Age-related changes in iron homeostasis in mouse ferroxidase mutants

Abstract

Disorders of iron metabolism are a significant problem primarily in young and old populations. In this study, We compared 1-year-old C57BL6/J mice on iron deficient, iron overload, or iron sufficient diets with two similarly aged genetic models of disturbed iron homeostasis, the sla (sex-linked anemia), and the ceruloplasmin knockout mice (Cp(-/-)) on iron sufficient diet. We found tissue specific changes in sla and nutritional iron deficiency including decreased liver Hamp1 expression and increased protein expression of the enterocyte basolateral iron transport components, hephaestin and ferroportin. In contrast, the Cp(-/-) mice did not show significantly increased Hamp1 expression despite increased liver iron suggesting that regulation is independent of liver iron levels. Together, these results suggest that older mice have a distinct response to alterations in iron metabolism and that age must be considered in future studies of iron metabolism.

Iron depletion in the intestines ofMalvoliomutant flies does not occur in the absence of a multicopper oxidase

“…A key prediction of the hypothesis that MCO3 encodes an insect multicopper ferroxidase responsible for iron mobilization from tissue stores is that MCO3 C359 mutants should have increased iron storage in the iron region, mimicking the phenotype in mice lacking ceruloplasmin (Chen et al, 2009;Harris et al, 1999;Nose et al, 2006). Our results are consistent with such an interpretation, and further demonstrated in larvae grown on copper-enriched medium (Fig.4).…”

“…An obvious candidate would be a multicopper ferroxidase, such as the yeast homologue involved in cellular iron import Dancis et al, 1994) and mammalian homologues functioning in cellular iron export (Chen et al, 2009;Harris et al, 1999;Osaki et al, 1966;Vulpe et al, 1999). We have identified a candidate protein that may act as a Drosophila ferroxidase, but as it is not uncommon for enzymes to defy homologybased predictions of their activity (Kanzok et al, 2001;Missirlis et al, 2003), a biochemical proof remains necessary.…”

“…Despite each metal having unique biochemical specificities (Waldron et al, 2009), there are notable interdependencies in terms of organismal acquisition, best documented in the case of copper and iron (Fox, 2003). In the absence of adequate dietary copper mammals develop anaemia because of compromised cellular iron mobilization, which depends on the plasma multicopper ferroxidases, ceruloplasmin and hephaestin (Chen et al, 2009;Harris et al, 1999;Hart et al, 1928;Osaki et al, 1966;Vulpe et al, 1999). Furthermore, iron absorption depends on divalent metal transporter-1 (DMT1), lack of which also results in anaemia (Beaumont et al, 2006;Donovan et al, 2002;Fleming et al, 1997;Gunshin et al, 1997;Iolascon et al, 2006;Mims et al, 2005).…”

Copper deficiency has minimal impact on ferroportin expression or function

“…When hepcidin null mice were evaluated there was significant augmentation in Fpn protein, consistent with the theory that when hepcidin is present it causes a decrease in Fpn abundance via accelerated degradation (Viatte et al 2005). Sla mice and Cp-/-mice both exhibit higher intestinal iron than controls, and higher Fpn protein (Chen et al 2009). However, the mechanism must differ as Sla mice display lower and Cp-/-mice normal levels of Hamp, the hepcidin gene.…”

“…This argument was based on iron tracer kinetics and the known requirement for iron efflux by the multicopper oxidase (MCO) hephaestin whose mutation in mice results in sex-linked anemia (Sla) (Reeves and DeMars 2004;Vulpe et al 1999). However, Sla mice as adults are not anemic (Chen et al 2009). Further, iron injection to anemic post weanling copper deficient rats does not reverse anemia, challenging the hephaestin iron trap theory (Reeves and DeMars 2006).…”