Nup133 and ERα mediate the differential effects of hyperoxia-induced damage in male and female OPCs.

IF 2.4 Q1 PEDIATRICS
Donna Elizabeth Sunny, Elke Hammer, Sebastian Strempel, Christy Joseph, Himanshu Manchanda, Till Ittermann, Stephanie Hübner, Frank Ulrich Weiss, Uwe Völker, Matthias Heckmann
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引用次数: 6

Abstract

Background: Hyperoxia is a well-known cause of cerebral white matter injury in preterm infants with male sex being an independent and critical risk factor for poor neurodevelopmental outcome. Sex is therefore being widely considered as one of the major decisive factors for prognosis and treatment of these infants. But unfortunately, we still lack a clear view of the molecular mechanisms that lead to such a profound difference. Hence, using mouse-derived primary oligodendrocyte progenitor cells (OPCs), we investigated the molecular factors and underlying mechanisms behind the differential response of male and female cells towards oxidative stress.

Results: We demonstrate that oxidative stress severely affects cellular functions related to energy metabolism, stress response, and maturation in the male-derived OPCs, whereas the female cells remain largely unaffected. CNPase protein level was found to decline following hyperoxia in male but not in female cells. This impairment of maturation was accompanied by the downregulation of nucleoporin and nuclear lamina proteins in the male cells. We identify Nup133 as a novel target protein affected by hyperoxia, whose inverse regulation may mediate this differential response in the male and female cells. Nup133 protein level declined following hyperoxia in male but not in female cells. We show that nuclear respiratory factor 1 (Nrf1) is a direct downstream target of Nup133 and that Nrf1 mRNA declines following hyperoxia in male but not in female cells. The female cells may be rendered resistant due to synergistic protection via the estrogen receptor alpha (ERα) which was upregulated following hyperoxia in female but not in male cells. Both Nup133 and ERα regulate mitochondrial function and oxidative stress response by transcriptional regulation of Nrf1.

Conclusions: These findings from a basic cell culture model establish prominent sex-based differences and suggest a novel mechanism involved in the differential response of OPCs towards oxidative stress. It conveys a strong message supporting the need to study how complex cellular processes are regulated differently in male and female brains during development and for a better understanding of how the brain copes up with different forms of stress after preterm birth.

Abstract Image

Abstract Image

Abstract Image

Nup133和ERα介导高氧损伤在雄性和雌性OPCs中的差异作用。
背景:高氧是男性早产儿脑白质损伤的一个众所周知的原因,是神经发育不良的一个独立和关键的危险因素。因此,性别被广泛认为是这些婴儿预后和治疗的主要决定性因素之一。但不幸的是,我们仍然对导致如此深刻差异的分子机制缺乏清晰的认识。因此,我们使用小鼠来源的原代少突胶质祖细胞(OPCs),研究了雄性和雌性细胞对氧化应激差异反应背后的分子因素和潜在机制。结果:我们证明氧化应激严重影响雄性来源的OPCs的能量代谢、应激反应和成熟相关的细胞功能,而雌性细胞基本不受影响。在雄性细胞中发现CNPase蛋白水平在高氧后下降,而在雌性细胞中则没有。这种成熟障碍伴随着核孔蛋白和核层蛋白在雄性细胞中的下调。我们发现Nup133是受高氧影响的一种新的靶蛋白,其反向调控可能介导了男性和女性细胞的这种差异反应。高氧后,雄性细胞中Nup133蛋白水平下降,而雌性细胞中没有。我们发现核呼吸因子1 (Nrf1)是Nup133的直接下游靶点,在男性细胞中Nrf1 mRNA在高氧后下降,而在女性细胞中则没有。雌性细胞可能由于雌激素受体α (ERα)的协同保护而产生抗性,雌激素受体α在雌性细胞高氧后上调,而在雄性细胞中没有上调。Nup133和ERα均通过Nrf1转录调控线粒体功能和氧化应激反应。结论:这些来自基本细胞培养模型的发现建立了显著的性别差异,并提示了一种涉及OPCs对氧化应激差异反应的新机制。它传达了一个强有力的信息,支持研究复杂的细胞过程在男性和女性大脑发育过程中如何受到不同的调节,以及更好地理解大脑如何应对早产后不同形式的压力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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