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.

中文翻译：

---

肿瘤坏死因子通过反向电子传递诱导结核病中的致病性线粒体活性氧

肿瘤坏死因子（TNF）是宿主抵抗结核病的关键因子。然而，过量的 TNF 通过增加线粒体活性氧 (mROS) 产生易感性，这会启动信号级联反应，导致分枝杆菌感染的巨噬细胞发生致病性坏死。在斑马鱼中，我们确定了 TNF 诱导的 mROS 在结核病中的机制。分枝杆菌感染的巨噬细胞中过量的 TNF 通过复合物 I 的反向电子传输 (RET) 提高 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，这是一种克雷布斯循环中间体。复合物 II 氧化这种升高的琥珀酸会驱动 RET，从而在复合物 I 处产生 mROS 超氧化物。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，可防止 TNF 诱导的 mROS 和细胞坏死结核分枝杆菌–感染的斑马鱼和人类巨噬细胞；因此，二甲双胍可用于结核病治疗。