Mitochondrial Reactive Oxygen Species in Infection and Immunity

Abstract

Reactive oxygen species (ROS) contain at least one oxygen atom and one or more unpaired electrons and include singlet oxygen, superoxide anion radical, hydroxyl radical, hydroperoxyl radical, and free nitrogen radicals. Intracellular ROS can be formed as a consequence of several factors, including ultra-violet (UV) radiation, electron leakage during aerobic respiration, inflammatory responses mediated by macrophages, and other external stimuli or stress. The enhanced production of ROS is termed oxidative stress and this leads to cellular damage, such as protein carbonylation, lipid peroxidation, deoxyribonucleic acid (DNA) damage, and base modifications. This damage may manifest in various pathological states, including ageing, cancer, neurological diseases, and metabolic disorders like diabetes. On the other hand, the optimum levels of ROS have been implicated in the regulation of many important physiological processes. For example, the ROS generated in the mitochondria (mitochondrial ROS or mt-ROS), as a byproduct of the electron transport chain (ETC), participate in a plethora of physiological functions, which include ageing, cell growth, cell proliferation, and immune response and regulation. In this current review, we will focus on the mechanisms by which mt-ROS regulate different pathways of host immune responses in the context of infection by bacteria, protozoan parasites, viruses, and fungi. We will also discuss how these pathogens, in turn, modulate mt-ROS to evade host immunity. We will conclude by briefly giving an overview of the potential therapeutic approaches involving mt-ROS in infectious diseases.

Keywords: bacteria; electron transport chain; fungi; inflammasome; mitochondrial reactive oxygen species; protozoa; virus.

Figure 1

Reactive oxygen species (ROS) generation at different subcellular locations. Reactive oxygen species (ROS) are generated by various organelles across the cell upon being stimulated by external stimuli like pathogens, radiation, or nanoparticles. NADPH oxidase (NOX), with the help of its cytosolic subunits p67, 47, and 40, and membrane proteins like p22^phox, converts NADPH to NADP⁺ and generates superoxide. Β-oxidation taking place in the peroxisome yields hydrogen peroxide, which is also formed during ER stress due to misfolded proteins, where ER-specialized NOX aids in ROS generation. When hydrogen peroxide reacts with Fe²⁺, it undergoes Fenton’s reaction and produces hydroxyl radicals, while the interaction of superoxide with protons yields hydroperoxyl radicals. For mitochondria, the major contributor of ROS is the electron transport chain.

Figure 2

Electron leakage leads to superoxide formation. The superoxide formed in mitochondria is converted to hydrogen peroxide by SOD enzyme in the mitochondria, which is later converted to water by antioxidants like catalase. Reverse electron transfer shown by red arrow also aids in ROS generation. Iron–sulfur clusters also aid in ROS generation.

Figure 3

mt-ROS signaling. mt-ROS is crucial in many signaling pathways. Here, in the diagram, we have shown how, under hypoxic conditions and normal physiological conditions, mt-ROS aids in regulation of transcription factors, release of neurotransmitters, apoptosis, mitophagy, and antioxidant system.

Figure 4

mt-ROS in NLRP3 inflammasome formation. mt-ROS aids NLRP3 formation in the following ways—(1) by aiding the transcription of NF-κB, which helps to overcome the naturally low levels of NLRP3 sensors. (2) By oxidizing the mt-DNA synthesized via TLR pathway, which directly binds to NLRP3 and activates it. (3) Through the deficiency of autophagic proteins, such as beclin-1, enhancing the mt-ROS generation and consequently NLRP3 activation. Upon activation, NLRP3 produces proinflammatory cytokines, which ultimately lead to ROS accumulation.