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.

Protective Effect of Mitochondria-Targeted Antioxidants against Inflammatory Response to Lipopolysaccharide Challenge: A Review

“…The development of mito-AOX was based on approaches that allow one to limit excessive ROS production inside mitochondria via different mechanisms. Up to now, our knowledge of mtROS generation, their role in cell signaling and their impact on cellular antioxidant and pro- and anti-inflammatory mechanisms, is still insufficient and scant [ 10 ]. Nevertheless, besides the beneficial application of mito-AOX in numerous animal pathogenic models mentioned above, many clinical studies demonstrated the protective efficacy of mito-AOX in different pathological conditions wherever inflammation as well as mitochondria damage are involved.…”

“…Considerable evidence indicates that oxidative stress and mitochondrial dysfunction are common features in the majority of inflammatory states and diseases, acute or chronic [ 9 , 10 , 11 ]. It is generally accepted that excessive generation of reactive oxygen/nitrogen species and mitochondrial injury driven by an uncontrolled inflammatory response play a central role in the genesis of multiple-organ failure observed in sepsis (for review, see [ 12 , 13 , 14 , 15 , 16 ]).…”

Oxidative Stress and Mitochondrial Damage in Dry Age-Related Macular Degeneration Like NFE2L2/PGC-1α -/- Mouse Model Evoke Complement Component C5a Independent of C3

“…Para-inflammation is a process in which specific tissues adopt and respond to various stresses in attempts to maintain homeostasis [40]. With tissue aging, there is a sustained buildup of low-grade chronic inflammation accompanied by oxidative stress, more and more mitochondrial damage, and an accumulation of detrimental oxidized cellular particles [41][42][43]. The mitochondrial derived ROS, mtDNA and oxidized particles can directly induce a non-infective ("sterile") systemic chronic inflammation (SCI) as these signals are recognized as DAMPs by PRRs, leading to the triggering of intracellular signals resulting in the production of pro-inflammatory cytokines and chemokines [19,[44][45][46].…”

Paeonol alleviates lipopolysaccharide‑induced hepatocytes injury through alteration of mitochondrial function and NF‑κB translocation

“…The present data demonstrated that PAE pretreatment markedly reduced the levels of MDA and increased SOD activity, suggesting an antioxidant effect of PAE. ROS serve a crucial role in cell injury induction under both physiological and pathological conditions (20). ROS are mainly generated in the mitochondria and unbalanced ROS generation results in the loss of mitochondrial membrane potential (21).…”