TNF induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport


Type
Article
Change log
Authors
Roca, Francisco J 
Ramakrishnan, Lalita  ORCID logo  https://orcid.org/0000-0003-0692-5533
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.

Description
Keywords
Journal Title
Science
Conference Name
Journal ISSN
0036-8075
1095-9203
Volume Title
Publisher
American Association for the Advancement of Science
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)