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Review
. 2018 Nov 13;11(4):124.
doi: 10.3390/ph11040124.

Emerging and Dynamic Biomedical Uses of Ferritin

Brian Chiou  1 , James R Connor  2
Affiliations
Review

Emerging and Dynamic Biomedical Uses of Ferritin

Brian Chiou et al. Pharmaceuticals (Basel). .

Abstract

Ferritin, a ubiquitously expressed protein, has classically been considered the main iron cellular storage molecule in the body. Owing to the ferroxidase activity of the H-subunit and the nucleation ability of the L-subunit, ferritin can store a large amount of iron within its mineral core. However, recent evidence has demonstrated a range of abilities of ferritin that extends well beyond the scope of iron storage. This review aims to discuss novel functions and biomedical uses of ferritin in the processes of iron delivery, delivery of biologics such as chemotherapies and contrast agents, and the utility of ferritin as a biomarker in a number of neurological diseases.

Keywords: drug delivery; ferritin; inflammation; iron; iron delivery; nanocage; nanotechnology; serum biomarker.

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Conflict of interest statement

J.R.C. is the founder and chairman of the board of Sidero Biosciences LLC, a company with a product involving oral consumption of ferritin for management of iron deficiency.

Figures

Figure 1
Figure 1
Schematic of transferrin and ferritin uptake and intracellular destiny. Left: Holo-Tf can bind to TfR1 and deliver iron into the labile iron pool through the endosome via DMT1. TfR1 can also be recycled to the cell surface, depositing apo-Tf into the extracellular matrix. An alternative hypothesis termed “kiss-and-run” results in endosomal delivery of iron to the mitochondria by brief interactions between the endosome and the mitochondria. Right: Ferritin binding has been shown for TfR1, Tim-1, Tim-2, Scara5, and CXCR4. After binding, ferritin is endocytosed. Note, while not all receptors are simultaneously required for endocytosis of ferritin, the schematic is demonstrating that all of the receptors in question have been found in the endosome. Ferritin trafficking after endocytosis has yet to be fully elucidated. Hypotheses include trafficking to the lysosome for protein degradation or for ferritin to leave the endosome through another means. Once ferritin is cytosolic, it can be shuttled to the lysosome via NCOA4 or it may be transported to the nucleus. There are a number of other potential hypotheses as well: (1) Ferritin may be poly-ubiquitinated and degraded by the proteasome or (2) ferritin may be shuttled to the mitochondria to deliver iron.
Figure 2
Figure 2
Schematic of iron export mechanisms. Ferritin has been hypothesized to be secreted in two different paradigms: (1) Ferritin is trafficked from the cell via secretory autophagy or (2) ferritin encapsulated in exosomes is released extracellularly from multivesicular bodies.
Figure 3
Figure 3
Schematic of encapsulation paradigms for ferritin. Fully formed 24-mer ferritin molecules can be disassembled using 8 M urea or acidic (pH 2–3) or basic (pH 11–12) conditions. A number of different molecules can be mixed with the disassembled ferritin, including chemotherapies, siRNAs/miRNAs, and contrast agents. Upon returning the ferritin mixture to neutral conditions (pH 7.0) coupled with dialysis, ferritin will spontaneously form the 24-mer around the molecule of interest. Free molecules can be dialyzed away from solution.
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