Rathnasamy Gurugirijha, Murugan Madhuvika, Ling Eng-Ang, Kaur Charanjit
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Blk MD10, 4 Medical Drive, Singapore, Singapore, 117594.
Mol Neurobiol. 2016 Sep;53(7):4713-27. doi: 10.1007/s12035-015-9389-6. Epub 2015 Aug 29.
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.
本研究旨在评估少突胶质细胞中铁蓄积增加的作用及其在新生鼠脑缺氧损伤后脑室周围白质损伤（PWMD）中对少突胶质细胞凋亡的作用。缺氧时，在脑室周围白质中，少突胶质细胞中参与铁摄取的蛋白质表达增加，如铁调节蛋白（IRP1、IRP2）和转铁蛋白受体。与此一致，缺氧暴露后，原代培养的少突胶质细胞中铁蓄积增加。发现缺氧少突胶质细胞内铁浓度升高会引发兰尼碱受体（RyR）表达，以及内质网（ER）应激标志物如结合免疫球蛋白蛋白（BiP）和肌醇需求酶（IRE）-1α的表达。与ER应激相关，缺氧少突胶质细胞内三磷酸腺苷（ATP）水平降低。然而，去铁胺治疗可降低缺氧少突胶质细胞中RyR、BiP和IRE-1α的表达增加，并提高ATP水平。与ER应激平行，缺氧少突胶质细胞线粒体中活性氧生成增强，用去铁胺处理这些细胞时活性氧生成减弱。在超微结构水平上，缺氧少突胶质细胞经常表现为内质网扩张和线粒体破坏，在用去铁胺处理的细胞中这种情况变得不那么明显。与这些亚细胞变化相关，缺氧少突胶质细胞凋亡明显，p53和半胱天冬酶-3表达增加，用去铁胺处理这些细胞时凋亡减弱。因此，本研究强调，缺氧脑室周围白质中少突胶质细胞内蓄积的过量铁可通过引发ER应激和线粒体破坏导致其死亡。
