Tumor necrosis factor induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport

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.

Automated summary

Excess TNF in mycobacterium-infected macrophages increases mitochondrial reactive oxygen species (mROS), causing susceptibility to tuberculosis. The study identifies the mechanism of TNF-induced mROS through reverse electron transport. The use of the drug metformin prevents TNF-induced mROS and necrosis in tuberculosis.