下调和上调
兴奋剂
细胞生物学
线粒体
受体
信号转导
生物
化学
内分泌学
生物化学
基因
作者
Ya Hui,Liuyu Kuang,Yuanmei Zhong,Yunyun Tang,Zhiqiang Xu,Tianyuan Zheng
出处
期刊:iScience
[Elsevier]
日期:2024-01-01
卷期号:27 (1): 108689-108689
标识
DOI:10.1016/j.isci.2023.108689
摘要
High glucose has been proved to impair cognitive function in type 2 diabetes, but the underlying mechanisms remain elusive. Here, we found that high glucose increased transcription factors' SP1 O-GlcNAcylation in regulatory T (Treg) cells. Glycosylated SP1 further enhanced HDAC2 recruitment and histone deacetylation on Na+/Ca2+/Li+ exchanger (NCLX) promoter, which downregulated NCLX expression and led to mitochondrial calcium overload and oxidative damage, thereby promoting Treg cell dysfunction, M1 microglia polarization, and diabetes-associated cognitive impairment. Importantly, GLP-1 receptor agonist alleviated these deleterious effects via GLP-1-receptor-mediated upregulation of OGA and inhibition of SP1 O-GlcNAcylation in Treg cells. Our study highlighted a link between high-glucose-mediated SP1 O-GlcNAcylation and HDAC2/NCLX signaling in control of mitochondrial calcium concentrations in Treg cells. It also revealed a mechanism for linking Treg cell dysfunction and cognitive impairment in type 2 diabetes and provides an insight into the mechanism underlying the neuroprotective effects of GLP-1 receptor agonist.
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