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Review
. 2013 Feb 25:6:19.
doi: 10.1186/1756-8722-6-19.

Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers

Xinyuan Li  1 , Pu Fang, Jietang Mai, Eric T Choi, Hong Wang, Xiao-feng Yang
Affiliations
Review

Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers

Xinyuan Li et al. J Hematol Oncol. .

Abstract

There are multiple sources of reactive oxygen species (ROS) in the cell. As a major site of ROS production, mitochondria have drawn considerable interest because it was recently discovered that mitochondrial ROS (mtROS) directly stimulate the production of proinflammatory cytokines and pathological conditions as diverse as malignancies, autoimmune diseases, and cardiovascular diseases all share common phenotype of increased mtROS production above basal levels. Several excellent reviews on this topic have been published, but ever-changing new discoveries mandated a more up-to-date and comprehensive review on this topic. Therefore, we update recent understanding of how mitochondria generate and regulate the production of mtROS and the function of mtROS both in physiological and pathological conditions. In addition, we describe newly developed methods to probe or scavenge mtROS and compare these methods in detail. Thorough understanding of this topic and the application of mtROS-targeting drugs in the research is significant towards development of better therapies to combat inflammatory diseases and inflammatory malignancies.

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Figures

Figure 1
Figure 1
Production and disposal of mtROS. Electrons (e-) donated from NADH and FADH2 pass through the electron transport chain and ultimately reduce O2 to form H2O at complex IV. MtROS are produced from the leakage of e- to form superoxide (O2  .-) at complex I and complex III. O2  .- is produced within matrix at complex I, whereas at complex III O2  .- is released towards both the matrix and the intermembrane space. Once generated, O2  .- is dismutated to H2O2 by superoxide dismutase 1 (SOD1) in the intermembrane space and by SOD2 in the matrix. Afterwards, H2O2 is fully reduced to water by glutathione peroxidase (GPX). Both O2  .- and H2O2 produced in this process are considered as mtROS. OM: outer membrane; IM: inner membrane.
Figure 2
Figure 2
Regulation of mtROS production. A number of factors including mitochondrial membrane potential (Δψm), metabolic state of mitochondrial, O2 concentration regulate the production of mtROS. Non-mitochondrial generated ROS can also augment mtROS production, a process known as “ROS-induced ROS”. Meanwhile, transcription factor STAT3 has recently been found to suppress mtROS production independent of its nuclear factor activity.
Figure 3
Figure 3
Signaling of mtROS. At low levels, mtROS participate in the process of hypoxia adaptation by regulating the stability of hypoxia-inducible factor 1α (HIF-1α); moderate levels of mtROS are involved in regulating the production of proinflammatory cytokines by directly activating the inflammasome and mitogen-activated protein kinase (MAPK); high levels of mtROS are capable of inducing apoptosis and autophagy by oxidation of the mitochondrial pores and autophagy-specific gene 4 (ATG4) respectively.
Figure 4
Figure 4
Modification of proteins by ROS. ROS can oxidize specific reactive cysteine (Cys) residues within target proteins generating sulfenic form (RSOH) of proteins. RSOH is unstable and can be further oxidized to sulfinic form (RSO2H). Under greater oxidative stress, sulfonic form (RSO3H) can be generated. Although the formation of RSOH and RSO2H is reversible, generation of RSO3H is irreversible.
Figure 5
Figure 5
Role of endothelial mtROS in atherosclerosis. Pathologic stressors as diverse as oxidized low-density lipoproteins (oxLDL), glucose, and Angiotensin II are all capable of inducing mtROS in endothelial cells through their receptors. Excessive mtROS then directly bind to NO and induce endothelial cell dysfunction. Overproduction of mtROS also leads to activation of proinflammatory transcription factors such as nuclear factor kappa B (NFκB). This in turn increases the expression of adhesion molecules and production of inflammatory cytokines in endothelial cells, both of which contribute to the development of atherosclerosis. LOX-1: lectin-type oxidized LDL receptor 1; TLRs: Toll-like receptors; AT1R: Angiotensin II receptor, type 1; GLUT4: glucose transporter type 4.
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