iron Handling in Heme Oxygenase 1-Deficient Mice

“…Kidney is an organ highly adapted to reabsorb both non-heme and heme iron filtered in the glomerulus to the primary urine and to recirculate it across epithelial cells of proximal tubules into the blood stream [ 14 ]. Under intravascular hemolysis conditions, such as chronic hereditary and acquired hemolytic anemias, kidneys participate in the management of iron released from disrupted erythrocytes to the blood plasma [ 27 , 28 , 29 , 30 ]. It is clear that the structural and functional maturity of the kidneys is indispensable for this process.…”

Reduced Neutrophil Extracellular Trap (NET) Formation During Systemic Inflammation in Mice With Menkes Disease and Wilson Disease: Copper Requirement for NET Release

“…On the other hand, mutations in the human ATP7A gene lead to a neurological disorder called Menkes disease, which usually results in mortality at 3-5 years of age in its classical form (16). The mouse ATP7A protein is encoded by the X-linked Atp7a gene, and among its several reported mutations in mice, one (Atp7a mo-ms ) results in the mottled phenotype resembling Menkes disease and affects mosaic mutant males (15,34). In these mice, similarly to patients with Menkes disease, copper accumulates in the small intestine (trapped in enterocytes) and kidneys, while liver, brain, and heart display its deficiency (34).…”

“…The mouse ATP7A protein is encoded by the X-linked Atp7a gene, and among its several reported mutations in mice, one (Atp7a mo-ms ) results in the mottled phenotype resembling Menkes disease and affects mosaic mutant males (15,34). In these mice, similarly to patients with Menkes disease, copper accumulates in the small intestine (trapped in enterocytes) and kidneys, while liver, brain, and heart display its deficiency (34). Additionally, as in the classical form of Menkes disease, the mosaic mutation of Atp7a leads to early death on about day 16.…”

“…The phenotype can be partially reversed by regular s.c. copper (II) chloride injections since the second day of life till day 45 (34,35). Mice still display symptoms of Menkes disease, and their copper levels are decreased.…”