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

Journal of Hematology & Oncology, Dec 2017

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

Journal of Hematology & Oncology Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers Xinyuan Li 0 Pu Fang 0 Jietang Mai 0 Eric T Choi 1 Hong Wang 0 Xiao-feng Yang 0 0 Cardiovascular Research Center, Department of Pharmacology and Thrombosis Research Center, Temple University School of Medicine , 3500 North Broad Street, Philadelphia, PA 19140 , USA 1 Cardiovascular Research Center and Department of Surgery, Temple University School of Medicine , 3500 North Broad Street, Philadelphia, PA 19140 , USA 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. Mitochondria; ROS; Inflammatory diseases Introduction Free radicals and other ROS are generated in a wide range of normal physiological conditions. However, ROS also participate in many pathological conditions including cardiovascular diseases, malignancies, autoimmune diseases, and neurological degenerative diseases. Despite intensive investigations in this field, current anti-oxidant therapeutics are not clinically effective in combating these pathological conditions suggesting that our understanding of this field is limited, and there is a need to narrow the “knowledge gap” in order to develop more effective new therapies [ 1 ]. Although ROS are historically considered toxic by-products of cellular metabolism, recent studies have suggested that cells “have learned” to harness the power of ROS for cell signaling purposes. In analogous to phosphorylation modification of proteins, the term “redox signaling” is emerging in reference to events of oxidation modification of proteins by ROS. Indeed, there are multiple sources of ROS in the cell including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) [ 2 ], xanthine oxidase (XO), uncoupling of nitric oxide synthase (NOS), cytochrome P450, and mitochondrial electron transport chain (ETC). Among these potential sources, however, mtROS have drawn increasing attentions because it was recently discovered that mtROS directly contribute to inflammatory cytokine production and innate immune responses [ 3 ] by activation of newly characterized RIG-I-like receptors (RLRs) [ 4 ], inflammasomes [ 5 ], and mitogenactivated protein kinases (MAPK) [ 6 ]. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the western world. Nearly 75% of the CVD-related death results from atherosclerosis 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 chronic autoimmune inflammatory condition associated with specific CVD risk factors, development of atherosclerosis is fueled by aberrant response of the innate immune system and overproduction of proinflammatory cytokines [ 9,10 ]. A recent progress in characterizing mtROS has led to the generation of a new paradigm, in which blockade of mtROS production may serve as a promising therapy for inhibiting proinflammatory cytokine production and in turn atherosclerosis. Although there were several excellent reviews published 5 years ago in this topic [ 11,12 ], new recent discoveries have mandated a more up-to-date and comprehensive review [ 13-15 ]. Therefore, in this review we consider current understandings of several compelling questions: 1) how mitochondria generate and dispose of ROS; 2) how production of mtROS is regulated; and 3) what signaling pathways are targeted by mtROS. In addition, we describe the methods to probe mtROS and analyze the merits and flaws of these different methods. Furthermore, we demonstrate how mtROS regulate important vascular function in physiological conditions and activate inflammatory pathways in response to CVD risk factors. In-depth understanding of these processes is critical to developing novel therapeutic drugs against chronic inflammatory conditions such as at (...truncated)


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Xinyuan Li, Pu Fang, Jietang Mai, Eric T Choi, Hong Wang, Xiao-feng Yang. Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers, Journal of Hematology & Oncology, pp. 19,