mTOR-regulated Mitochondrial Metabolism Limits Mycobacterium-induced Cytotoxicity

Pagan, A. J.; Lee, L. J.; Edwards-Hicks, J.; Moens, C. B.; Tobin, D. M.; Busch-Nentwich, E. M.; Pearce, E. L.; Ramakrishnan, L.

doi:10.1101/2022.01.30.478369

bioRxiv · 10.1101/2022.01.30.478369

mTOR-regulated Mitochondrial Metabolism Limits Mycobacterium-induced Cytotoxicity

Pagan, A. J.·Lee, L. J.·Edwards-Hicks, J.·Moens, C. B.·Tobin, D. M.·Busch-Nentwich, E. M.·Pearce, E. L.·Ramakrishnan, L.

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Abstract

Necrosis of macrophages in the tuberculous granuloma represents a major pathogenic event in tuberculosis. 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 humanitys most lethal pathogen, is successful in only a minority of infected individuals.

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Pagan, A. J., Lee, L. J., Edwards-Hicks, J., Moens, C. B., Tobin, D. M., Busch-Nentwich, E. M., Pearce, E. L., Ramakrishnan, L.. 2022-01-30. mTOR-regulated Mitochondrial Metabolism Limits Mycobacterium-induced Cytotoxicity. https://doi.org/10.1101/2022.01.30.478369

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