PI3K/AKT/mTOR通路
柠檬酸循环
肠沙门氏菌
糖酵解
代谢途径
生物
雷帕霉素的作用靶点
厌氧糖酵解
巴基斯坦卢比
免疫系统
细胞生物学
新陈代谢
化学
生物化学
丙酮酸激酶
沙门氏菌
信号转导
细菌
免疫学
遗传学
作者
Julia Telser,Chiara Volani,Richard Hilbe,Markus Seifert,Natascha Brigo,Giuseppe Paglia,Günter Weiß
出处
期刊:Microbial Cell
[Shared Science Publishers OG]
日期:2019-12-02
卷期号:6 (12): 531-543
被引量:14
标识
DOI:10.15698/mic2019.12.700
摘要
Iron is an essential nutrient for immune cells and microbes, therefore the control of its homeostasis plays a decisive role for infections. Moreover, iron affects metabolic pathways by modulating the translational expression of the key tricarboxylic acid cycle (TCA) enzyme mitochondrial aconitase and the energy formation by mitochondria. Recent data provide evidence for metabolic re-programming of immune cells including macrophages during infection which is centrally controlled by mTOR. We herein studied the effects of iron perturbations on metabolic profiles in macrophages upon infection with the intracellular bacterium Salmonella enterica serovar Typhimurium and analysed for a link to the mTOR pathway. Infection of the murine macrophage cell line RAW264.7 with Salmonella resulted in the induction of mTOR activity, anaerobic glycolysis and inhibition of the TCA activity as reflected by reduced pyruvate and increased lactate levels. In contrast, iron supplementation to macrophages not only affected the mRNA expression of TCA and glycolytic enzymes but also resulted in metabolic reprogramming with increased pyruvate accumulation and reduced lactate levels apart from modulating the concentrations of several other metabolites. While mTOR slightly affected cellular iron homeostasis in infected macrophages, mTOR inhibition by rapamycin resulted in a significant growth promotion of bacteria. Importantly, iron further increased bacterial numbers in rapamycin treated macrophages, however, the metabolic profiles induced by iron in the presence or absence of mTOR activity differed in several aspects. Our data indicate, that iron not only serves as a bacterial nutrient but also acts as a metabolic modulator of the TCA cycle, partly reversing the Warburg effect and resulting in a pathogen friendly nutritional environment.
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