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Cell Mol Neurobiol. 2018 May;38(4):941-954. doi: 10.1007/s10571-017-0568-z. Epub 2017 Nov 25.

The Ferroxidase Hephaestin But Not Amyloid Precursor Protein is Required for Ferroportin-Supported Iron Efflux in Primary Hippocampal Neurons.

Author information

1
Department of Biochemistry, School of Medicine and Biomedical Sciences Buffalo, State University of New York, New York, NY, 14214, USA.
2
Department of Biochemistry, School of Medicine and Biomedical Sciences Buffalo, State University of New York, New York, NY, 14214, USA. camkos@buffalo.edu.
3
Department of Biochemistry, The University at Buffalo, Farber Hall Room 140, 3435 Main St, Buffalo, NY, 14214-3000, USA. camkos@buffalo.edu.

Abstract

Iron efflux in mammalian cells is mediated by the ferrous iron exporter ferroportin (Fpn); Fpn plasma membrane localization and function are supported by a multicopper ferroxidase and/or the soluble amyloid precursor protein (sAPP). Fpn and APP are ubiquitously expressed in all cell types in the central nervous system including neurons. In contrast, neuronal ferroxidase(s) expression has not been well characterized. Using primary cultures of hippocampal neurons, we examined the molecular mechanism of neuronal Fe efflux in detail. Developmental increases of Fpn, APP, and the ferroxidase hephaestin (Hp) were observed in hippocampal neurons. Iron efflux in these neurons depended on the level of Fpn localized at the cell surface; as noted, Fpn stability is supported by ferroxidase activity, an enzymatic activity that is required for Fe efflux. Iron accumulation increases and iron efflux decreases in Hp knockout neurons. In contrast, suppression of endogenous APP by RNAi knockdown does not affect surface Fpn stability or Fe efflux. These data support the model that the neuronal ferroxidase Hp plays a unique role in support of Fpn-mediated Fe efflux in primary hippocampal neurons. Our data also demonstrate that Hp ferroxidase activity relies on copper bioavailability, which suggests neuronal iron homeostasis will be modulated by cellular copper status.

KEYWORDS:

Amyloid precursor protein (APP); Ferroportin (Fpn); Ferroxidase; Hephaestin (Hp); Iron efflux; Primary hippocampal neurons

PMID:
29177638
PMCID:
PMC5884744
[Available on 2019-05-01]
DOI:
10.1007/s10571-017-0568-z
[Indexed for MEDLINE]

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