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

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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.

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Acknowledgments

This study was supported by research grant R-181-000-120-213 from the National Medical Research Council (NMRC) and R-181-000-148-750 from the National University Health System (NUHS), Singapore.

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  1. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Blk MD10, 4 Medical Drive, Singapore, Singapore, 117594

    Gurugirijha Rathnasamy, Madhuvika Murugan, Eng-Ang Ling & Charanjit Kaur

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  1. Gurugirijha Rathnasamy
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Rathnasamy, G., Murugan, M., Ling, EA. et al. Hypoxia-Induced Iron Accumulation in Oligodendrocytes Mediates Apoptosis by Eliciting Endoplasmic Reticulum Stress. Mol Neurobiol 53, 4713–4727 (2016). https://doi.org/10.1007/s12035-015-9389-6

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