Iron Metabolism in Oligodendrocytes and Astrocytes, Implications for Myelination and Remyelination

Abstract

Iron is a key nutrient for normal central nervous system (CNS) development and function; thus, iron deficiency as well as iron excess may result in harmful effects in the CNS. Oligodendrocytes and astrocytes are crucial players in brain iron equilibrium. However, the mechanisms of iron uptake, storage, and efflux in oligodendrocytes and astrocytes during CNS development or under pathological situations such as demyelination are not completely understood. In the CNS, iron is directly required for myelin production as a cofactor for enzymes involved in ATP, cholesterol and lipid synthesis, and oligodendrocytes are the cells with the highest iron levels in the brain which is linked to their elevated metabolic needs associated with the process of myelination. Unlike oligodendrocytes, astrocytes do not have a high metabolic requirement for iron. However, these cells are in close contact with blood vessel and have a strong iron transport capacity. In several pathological situations, changes in iron homoeostasis result in altered cellular iron distribution and accumulation and oxidative stress. In inflammatory demyelinating diseases such as multiple sclerosis, reactive astrocytes accumulate iron and upregulate iron efflux and influx molecules, which suggest that they are outfitted to take up and safely recycle iron. In this review, we will discuss the participation of oligodendrocytes and astrocytes in CNS iron homeostasis. Understanding the molecular mechanisms of iron uptake, storage, and efflux in oligodendrocytes and astrocytes is necessary for planning effective strategies for iron management during CNS development as well as for the treatment of demyelinating diseases.

Keywords: DMT1; astrocytes; ferritin; iron; myelination; oligodendrocytes; remyelination; transferrin; transferrin receptor.

Figure 1.

Schematic Representation of the Tf Cycle. Fe³⁺ in the brain interstitial fluid binds to apo-Tf to form holo‑Tf. Holo‑Tf binds to TfR on the cell surface. The TfR–holo-Tf complex undergoes endocytosis through clathrin pit formation. The endosome then acidifies, and the endosomal metalloreductase reduces Fe³⁺ to Fe²⁺, allowing iron, now released from Tf, to be transported into the cytosol by DMT1. Iron can then bind to chaperones that donate iron to specific proteins (not shown), enter mitochondria, or be stored in ferritin. At the plasma membrane, DMT1 can uptake Fe²⁺ independent of the Tf cycle. Finally, apo-Tf and the TfR are recycled back to the luminal membrane. DMT1: divalent metal transporter 1.

Figure 2.

A: Schematic illustration of glial iron metabolism. This hypothetical model illustrates the possible interactions between oligodendrocytes and astrocytes in iron metabolism during development as well as in the adult brain. (1) Most Tf in the brain is synthesized and secreted by OPCs and oligodendrocytes as apo‑Tf. (2) Astrocytes, OPCs and mature oligodendrocytes probably acquire most iron through TfR and holo‑Tf that is present in interstitial fluid and cerebrospinal fluid. (3) DMT1 can participate in Fe²⁺ absorption independent of the Tf cycle. (4) Ceruloplasmin can oxidize Fe²⁺ to Fe³⁺ and then promote ferroportin-mediated Fe²⁺ release in astrocytes, OPCs and mature oligodendrocytes. (5) Iron is stored in astrocytes, OPCs and myelinating oligodendrocytes mainly in the form of ferritin. Ferritin released from astrocytes could be the main mechanism of OPC and matue oligodendrocyte iron intake. B: Schematic representation of the neurovascular unit organization. DMT1: divalent metal transporter 1; OPC: oligodendrocyte progenitor cells.