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.

Chorioamnionitis Precipitates Perinatal Alterations of Heme-Oxygenase-1 (HO-1) Homeostasis in the Developing Rat Brain

“…Persistent white matter injury is a hallmark of preterm brain injury from chorioamnionitis [32]. Furthermore, TfR1 is important in iron regulation which is essential for developing brain [35]. When taken together, the sustained increase in HO-1/TfR1 ratio, with a relative deficiency of TfR1 following CHORIO at the critical CNS developmental window of E18-P2 may highlight an important link between increased oxidative microenvironment and inflammation.…”

A primary cilium in oligodendrocytes: a fine structure signal of repairs in thalamic Osmotic Demyelination Syndrome (ODS)

“…93 Such ultrastructure findings were explained by Peters and others 88 as they have illustrated the oligodendrocytes to contain, as quoted: 'a matrix of fine dense particles that are responsible for the inherent density of the oligodendrocytic cytoplasm'. Others identified these particles as iron in the form of heavy or H-ferritin that can be taken up by Tim-2 receptors 94,95 and iron uptake through transferrin by the normal BBB. 96,97 In ODS, the blood-brain barrier has been shown to be breached 19 and, excessive, uncontrolled extracellular iron level could have induced an oxidative stress 98 that may have triggered changes in nucleus and cytoplasm of key cells of the brain parenchyma.…”

“…At a low and with control by the intact BBB, iron is involved in both functional astrocytes, oligodendrocytes and myelination as well as remyelination. 95…”

Iron induces two distinct Ca2+ signalling cascades in astrocytes

“…Ionised Fe 2+ enters astrocytes through DMT1/SLC11A2 transporters which are particularly concentrated in the endfeet of cerebral and hippocampal astrocytes 10 . In physiological condition, DMT1 is widely distributed in the nervous system, being expressed in neurones 11 – 13 , astrocytes 13 – 15 and oligodendrocytes 14 , 16 in vitro and in the brain tissue. In astrocytes, DMT1 mediates non‐transferrin‐bound iron (NTBI) transport, thus contributing to the brain iron homoeostasis in development and adulthood 17 – 19 .…”