Kramer Joshua, Fu Sarah, Ouyang Xiaosen, Rohwer Eric, Chatham John C, Young Martin E, Darley-Usmar Victor, Zhang Jianhua
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
J Neurochem. 2025 Aug;169(8):e70205. doi: 10.1111/jnc.70205.
O-GlcNAcylation is a dynamic and reversible protein posttranslational modification of serine or threonine residues which modulates the activity of transcriptional and signaling pathways and controls cellular responses to metabolic and inflammatory stressors. We and others have shown that O-GlcNAcylation has the potential to regulate autophagy and mitophagy to play a critical role in mitochondrial quality control, but this has not been assessed in vivo in the brain. This is important since mitochondrial dysfunction contributes to the development of neurodegenerative diseases. We used mito-QC reporter mice to assess mitophagy in diverse cells in the dentate gyrus in response to pharmacological inhibition of O-GlcNAcase (OGA) with thiamet G which leads to elevation of protein O-GlcNAcylation. We demonstrate that mitophagy occurs predominantly in the GFAP-positive astrocytes and is significantly decreased in response to elevated O-GlcNAcylation. Furthermore, with increased O-GlcNAcylation, the levels of astrocyte markers GFAP and S100B, and the microglial cell marker IBA1, decreased in the dentate gyrus, while the levels of microglial cell marker TMEM119 were increased, indicating significant changes in glia homeostasis. These results provide strong evidence of the regulation of mitophagy and glia signatures by the O-GlcNAc pathway.
O-连接的N-乙酰葡糖胺化（O-GlcNAcylation）是一种针对丝氨酸或苏氨酸残基的动态可逆蛋白质翻译后修饰，它可调节转录和信号通路的活性，并控制细胞对代谢和炎症应激源的反应。我们和其他研究人员已表明，O-GlcNAcylation有调节自噬和线粒体自噬的潜力，从而在线粒体质量控制中发挥关键作用，但尚未在大脑的体内环境中对此进行评估。这一点很重要，因为线粒体功能障碍会导致神经退行性疾病的发展。我们使用线粒体质量控制（mito-QC）报告基因小鼠，来评估齿状回中不同细胞内的线粒体自噬情况，这些细胞对用噻美因G药物抑制O-连接的N-乙酰葡糖胺酶（OGA）作出反应，而这会导致蛋白质O-GlcNAcylation水平升高。我们证明，线粒体自噬主要发生在胶质纤维酸性蛋白（GFAP）阳性星形胶质细胞中，并且响应O-GlcNAcylation水平升高而显著减少。此外，随着O-GlcNAcylation水平升高，齿状回中星形胶质细胞标志物GFAP和S100B以及小胶质细胞标志物离子钙结合衔接分子-1（IBA1）的水平降低，而小胶质细胞标志物跨膜蛋白119（TMEM119）水平升高，表明神经胶质细胞内环境稳定发生了显著变化。这些结果为O-GlcNAc途径对线粒体自噬和神经胶质细胞特征的调节提供了有力证据。
