Iron homeostasis in peripheral nervous system, still a black box?

Abstract

Significance: Iron is the most abundant transition metal in biology and an essential cofactor for many cellular enzymes. Iron homeostasis impairment is also a component of peripheral neuropathies.

Recent advances: During the past years, much effort has been paid to understand the molecular mechanism involved in maintaining systemic iron homeostasis in mammals. This has been stimulated by the evidence that iron dyshomeostasis is an initial cause of several disorders, including genetic and sporadic neurodegenerative disorders.

Critical issues: However, very little has been done to investigate the physiological role of iron in peripheral nervous system (PNS), despite the development of suitable cellular and animal models.

Future directions: To stimulate research on iron metabolism and peripheral neuropathy, we provide a summary of the knowledge on iron homeostasis in the PNS, on its transport across the blood-nerve barrier, its involvement in myelination, and we identify unresolved questions. Furthermore, we comment on the role of iron in iron-related disorder with peripheral component, in demyelinating and metabolic peripheral neuropathies.

FIG. 1.

The reaction catalyzed by iron and O₂. In the presence of H₂O₂, Fe²⁺ triggers the formation of hydroxyl radicals via the equations named Fenton reaction (Eq. 1). In the presence of trace amount of iron, the so-called Haber and Weiss reactions (Eqs. 2 and 3) occur. (Eq. 4) Equation of GSH consumption by iron. GSH, glutathione.

FIG. 2.

Schematic representation of cellular components involved in iron homeostasis. Nonheme iron can enter mammalian cells via two distinct mechanisms. Fe³⁺ is transported via receptor-mediated endocytosis of Tf/TfR1/2 (transferrin/transferrin receptor1/2) or ferritin/Tim2. HFE interacts with TfR1 to influence the rate of receptor-mediated uptake of transferrin-bound iron. Transport of Fe²⁺ is mediated by divalent channel located on the plasmamembrane (DMT1, ZIP14, ZIP8), on endosomes (DMT1), and lysosomes (not shown). Their activity is joined to ferric reductases (Dcytb, Steap). When in cytosol, iron forms the LIP, which is the redox-reactive form of iron. It is sensed by IRPs, the excess stored into the iron-storage ferritin molecule or addressed to mitochondria. The mitochondrial iron importers are Mfrn 1/2, assisted by ABC10, and, at least in dopaminergic neurons, the TfR2. In the organelle, iron is utilized for maintaining iron-dependent cofactor biosynthesis, like heme and iron–sulfur cluster (Fe/S). These cofactors are coupled with enzymes inside mitochondria and also exported by specialized transporters (ABCB7 for Fe/S and FLVCR1b for heme, in erythroid progenitors) into cytosol for the loading into cytosolic enzymes. Iron excess is stored by FtMt, which is expressed in cells with high metabolic activity. The only iron exporter so far identified is ferroportin. Its activity is supported by the feroxidases, named Cp or Hp. Cp, ceruloplasmin; DMT1, dimetal transporter 1; FtMt, mitochondrial ferritin; Hp, hephestin; IRPs, iron protein expression regulatory proteins; LIP, labile iron pool; Tf, transferrin; TfR, transferrin receptor; HFE, MHC-related protein, that is mutated in hereditary hemochromatosis.

FIG. 3.

Schematic representation of iron homeostasis in SC. The scheme summarizes the data available on iron proteins expression in SC and the small amount of information regarding the Tf/TfR1 complex, DMT1, ferritin, frataxin, and ferroportin. Of note, the presence of transferrin in cytosolic compartment. Symbols and abbreviations as in Figure 2. SC, Schwann cell.

FIG. 4.

Schematic representation of the proposed myelination pathway in SC. The scheme described the myelination pathway in SC proposed by Salis and coworkers. Question marks indicate the still not conclusive results obtained on the role of human transferrin (hTf) and low Fe³⁺ amount on SC differentiation (123). The data presented, although suggestive, do not allow a definitive conclusion on the role of hTf in SC differentiation. To further substantiate the presented results, it would be important to assess the role of Fe³⁺ and hTf in myelinating cocultures and to determine whether this may impact the effectiveness of NRG1 signaling in SC differentiation and in myelination. NRG1, neuregulin 1.