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

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Tuberculosis (TB) is a major global health challenge.
• Tumor necrosis factor (TNF) plays a dual role in TB, acting as both a resistance factor and a mediator of susceptibility.
• Excess TNF can lead to pathogenic macrophage necrosis, exacerbating TB.

Purpose of the Study:

• To elucidate the mechanism of TNF-induced mitochondrial reactive oxygen species (mROS) production in Mycobacterium tuberculosis-infected macrophages.
• To investigate the potential therapeutic role of metformin in TB.

Main Methods:

• Utilized zebrafish and human macrophage models of TB.
• Investigated the role of reverse electron transport (RET) through mitochondrial complex I in mROS generation.
• Assessed the impact of TNF and metformin on cellular glutamine uptake, succinate levels, and mROS production.

Main Results:

• Excess TNF in infected macrophages increases mROS via RET at complex I.
• TNF-induced glutamine uptake elevates succinate, which drives RET and superoxide generation at complex I.
• Metformin, a complex I inhibitor, abrogated TNF-induced mROS and macrophage necrosis in both zebrafish and human cells.

Conclusions:

• TNF-induced mROS production in TB pathogenesis is mediated by succinate-driven RET at mitochondrial complex I.
• Metformin effectively inhibits this pathway, preventing pathogenic macrophage necrosis.
• Metformin shows promise as a host-directed therapy for tuberculosis.