Figure 1.

Protective and detrimental roles of mitochondrial reactive oxygen species (mtROS) during infection. (A) Majority of mtROS are generated by oxidative phosphorylation (OXPHOS) complexes I and III in macrophages activated through TLR signaling, interferon (IFN)-γ, and microbial infection. Both Mst1 and Mst2 promoted Toll-like receptor (TLR)-mediated assembly of the tumor necrosis factor receptor-associated factor 6–evolutionarily conserved signaling intermediate in Toll pathway (TRAF6-ECSIT) complex, to enhance antibacterial killing effects through mtROS. IFN-γ signaling activates estrogen-related receptor α (ERRα) to enhance antimicrobial clearance through mtROS generation. mtROS are closely related to the pathways of autophagy and inflammasome, both essential in the maintenance of cellular homeostasis and activation of innate host defense. 5′ AMP-activated protein kinase (AMPK) inhibits, but hypoxia-inducible factor (HIF)-1α enhances, the generation of mtROS, thereby influencing innate defense against several pathogenic bacteria. HIF-1α/mTOR signaling drives aerobic glycolysis and reactive oxygen species (ROS) generation; mTOR inhibition leads to the enhancement of mtROS to promote host defense against Trypanosoma cruzi infection. AMPK activation by metformin is beneficial in the clearance of intracellular bacterial infection through phosphorylation of AMPK and mtROS generation. In addition, AMPK is the upstream kinase for ERRα-mediated antimicrobial responses during Mycobacterium tuberculosis (Mtb) infection. During oxidative stress, NRF2 translocates to the nucleus after dissociation from Keap1 to induce the expression of protective antioxidant genes. Mitochondrial antiviral signaling (MAVS) activation results in the expression of COX5B, which inhibit the mtROS to block the MAVS-mediated antiviral signaling. mtROS involvement in antiviral responses is described in the text in details. (B) Uncontrolled mtROS production leads to excessive inflammatory responses, tissue damage, and necrosis, thus detrimental to host defense. Dysregulated activation of NLRP3 inflammasome results in tissue damage and pathological inflammation through mitochondrial dysfunction and mtROS generation. Several host factors [sirtuin 3 (SIRT3), miR-23a, and peroxisome proliferator-activated receptor gamma (PPARγ)] are negative regulators for controlling excessive mtROS generation, thereby coordinating antimicrobial host defense. Excessive ROS production blocks the nuclear translocation and activity of NRF2. The accumulation of mtROS, which is also mediated by sustained endoplasmic reticulum (ER) stress, is detrimental to host defense.