Hypoxia-Induced Iron Accumulation in Oligodendrocytes Mediates Apoptosis by Eliciting Endoplasmic Reticulum Stress

Abstract

This study was aimed at evaluating the role of increased iron accumulation in oligodendrocytes and its role in their apoptosis in the periventricular white matter damage (PWMD) following a hypoxic injury to the neonatal brain. In response to hypoxia, in the PWM, there was increased expression of proteins involved in iron acquisition, such as iron regulatory proteins (IRP1, IRP2) and transferrin receptor in oligodendrocytes. Consistent with this, following a hypoxic exposure, there was increased accumulation of iron in primary cultured oligodendrocytes. The increased concentration of iron within hypoxic oligodendrocytes was found to elicit ryanodine receptor (RyR) expression, and the expression of endoplasmic reticulum (ER) stress markers such as binding-immunoglobulin protein (BiP) and inositol-requiring enzyme (IRE)-1α. Associated with ER stress, there was reduced adenosine triphosphate (ATP) levels within hypoxic oligodendrocytes. However, treatment with deferoxamine reduced the increased expression of RyR, BiP, and IRE-1α and increased ATP levels in hypoxic oligodendrocytes. Parallel to ER stress there was enhanced reactive oxygen species production within mitochondria of hypoxic oligodendrocytes, which was attenuated when these cells were treated with deferoxamine. At the ultrastructural level, hypoxic oligodendrocytes frequently showed dilated ER and disrupted mitochondria, which became less evident in those treated with deferoxamine. Associated with these subcellular changes, the apoptosis of hypoxic oligodendrocytes was evident with an increase in p53 and caspase-3 expression, which was attenuated when these cells were treated with deferoxamine. Thus, the present study emphasizes that the excess iron accumulated within oligodendrocytes in hypoxic PWM could result in their death by eliciting ER stress and mitochondrial disruption.

Long‐term sequelae of hippocampal lesions in patients with transient global amnesia: A multiparametric MRI study

“…The underlying mechanisms for iron deposition after ischemia may include the formation of Fe 2+ from degradation of hemoglobin, transportation of Fe 2+ from the damaged blood–brain barrier, and the release of Fe 2+ stimulated by the increase of oxidative stress in the hypoxia state . Increased expressions of iron regulatory proteins and transferrin receptors may also be involved in iron acquisition . Moreover, bulk tissue magnetic susceptibility of white matter can be affected by diamagnetic myelin, which counteracts the effect of tissue iron on the susceptibility value .…”

Intraspinal TLR4 activation promotes iron storage but does not protect neurons or oligodendrocytes from progressive iron-mediated damage

“…Once inside cells, iron can catalyze production of highly reactive hydroxyl radicals via the Fenton reaction, which directly damage proteins, DNA and lipids (Winterbourn, 1995). Iron can also induce endoplasmic reticulum stress and apoptosis in cultured hypoxic OLs (Rathnasamy et al, 2016). Thus, assuming the injected iron was initially internalized, direct iron-induced cytotoxicity may have killed local neurons and glia (Bao & Liu, 2004; Liu et al, 2004).…”

The role of oligodendrocytes and their progenitors on neural interface technology: A novel perspective on tissue regeneration and repair

“…Binding of ferritin to iron occurs coincidentally with the formation of myelin in the developing brain and it has been suggested that oligodendrocytes are responsible for regulating iron throughout the CNS [160, 161]. Oxidative stress has been linked to iron dysfunction in oligodendrocytes and, when exposed to hypoxic conditions, iron accumulates inside the cell and induces endoplasmic reticulum (ER) stress and mitochondrial dysfunction resulting in cell death [162]. Likewise, excess levels of iron can result in the formation of hydroxyl radicals, a toxic reactive species implicated in DNA, lipid, and protein disruption [163].…”