TNF induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport
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Publication Date
2022-06-24Journal Title
Science
ISSN
0036-8075
Publisher
American Association for the Advancement of Science
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Roca, F. J., Whitworth, L., Prag, H., Murphy, M., & Ramakrishnan, L. (2022). TNF induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport. Science https://doi.org/10.1126/science.abh2841
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. Here, using the zebrafish, we identify 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 increases the Krebs cycle intermediate succinate. 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 anti-diabetic drug, prevents TNF-induced mROS and necrosis of Mycobacterium tuberculosis-infected zebrafish and human macrophages,
suggesting its utility in tuberculosis therapy.
Sponsorship
National Institutes of Health (NIH) (7R37A1054503-13)
Wellcome Trust (223103/Z/21/Z)
Medical Research Council (MC_U105663142)
Wellcome Trust (110159/Z/15/Z)
Identifiers
External DOI: https://doi.org/10.1126/science.abh2841
This record's URL: https://www.repository.cam.ac.uk/handle/1810/337115
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