Targeting Mitochondrial Reactive Oxygen Species As Novel Therapy For

Li et al. Journal of Hematology & Oncology 2013, 6:19 http://www.jhoonline.org/content/6/1/19 JOURNAL OF HEMATOLOGY & ONCOLOGY REVIEW Open Access Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers Xinyuan Li1, Pu Fang1, Jietang Mai1, Eric T Choi2, Hong Wang1 and Xiao-feng Yang1* 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. Keywords: Mitochondria, ROS, Inflammatory diseases Introduction events of oxidation modification of proteins by ROS. In- Free radicals and other ROS are generated in a wide deed, there are multiple sources of ROS in the cell in- range of normal physiological conditions. However, ROS cluding nicotinamide adenine dinucleotide phosphate also participate in many pathological conditions includ- (NADPH) oxidase (NOX) [2], xanthine oxidase (XO), ing cardiovascular diseases, malignancies, autoimmune uncoupling of nitric oxide synthase (NOS), cytochrome diseases, and neurological degenerative diseases. Despite P450, and mitochondrial electron transport chain intensive investigations in this field, current anti-oxidant (ETC). Among these potential sources, however, mtROS therapeutics are not clinically effective in combating have drawn increasing attentions because it was recently these pathological conditions suggesting that our under- discovered that mtROS directly contribute to inflamma- standing of this field is limited, and there is a need to tory cytokine production and innate immune responses narrow the “knowledge gap” in order to develop more [3] by activation of newly characterized RIG-I-like recep- effective new therapies [1]. Although ROS are historic- tors (RLRs) [4], inflammasomes [5], and mitogen- ally considered toxic by-products of cellular metabolism, activated protein kinases (MAPK) [6]. recent studies have suggested that cells “have learned” to Cardiovascular disease (CVD) is the leading cause of harness the power of ROS for cell signaling purposes. In morbidity and mortality in the western world. Nearly analogous to phosphorylation modification of proteins, 75% of the CVD-related death results from atheroscler- the term “redox signaling” is emerging in reference to osis which is found in 80-90% of Americans over the age of 30. Early atherosclerotic lesions can be detected in youths as young as 7 years of age [7,8]. As a form of * Correspondence: [email protected] 1Cardiovascular Research Center, Department of Pharmacology and chronic autoimmune inflammatory condition associated Thrombosis Research Center, Temple University School of Medicine, 3500 with specific CVD risk factors, development of athero- North Broad Street, Philadelphia, PA 19140, USA sclerosis is fueled by aberrant response of the innate Full list of author information is available at the end of the article © 2013 Li et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Li et al. Journal of Hematology & Oncology 2013, 6:19 Page 2 of 19 http://www.jhoonline.org/content/6/1/19 immune system and overproduction of proinflammatory Five big protein complexes are involved in this process cytokines [9,10]. A recent progress in characterizing (HUGO Gene Nomenclature Committee Website, mtROS has led to the generation of a new paradigm, in Table 1). These ETC complexes are named complex I which blockade of mtROS production may serve as a (NADH dehydrogenase (ubiquinone), 45 protein sub- promising therapy for inhibiting proinflammatory cyto- units), complex II (succinate dehydrogenase, 4 protein kine production and in turn atherosclerosis. Although subunits), complex III (ubiquinol-cytochrome c reduc- there were several excellent reviews published 5 years tase, 10 protein subunits), complex IV (cytochrome c ago in this topic [11,12], new recent discoveries have oxidase, 19 protein subunits), and complex V (ATP syn- mandated a more up-to-date and comprehensive review thase, 19 protein subunits). Electrons donated from [13-15]. Therefore, in this review we consider current nicotine adenine dinucleotide (NADH) at complex I and understandings of several compelling questions: 1) how flavin adenine dinucleotide (FADH2) at complex II pass mitochondria generate and dispose of ROS; 2) how pro- through ETC and ultimately reduce O2 to water at com- duction of mtROS is regulated; and 3) what signaling plex IV. Meanwhile, positively charged protons (H+) are pathways are targeted by mtROS. In addition, we de- actively being pumped from the mitochondrial matrix scribe the methods to probe mtROS and analyze the into the intermembrane space, resulting in the increased merits and flaws of these different methods. Further- negative charges in the mitochondrial matrix and the more, we demonstrate how mtROS regulate important upregulated positive charges in the intermembrane vascular function in physiological conditions and activate space, and thus creating a mitochondrial membrane po- inflammatory pathways in response to CVD risk factors. tential (Δψm) across the inner mitochondrial membrane. In-depth understanding of these processes is critical to This proton-motive force allows complex V - ATP syn- developing novel therapeutic drugs against chronic in- thase (ATP-ase) to generate ATP from adenosine di- flammatory conditions such as atherosclerosis. phosphate (ADP) and inorganic phosphate when protons re-enter the mitochondrial matrix through the Production of mtROS complex V enzyme. However, either by accident or by Mitochondria have a four-layer structure, including design, the process of ETC is not perfect. Leakage of outer mitochondrial membrane, intermembrane space, electrons at complex I and complex III leads to partial .- inner mitochondrial membrane and matrix (Figure 1). reduction of oxygen to form superoxide (O2 ). It has Generation of mtROS mainly takes place at the ETC lo- been estimated that 0.2% to 2.0% of O2 consumed by .- cated on the inner mitochondrial membrane during the mitochondria generates O2 [11]. There are three leak .- process of oxidative phosphorylation (OXPHOS). Oxida- events: complex I leaks O2 towards the mitochondrial .- tive phosphorylation is an essential cellular process that matrix, while complex III leaks O2 towards both the uses oxygen and simple sugars to create adenosine tri- intermembrane space and mitochondrial matrix [11,16]. .- phosphate (ATP), which is the cell's main energy source. Subsequently, O2 is quickly dismutated to hydrogen Cytosolic OM SOD1 GPX .- Intermembrane O2 H2O2 H2O H+ H+ H+ space e- e- e- e- C Q I III IV V IM II Matrix O .- O .- + 2 2 H+ NADH NAD FADH 2 FADH O2 H2O ADP ATP SOD2 GPX Citric acid O .- H O H O cycle 2 2 2 2 - 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. Li et al. Journal of Hematology & Oncology 2013, 6:19 Page 3 of 19 http://www.jhoonline.org/content/6/1/19 Table 1 Mitochondrial DNA (mtDNA) and nuclear DNA space. The physiological importance of SOD2 is high- (nDNA) encoded subunits for the electron transport chain lighted by the finding that in contrast to other SOD Complex isoforms, the deficiency of SOD2 causes early neonatal Genome I II III IV V Total death in gene knockout mice [19] and endothelial dys- mtDNA 7 0 1 3 2 13 function in carotid artery of proatherogenic apolipopro- tein E (ApoE)-deficient mice [11,20]. nDNA 38 4 9 16 17 84 Total 45 4 10 19 19 97 Catalase Source: www.genenames.org/genefamilies/mitocomplex#coml. Catalase is a heme-containing tetramer of four polypep- tide chains that reduces H2O2 to water. Although cata- peroxide (H2O2) by two dismutases including superoxide lase is highly efficient

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