Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 May;25(3):183-188.
doi: 10.1097/MOH.0000000000000417.

The flux of iron through ferritin in erythrocyte development

Caroline C Philpott  1
Affiliations
Review

The flux of iron through ferritin in erythrocyte development

Caroline C Philpott. Curr Opin Hematol. 2018 May.

Abstract

Purpose of review: Terminal differentiation of erythropoietic progenitors requires the rapid accumulation of large amounts of iron, which is transported to the mitochondria, where it is incorporated into heme. Ferritin is the sole site of iron storage present in the cytosol. Yet the role of iron accumulation into ferritin in the context of red cell development had not been clearly defined. Early studies indicated that at the onset of terminal differentiation, iron initially accumulates in ferritin and precedes heme synthesis. Whether this accumulation is physiologically important for red cell development was unclear until recent studies defined an obligatory pathway of iron flux through ferritin.

Recent findings: The iron chaperone functions of poly rC-binding protein 1 (PCBP1) and the autophagic cargo receptor for ferritin, nuclear co-activator 4 (NCOA4) are required for the flux of iron through ferritin in developing red cells. In the absence of these functions, iron delivery to mitochondria for heme synthesis is impaired.

Summary: The regulated trafficking of iron through ferritin is important for maintaining a consistent flow of iron to mitochondria without releasing potentially damaging redox-active species in the cell. Other components of the iron trafficking machinery are likely to be important in red cell development.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest – The author declares no conflicts of interest.

Figures

Figure 1
Figure 1. Regulation of iron flux through ferritin: Cytosolic iron levels can affect activity of PCBP1 and NCOA4
A. Under normal [Fe] conditions, labile iron in the cytosol is low. PCBP1-bound iron is efficiently delivered to ferritin. Under high iron conditions, both PCBP1 and ferritin iron-binding sites are saturated, and iron is not delivered to ferritin. B. Under normal [Fe] conditions, NCOA4 progressively accumulates and binds ferritin, directing it to the lysosome via ferritinophagy. Under high [Fe] conditions, NCOA4 binds iron, which is recognized and ubiquitinated by HERC2. Ubiquitination targets NCOA4 for degradation in the lysosome. Reproduced from [23]. Ryu MS, Duck KA, Philpott CC: Ferritin iron regulators, PCBP1 and NCOA4, respond to cellular iron status in developing red cells. Blood Cells Mol Dis 2017.
Figure 2
Figure 2. Iron flux through ferritin in the developing erythrocyte
A. Early stages of terminal differentiation (Proerythroblast) are characterized by PCBP1-mediated, iron accumulation in ferritin. NCOA4 levels are low and ferritin turnover is slow. B. Mid stages of development (basophilic to orthochromatic erythroblast) are characterized by high levels of iron flux through ferritin, high rates of ferritin turnover, and high rates of iron transfer to the mitochondria. A direct mechanism involving Mucolipin1 (Mln1) and Mitofusin 2 (Mfn2) may be operating. C. Late stage development (Reticulocyte) is characterized by low levels of iron uptake and heme synthesis. Ferritin levels are low and intracellular organelles are rapidly lost. Iron may be directly transferred to mitochondria. Modified from [22]. Ryu MS, Zhang D, Protchenko O, Shakoury-Elizeh M, Philpott CC: PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis. J Clin Invest 2017, 127:1786-1797.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ganz T, Nemeth E. Iron metabolism: interactions with normal and disordered erythropoiesis. Cold Spring Harb Perspect Med. 2012;2:a011668. - PMC - PubMed
    1. Philpott CC, Ryu MS. Special delivery: distributing iron in the cytosol of mammalian cells. Front Pharmacol. 2014;5:173. - PMC - PubMed
    1. Arosio P, Elia L, Poli M. Ferritin, cellular iron storage and regulation. IUBMB Life. 2017;69:414–422. - PubMed
    1. Kidane TZ, Sauble E, Linder MC. Release of iron from ferritin requires lysosomal activity. Am J Physiol Cell Physiol. 2006;291:C445–455. - PubMed
    1. Ohgami RS, Campagna DR, McDonald A, Fleming MD. The Steap proteins are metalloreductases. Blood. 2006;108:1388–1394. - PMC - PubMed

Publication types