Mitochondrial Reactive Oxygen Species: Double-Edged Weapon in Host Defense and Pathological Inflammation During Infection

Abstract

Mitochondria are inevitable sources for the generation of mitochondrial reactive oxygen species (mtROS) due to their fundamental roles in respiration. mtROS were reported to be bactericidal weapons with an innate effector function during infection. However, the controlled generation of mtROS is vital for the induction of efficient immune responses because excessive production of mtROS with mitochondrial damage leads to sustained inflammation, resulting in pathological outcomes such as sepsis. Here, we discuss the beneficial and detrimental roles of mtROS in the innate immune system during bacterial, viral, and fungal infections. Recent evidence suggests that several pathogens have evolved multiple strategies to modulate mtROS for their own benefit. We are just beginning to understand the mechanisms by which mtROS generation is regulated and how mtROS affect protective and pathological responses during infection. Several agents/small molecules that prevent the uncontrolled production of mtROS are known to be beneficial in the maintenance of tissue homeostasis during sepsis. mtROS-targeted approaches need to be incorporated into preventive and therapeutic strategies against a variety of infections.

Keywords: host defense; immunity; infection; inflammation; mitochondrial ROS.

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.