PUBLICATION
Tumor necrosis factor induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport
- Authors
- Roca, F.J., Whitworth, L.J., Prag, H.A., Murphy, M.P., Ramakrishnan, L.
- ID
- ZDB-PUB-220624-18
- Date
- 2022
- Source
- Science (New York, N.Y.) 376: eabh2841 (Journal)
- Registered Authors
- Ramakrishnan, Lalita, Roca, Francisco Jose
- Keywords
- none
- MeSH Terms
-
- Animals
- Electron Transport
- Succinic Acid/metabolism
- Tuberculosis*/metabolism
- Tuberculosis*/microbiology
- Tuberculosis*/pathology
- Humans
- Macrophages*/metabolism
- Macrophages*/microbiology
- Macrophages*/pathology
- Metformin*/pharmacology
- Mycobacterium tuberculosis*/metabolism
- Electron Transport Complex I*/antagonists & inhibitors
- Electron Transport Complex I*/metabolism
- Tumor Necrosis Factor-alpha*/metabolism
- Citric Acid Cycle/drug effects
- Zebrafish
- Necrosis
- Reactive Oxygen Species*/metabolism
- PubMed
- 35737799 Full text @ Science
Citation
Roca, F.J., Whitworth, L.J., Prag, H.A., Murphy, M.P., Ramakrishnan, L. (2022) Tumor necrosis factor induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport. Science (New York, N.Y.). 376:eabh2841.
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. 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping