Hephaestin is a ferroxidase that maintains partial activity in sex-linked anemia mice

Chen, Huijun; Attieh, Zouhair; Su, Trent; Syed, Basharut A.; Gao, Hua; Alaeddine, Rima M; Fox, Tama C.; Usta, Jinan; Naylor, C.E.; Evans, Robert W.; McKie, Andrew T.; Anderson, Gregory J.; Vulpe, Chris D.

doi:10.1182/blood-2003-09-3139

Cited by 137 publications

(79 citation statements)

References 48 publications

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“…The sla mouse, however, represents a sex-linked anemia that maps to a Heph allele carrying an in-frame mutation leading to expression of a protein missing 194 internal residues (26). This protein does exhibit ferroxidase activity but does not traffic to the basolateral membrane of enterocytes in support of iron efflux from the gut into the circulation (53,54). sla mice are anemic as a result even though they hyperaccumulate iron in their intestinal epithelia.…”

Section: Genetic Arguments For Ferroxidases As a Key To Iron Homeostasismentioning

confidence: 99%

Redox Cycling in Iron Uptake, Efflux, and Trafficking

Kosman

2010

Journal of Biological Chemistry

106

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Aerobic organisms are faced with a dilemma. Environmental iron is found primarily in the relatively inert Fe(III) form, whereas the more metabolically active ferrous form is a strong pro-oxidant. This conundrum is solved by the redox cycling of iron between Fe(III) and Fe(II) at every step in the iron metabolic pathway. As a transition metal ion, iron can be "metabolized" only by this redox cycling, which is catalyzed in aerobes by the coupled activities of ferric iron reductases (ferrireductases) and ferrous iron oxidases (ferroxidases).Following the first crystallization of a protein, jack bean urease, reported by Sumner in 1926 (1), the evolution of protein chemistry remained a slow process, hampered by limitations in techniques for protein resolution and analysis. Not surprisingly, many proteins obtained in relatively pure form were those with prosthetic metal ion groups that imparted a visible absorbance to guide the purification. Some were copper proteins whose Cu(II) spectral properties gave their protein host a greenish blue to bright blue hue. Two of these were from mammalian whole blood: hemocuprein (cupric species from erythrocytes, superoxide dismutase) and ceruloplasmin (cerulean blue species from plasma). Superoxide dismutase was first isolated in 1938 by Mann and Keilin (5); Cp 2 was first isolated in 1948 by Holmberg and Laurell (6). Both proteins play essential roles in aerobic homeostasis. In the case of ceruloplasmin and the other copper proteins that share its substrate specificity, this role is to manage the redox state of iron in the metabolism of this essential yet potentially cytotoxic transition metal ion. These proteins, all of which are members of the MCO family (7-9), and the mechanism by which they provide this function are a focus of this minireview.

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Section: Genetic Arguments For Ferroxidases As a Key To Iron Homeostasismentioning

confidence: 99%

Redox Cycling in Iron Uptake, Efflux, and Trafficking

Kosman

2010

Journal of Biological Chemistry

106

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“…We have evidence that Fpn is also expressed in astrocytes and neurons (data not shown). As mentioned previously, sla mutant mice express a truncated, partially active form of Heph in non-CNS tissues (Vulpe et al, 1999;Chen et al, 2004). We therefore compared the expression of Heph and Fpn in the CNS of sla and wild-type mice by Western blot analysis.…”

Section: Hephaestin and Ferroportin Are Expressed In The Adult Mouse mentioning

confidence: 99%

“…Another copperdependent ferroxidase, hephaestin (Heph), was identified in duodenal enterocytes (Vulpe et al, 1999) and was also shown to play a role in iron efflux. In the sex-linked anemia (sla) mouse, a partial deletion of the heph gene results in the expression of a truncated Heph protein that exhibits only partial ferroxidase activity (Vulpe et al, 1999;Chen et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Iron Efflux from Oligodendrocytes Is Differentially Regulated in Gray and White Matter

Schulz¹,

Vulpe²,

Harris³

et al. 2011

J. Neurosci.

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Accumulation of iron occurs in the CNS in several neurodegenerative diseases. Iron is essential for life but also has the ability to generate toxic free radicals if not properly handled. Iron homeostasis at the cellular level is therefore important to maintain proper cellular function, and its dysregulation can contribute to neurodegenerative diseases. Iron export, a key mechanism to maintain proper levels in cells, occurs via ferroportin, a ubiquitously expressed transmembrane protein that partners with a ferroxidase. A membrane-bound form of the ferroxidase ceruloplasmin is expressed by astrocytes in the CNS and regulates iron efflux. We now show that oligodendrocytes use another ferroxidase, called hephaestin, which was first identified in enterocytes in the gut. Mice with mutations in the hephaestin gene (sex-linked anemia mice) show iron accumulation in oligodendrocytes in the gray matter, but not in the white matter, and exhibit motor deficits. This was accompanied by a marked reduction in the levels of the paranodal proteins contactin-associated protein 1 (Caspr) and reticulon-4 (Nogo A). We show that the sparing of iron accumulation in white matter oligodendrocytes in sex-linked anemia mice is due to compensatory upregulation of ceruloplasmin in these cells. This was further confirmed in ceruloplasmin/hephaestin double-mutant mice, which show iron accumulation in both gray and white matter oligodendrocytes. These data indicate that gray and white matter oligodendrocytes can use different iron efflux mechanisms to maintain iron homeostasis. Dysregulation of such efflux mechanisms leads to iron accumulation in the CNS.

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“…76 Placental transfer of maternally injected radioiron in the second half of pregnancy was not different between sla and wild-type mice, although sla pups accumulated less radioiron given in the maternal diet throughout pregnancy. 76 It is worth pointing out that the sla allele of Heph retains partial ferroxidase activity, 77 so the minimally perturbed placental iron transfer in sla pups may underrepresent the degree to which Heph is important for placental iron transport. A third ferroxidase in the placenta has been described by Danzeisen et al, 78 who detected an intracellular, membrane-bound protein in BeWo cells that exhibited ceruloplasmin-like oxidase activity and reacted with a ceruloplasmin antibody.…”

Section: Basal Transport Of Ironmentioning

confidence: 99%