Abstract
Iron is an essential molecule for biological processes, but its accumulation can lead to oxidative stress and cellular death. Due to its oxidative effects, iron accumulation is implicated in the process of aging and neurodegenerative diseases. However, the mechanism for this increase in iron with aging, and whether this increase is localized to specific cellular compartment(s), are not known. Here, we measured the levels of iron in different tissues of aged mice, and demonstrated that while cytosolic non-heme iron is increased in the liver and muscle tissue, only the aged brain cortex exhibits an increase in both the cytosolic and mitochondrial non-heme iron. This increase in brain iron is associated with elevated levels of local hepcidin mRNA and protein in the brain. We also demonstrate that the increase in hepcidin is associated with increased ubiquitination and reduced levels of the only iron exporter, ferroportin-1 (FPN1). Overall, our studies provide a potential mechanism for iron accumulation in the brain through increased local expression of hepcidin, and subsequent iron accumulation due to decreased iron export. Additionally, our data support that aging is associated with mitochondrial and cytosolic iron accumulation only in the brain and not in other tissues.
Highlights
Iron is an essential molecule for almost every organism on earth
We demonstrate that hepcidin levels are upregulated in the brain cortex of aged mice, which is associated with ubiquitination of FPN1 and a reduction in its protein levels
We noted a significant increase in the mRNA levels of Fpn1, heme oxygenase 1 (Hmox1), ALA dehydrogenase (Alad), and bone morphogenetic protein 6 (Bmp6), and a significant decrease in the mRNA level of Metalloreductase Six-Transmembrane Epithelial Antigen of Prostate-3 (Steap3) (Figure 2A)
Summary
Iron is an essential molecule for almost every organism on earth. It is generally found naturally in two oxidation states, either as the oxidized form of ferric iron (Fe3+), or as the reduced form of ferrous iron (Fe2+). Ferrous iron is the major form of iron used in mammalian cells, and due to the scarcity of the reduced form of iron on earth, mammalian cells have developed mechanisms for efficient uptake of oxidized iron through its solubilization by acidification, followed by reduction and its cellular transportation. Aging has been shown to be associated with iron accumulation in various organs and tissues both in humans and in animal models of aging (Xu et al, 2012). We demonstrate that hepcidin levels are upregulated in the brain cortex of aged mice, which is associated with ubiquitination of FPN1 and a reduction in its protein levels. Our studies suggest that local expression of hepcidin in the brain may be a driver in increasing iron levels due to a reduction in iron export by FPN1 degradation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
