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

Abstract

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.

Ferroportin and Exocytoplasmic Ferroxidase Activity Are Required for Brain Microvascular Endothelial Cell Iron Efflux

“…Cooperation of Fpn and Hp in supporting iron export from cells endogenous to the CNS has been demonstrated previously (13,29). Here, we have presented evidence that Fpn and Hp cooperate in the process by which iron is released from the barrier cells of the brain, the BMVEC; note that the polarity of this efflux could not be determined in our monolayer system.…”

“…mulation is observed in oligodendrocytes (9,13). This hypothesis is the subject of ongoing research.…”

“…transferrin (Tf), ferritin, and citrate; this same cohort of ferric iron ligands are found in the brain (12). In the brains of sex-linked anemic mice (sla Ϫ/Ϫ ), which contain mutations in the Hp gene, iron accumulation has been shown in oligodendrocytes of the gray matter, suggesting a role for Hp in iron efflux from cells of the CNS (9,13). Although these mice still accumulate brain iron, they likely do so via soluble Cp (sCp) present in the interstitial fluid localized to the abluminal surface of the BMVEC.…”

Histochemical evaluation of iron content in oligodendrocytes in selected regions of the rat brain

“…Oligodendrocytes are located in the close vicinity of capillaries [10,22,26]. Already during the second week after birth, the distribution of iron in oligodendrocytes accurately corresponds to the places of myelination, which indicates the functional dependence between iron accumulation and myelin production [1,9,11,15,16]. The above findings were confirmed by Connor et al [11,15,17,18], who demonstrated that the peak iron absorption in the CNS coincides with the peak myelination.…”

“…Many hypotheses have been put forward regarding the role of iron in the CNS and the issue still causes heated debates. Initially, the presence of iron in oligodendrocytes was linked with γ-amino butyric acid (GABA) metabolism as elevated levels of iron were correlated with the regions in which GABA is a neurotransmitter [13,14,15,16]. The second hypothesis is based on the presence of iron in oligodendrocytes and myelin, which confirms its involvement in myelination.…”