PUBLICATION
mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity
- Authors
- Pagán, A.J., Lee, L.J., Edwards-Hicks, J., Moens, C.B., Tobin, D.M., Busch-Nentwich, E.M., Pearce, E.L., Ramakrishnan, L.
- ID
- ZDB-PUB-220920-7
- Date
- 2022
- Source
- Cell 185(20): 3720-3738.e13 (Journal)
- Registered Authors
- Busch-Nentwich, Elisabeth, Moens, Cecilia, Ramakrishnan, Lalita, Tobin, David
- Keywords
- ESAT-6 mitotoxicity, Mycobacterium marinum, Mycobacterium tuberculosis, granuloma necrosis, mTOR, macrophage death, mitochondrial metabolism, oxidative phosphorylation, tuberculosis, zebrafish TB model
- MeSH Terms
-
- Animals
- Mycobacterium marinum*
- Mycobacterium tuberculosis*/metabolism
- TOR Serine-Threonine Kinases/metabolism
- Tuberculosis*
- Zebrafish
- PubMed
- 36103894 Full text @ Cell
Citation
Pagán, A.J., Lee, L.J., Edwards-Hicks, J., Moens, C.B., Tobin, D.M., Busch-Nentwich, E.M., Pearce, E.L., Ramakrishnan, L. (2022) mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity. Cell. 185(20):3720-3738.e13.
Abstract
Necrosis of macrophages in the granuloma, the hallmark immunological structure of tuberculosis, is a major pathogenic event that increases host susceptibility. Through a zebrafish forward genetic screen, we identified the mTOR kinase, a master regulator of metabolism, as an early host resistance factor in tuberculosis. We found that mTOR complex 1 protects macrophages from mycobacterium-induced death by enabling infection-induced increases in mitochondrial energy metabolism fueled by glycolysis. These metabolic adaptations are required to prevent mitochondrial damage and death caused by the secreted mycobacterial virulence determinant ESAT-6. Thus, the host can effectively counter this early critical mycobacterial virulence mechanism simply by regulating energy metabolism, thereby allowing pathogen-specific immune mechanisms time to develop. Our findings may explain why Mycobacterium tuberculosis, albeit humanity's most lethal pathogen, is successful in only a minority of infected individuals.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping