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
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.
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