Tumor necrosis factor induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport

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.

mTOR-regulated Mitochondrial Metabolism Limits Mycobacterium-induced Cytotoxicity

“…We find here that early in infection, Mm infection of cultured human macrophages induces OXPHOS without altering glycolysis. This is consistent with our findings in the zebrafish where Mm- and Mtb-infected macrophages exhibit small increases in mitochondrial respiration early on (Roca et al ., 2022). While adaptive glycolytic shifts may occur later in infection, mTORC1’s role in early resistance to mycobacteria stems not from a glycolytic shift but from the boost in OXPHOS from its stimulation of glycolysis (Weichhart et al ., 2015).…”

“…mTOR and glycolysis had a cytoprotective effect in Mtb infection also. To assess this, we used mc 2 6206, the isogenic leucine and pantothenate auxotrophic mutant of the virulent H37Rv Mtb strain, a biosafety 2 level pathogen that elicits similar inflammatory responses and triggers diverse cell death programs (Beckwith et al ., 2020; Mouton et al, 2019; Roca et al ., 2022; Roca et al ., 2019; Sampson et al, 2004; Sampson et al, 2011). Mtb infection caused increased death of both mTOR-deficient and glycolysis-deficient THP-1 cells (Figure 5C).…”

“…The use of unbiased genetic screens and candidate gene approaches in zebrafish larvae has shed light on granuloma biology (Ramakrishnan, 2013). Hypersusceptible zebrafish mutants displaying accelerated granuloma necrosis have identified innate immune host determinants that protect against necrosis and that are relevant to human TB (Berg et al, 2016; Clay et al, 2008; Pagan et al, 2015; Roca and Ramakrishnan, 2013; Roca et al, 2022; Roca et al, 2019; Tobin et al, 2012; Tobin et al, 2010; Whitworth et al, 2021a; Whitworth et al, 2021b).…”

Resistance and Susceptibility Immune Factors at Play during Mycobacterium tuberculosis Infection of Macrophages

“…Consequently, TNF signaling can result in a diversity of biological functions. Although TNF-α is considered to be a critical host resistance factor against TB, a recent report [ 43 ] showed that excess TNF confers susceptibility by increasing mitochondrial ROS, which initiates a signaling cascade to cause the pathogenic necrosis of mycobacterium-infected macrophages. In the context of M.tb infection, TNF-α is also involved in granuloma formation [ 142 ], and with the rise in the use of anti-inflammatory biologics like TNF-α inhibitors or antagonists, more recent studies have begun to characterize their roles in the reactivation of latent TB infection (LTBI) [ 143 ].…”

mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity

“…The use of unbiased genetic screens and candidate gene approaches in zebrafish larvae has shed light on granuloma biology ( Ramakrishnan, 2013 ). Hypersusceptible zebrafish mutants displaying accelerated granuloma necrosis have identified innate immune host determinants that protect against necrosis and that are relevant to human TB ( Berg et al., 2016 ; Clay et al., 2008 ; Pagán et al., 2015 ; Roca and Ramakrishnan, 2013 ; Roca et al., 2019 , 2022 ; Tobin et al., 2010 , 2012 ; Whitworth et al., 2021a , 2021b ).…”