研究人员表示，肿瘤坏死因子（TNF）是抵抗结核病的一个关键宿主抵抗因子。然而，过量的TNF通过增加线粒体活性氧（mROS）产生易感性，线粒体活性氧启动一个信号级联，导致感染分枝杆菌的巨噬细胞致病性坏死。
在斑马鱼中，研究人员确定了TNF诱导结核病mROS的机制。分枝杆菌感染的巨噬细胞中过量的TNF通过复合物I的逆向电子运输（RET）提高了mROS的产生。TNF激活的细胞谷氨酰胺摄取导致琥珀酸浓度增加，这是克雷布斯循环的一个中间体。复合物I抑制剂二甲双胍是一种广泛使用的抗糖尿病药物，它可以防止TNF诱导的mROS和结核分枝杆菌感染的斑马鱼和人类巨噬细胞的坏死，因此二甲双胍可能对结核病治疗有用。
附：英文原文
Title: Tumor necrosis factor induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport
Author: Francisco J. Roca, Laura J. Whitworth, Hiran A. Prag, Michael P. Murphy, Lalita Ramakrishnan
Issue&Volume: 2022-06-24
Abstract: Tumor necrosis factor (TNF) is a critical host resistance factor against tuberculosis. However, excess TNF produces susceptibility by increasing mitochondrial reactive oxygen species (mROS), which initiate a signaling cascade to cause pathogenic necrosis of mycobacterium-infected macrophages. In zebrafish, we identified the mechanism of TNF-induced mROS in tuberculosis. Excess TNF in mycobacterium-infected macrophages elevates mROS production by reverse electron transport (RET) through complex I. TNF-activated cellular glutamine uptake leads to an increased concentration of succinate, a Krebs cycle intermediate. Oxidation of this elevated succinate by complex II drives RET, thereby generating the mROS superoxide at complex I. The complex I inhibitor metformin, a widely used antidiabetic drug, prevents TNF-induced mROS and necrosis of Mycobacterium tuberculosis–infected zebrafish and human macrophages; metformin may therefore be useful in tuberculosis therapy.
DOI: abh2841
Source: https://www.science.org/doi/10.1126/science.abh2841