英国剑桥大学Lalita Ramakrishnan和Francisco J. Roca等研究人员合作发现，TNF通过线粒体-溶酶体-内质网回路诱导结核病引起的程序性巨噬细胞坏死。2019年8月29日，《细胞》在线发表了这项成果。
在感染海分枝杆菌（Mycobacterium marinum）或结核分枝杆菌（Mycobacterium tuberculosis）的斑马鱼中，过量的肿瘤坏死因子通过线粒体活性氧（ROS）的产生和亲环素D（线粒体通透性转换孔的组分）的参与触发了受感染的巨噬细胞的程序性坏死。研究人员发现这种坏死途径本质上不是线粒体的，而是由细胞器内回路启动并在线粒体中达到顶峰。线粒体ROS诱导溶酶体神经酰胺的产生，最终激活胞浆蛋白BAX。BAX通过ryanodine受体促进钙从内质网流入线粒体，并且所产生的线粒体钙超载引发亲环素-D介导的坏死。研究人员认为ryanodine受体和质膜L型钙通道是可制药的靶标，从而在分枝杆菌感染的斑马鱼和人巨噬细胞中拦截线粒体钙超载和坏死。
据介绍，受感染巨噬细胞的坏死通过将分枝杆菌释放到允许其生长的细胞外环境中，造成了结核病中的关键致病事件。
附：英文原文
Title: TNF Induces Pathogenic Programmed Macrophage Necrosis in Tuberculosis through a Mitochondrial-Lysosomal-Endoplasmic Reticulum Circuit
Author: Francisco J. Roca, Laura J. Whitworth, Sarah Redmond , Ana A. Jones, Lalita Ramakrishnan
Issue&Volume: 29 August 2019
Abstract: Necrosis of infected macrophages constitutes a critical pathogenetic event in tuberculosis by releasing mycobacteria into the growth-permissive extracellular environment. In zebrafish infected with Mycobacterium marinum or Mycobacterium tuberculosis, excess tumor necrosis factor triggers programmed necrosis of infected macrophages through the production of mitochondrial reactive oxygen species (ROSs) and the participation of cyclophilin D, a component of the mitochondrial permeability transition pore. Here, we show that this necrosis pathway is not mitochondrion-intrinsic but results from an inter-organellar circuit initiating and culminating in the mitochondrion. Mitochondrial ROSs induce production of lysosomal ceramide that ultimately activates the cytosolic protein BAX. BAX promotes calcium flow from the endoplasmic reticulum into the mitochondrion through ryanodine receptors, and the resultant mitochondrial calcium overload triggers cyclophilin-D-mediated necrosis. We identify ryanodine receptors and plasma membrane L-type calcium channels as druggable targets to intercept mitochondrial calcium overload and necrosis of mycobacterium-infected zebrafish and human macrophages.
DOI: https://doi.org/10.1016/j.cell.2019.08.004
Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30892-X#