mTOR-regulated Mitochondrial Metabolism Limits Mycobacterium-induced Cytotoxicity

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 specifically by ESAT-6, the principal secreted substrate of the specialized mycobacterial secretion system ESX-1, a key virulence mediator. Thus, the host can effectively counter this early critical mycobacterial virulence mechanism simply by regulating energy metabolism, 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.

A Case of MELAS Syndrome with Tuberculous Meningitis

“…A recent study conducted by Pagán AJ and colleagues, published online in Cell last year, revealed that the mTOR kinase serves as one of the frontline defenders against Mycobacterium tuberculosis infection within the body. mTOR possesses the capacity to regulate mitochondrial metabolism, thereby preventing macrophage death and buying crucial time for the immune system [7]. As early as 2010, a zebra sh fh718 mutant was obtained via forwards genetic screening, which exhibited heightened susceptibility to natural pathogen M. marinum (Mm) infection [8].…”