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)