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酸脱酶支持线粒体的代谢重定位以驱动炎症性巨细胞

Evanna L Mills¹, Beth Kelly¹, Angela Logan²

¹School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.

|September 27, 2016

概括

激活的巨细胞重新编程新陈代谢,从氧化化转变为糖解. 这种新陈代谢转变增加了糖酸盐,促使线粒体的ROS产生和促炎状态,可用于治疗.

科学领域:

免疫学
细胞代谢
线粒体生物学

背景情况:

激活的巨细胞表现出与其促炎功能相关的代谢重编程.
这种代谢转变及其促炎后果的确切机制尚未完全理解.

研究的目的:

阐明激活的巨细胞中的代谢重编程的机制基础.
研究线粒体代谢和反应性氧物种 (ROS) 在驱动巨诱导的炎症中的作用.

主要方法:

使用脂聚糖 (LPS) 刺激巨细胞.
代谢分析包括ATP生产途径 (氧化酸化与糖解) 和糖酸盐水平.
评估线粒体膜潜力和ROS的产生.
用于基因表达特征的RNA测序.
药理上抑制酸盐氧化 (二甲基酸盐 - - DMM) 和ROS生成 (氨酸,替代氧化酶 - - AOX).
使用AOX进行体内研究,以评估对LPS致死性的保护.

主要成果:

在巨细胞中,LPS刺激诱导了从氧化化转向糖解的代谢转变,从而增加了酸盐水平.
通过糖酸脱酶 (SDH) 增加的线粒体糖酸氧化和增加的线粒体膜潜能促进了ROS的产生.
这种ROS产生被确定为促炎性基因表达特征的关键驱动因素.
抑制糖酸氧化 (DMM) 或ROS (氨酸,AOX) 抑制了炎症表型.
在小鼠中,AOX的表达对LPS诱导的致死性进行了保护.

结论:

巨细胞激活通过代谢重编程将线粒体从ATP合成转变为ROS.
酸盐积累和随后的线粒体ROS生成是促炎性巨细胞表型的关键媒介.
针对线粒体新陈代谢和ROS产生是一种潜在的炎症疾病治疗策略.

关键词:

免疫新陈代谢天生的免疫力巨细胞反向电子传输精制剂酸脱酶类似收费的接收器

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