Multi-copper ferroxidase deficiency leads to iron accumulation and oxidative damage in astrocytes and oligodendrocytes

Abstract

Accumulation of iron has been associated with the pathobiology of various disorders of the central nervous system. Our previous work has shown that hephaestin ( Heph ) and ceruloplasmin ( Cp ) double knockout (KO) mice induced iron accumulation in multiple brain regions and that this was paralleled by increased oxidative damage and deficits in cognition and memory. In this study, we enriched astrocytes and oligodendrocytes from the cerebral cortex of neonatal wild-type (WT), Heph KO and Cp KO mice. We demonstrated that Heph is highly expressed in oligodendrocytes, while Cp is mainly expressed in astrocytes. Iron efflux was impaired in Cp KO astrocytes and Heph KO oligodendrocytes and was associated with increased oxidative stress. The expression of Heph , Cp , and other iron-related genes was examined in astrocytes and oligodendrocytes both with and without iron treatment. Interestingly, we found that the expression of the mRNA encoding ferroportin 1, a transmembrane protein that cooperates with CP and HEPH to export iron from cells, was positively correlated with Cp expression in astrocytes, and with Heph expression in oligodendrocytes. Our findings collectively demonstrate that HEPH and CP are important for the prevention of glial iron accumulation and thus may be protective against oxidative damage.

Iron Metabolism in Oligodendrocytes and Astrocytes, Implications for Myelination and Remyelination

“…The ferroportin-ceruloplasmin system represents the main pathway for cellular iron efflux, and it is responsible for physiological regulation of cellular iron levels (Musci et al, 2014). Ferroportin and ceruloplasmin are highly expressed on astrocytic cell membranes, and both proteins likely play an important role in iron mobilization from these cells into the extracellular brain space (Figure 2A; Jeong and David, 2003;Z. Chen et al, 2019).…”

“…Although, the role of microglial cells in demyelinating diseases is beyond the scope of this review, published data suggest that iron-positive microglia may be a significant contributor to tissue injury and disease severity in MS. Astrocytes located near EAE lesions upregulate iron importers such as TfR, DMT1, and ZIP14, which suggests that these cells possess at least three different mechanisms to actively uptake iron during demyelination (Zarruk et al, 2015). In the other hand, the multicopper ferroxidase ceruloplasmin, which promote cell iron efflux through ferroportin, is highly expressed in astrocyte membranes (Vashchenko and MacGillivray, 2013;Z. Chen et al, 2019).…”

“…In the other hand, the multicopper ferroxidase ceruloplasmin, which promote cell iron efflux through ferroportin, is highly expressed in astrocyte membranes ( Vashchenko and MacGillivray, 2013 ; Z. Chen et al., 2019 ). Iron efflux deficiency, iron overload, and increased free radical production were found in multicopper ferroxidases knock-out astrocytes (Z.…”

“…This ferric iron could be released by astrocytes and microglial cells (Z. Chen et al., 2019); thus, this could be a central mechanism by which iron is distributed in the CNS throughout development.…”

Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated Angiogenesis

“…Enhancement of HIF-2α has been linked to cancers in brain, head/neck, melanoma, lung and confers poor prognosis [ 10 ]. A recent study indicates that deficiency of CP decreases iron efflux, resulting in iron accumulation in astrocytes [ 36 ]. Our data indicated both sCP and GPI-CP are overexpressed in lung cancer, although the sCP level was 4-fold higher than GPI-CP.…”