柠檬酸循环
糖酵解
氧化磷酸化
线粒体
生物化学
细胞生物学
谷氨酰胺
乙酰化
线粒体生物发生
厌氧糖酵解
化学
谷氨酰胺分解
三羧酸
生物
新陈代谢
基因
氨基酸
作者
Yang Li,Yuchen Li,Xiaotian Liu,Lu Zhang,Yihua Chen,Qiong Zhao,Wen Gao,Baolin Liu,Hua Yang,Ping Li
出处
期刊:Cell Reports
[Elsevier]
日期:2022-02-01
卷期号:38 (7): 110391-110391
被引量:27
标识
DOI:10.1016/j.celrep.2022.110391
摘要
The metabolism of activated macrophages relies on aerobic glycolysis, while mitochondrial oxidation is disrupted. In lipopolysaccharide-activated macrophages, the citrate carrier (CIC) exports citrate from mitochondria to enhance glycolytic genes through histone acetylation. CIC inhibition or Slc25a1 knockdown reduces the occupancy of H3K9ac to hypoxia-inducible factor-1α (HIF-1α) binding sites in promoters of glycolytic genes to restrain glycolysis. HIF-1α also transcriptionally upregulates immune-responsive gene 1 for itaconate production, which is inhibited by CIC blocking. Isotopic tracing of [U-13C6] glucose shows that CIC blockage prevents citrate accumulation and itaconate production by reducing glycolytic flux and facilitating metabolic flux in the TCA cycle. Isotopic tracing of [U-13C5] glutamine reveals that CIC inhibition reduces succinate accumulation from glutaminolysis and the gamma-aminobutyric acid shunt by enhancing mitochondrial oxidation. By restraining glycolysis, CIC inhibition increases NAD+ content to ensure mitochondrial biogenesis for oxidative phosphorylation. Furthermore, blockage of citrate export reduces cerebral thrombosis by inactivation of peripheral macrophages.
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