Acute and Critical Care

2018 May 33(2):65-72 / https://doi.org/10.4266/acc.2018.00157

ISSN 2586-6052 (Print)ㆍISSN 2586-6060 (Online) ■ Review ■

Role of Mitochondrial Oxidative Stress in Sepsis

Harsha Nagar*, Shuyu Piao*, and Cuk-Seong Kim

Department of Physiology, Chungnam National University School of Medicine, Daejeon, Korea

Mitochondria are considered the power house of the cell and are an essential part of the cellular infrastructure, serving as the primary
site for adenosine triphosphate production via oxidative phosphorylation. These organelles also release reactive oxygen species (ROS),
which are normal byproducts of metabolism at physiological levels; however, overproduction of ROS under pathophysiological condi-
tions is considered part of a disease process, as in sepsis. The inflammatory response inherent in sepsis initiates changes in normal mi-
tochondrial functions that may result in organ damage. There is a complex system of interacting antioxidant defenses that normally
function to combat oxidative stress and prevent damage to the mitochondria. It is widely accepted that oxidative stress-mediated
injury plays an important role in the development of organ failure; however, conclusive evidence of any beneficial effect of systemic
antioxidant supplementation in patients with sepsis and organ dysfunction is lacking. Nevertheless, it has been suggested that anti-
oxidant therapy delivered specifically to the mitochondria may be useful.
Key Words: mitochondria; oxidative stress; sepsis

Introduction

Despite the availability of advanced treatments, sepsis is one of the leading causes of death in intensive care units
[1,2]. Multiple factors contribute to the development of this condition; both extrinsic and intrinsic mechanisms are in-
volved in hemodynamic collapse [3]. Extrinsic mechanisms involve endotoxins, viruses, fungi, or other toxins, while in-
trinsic mechanisms include proinflammatory mediators released by host immune cells. Both of these mechanisms induce
a complex cascade of cellular events, resulting in the release of proinflammatory and anti-inflammatory mediators.
Sepsis develops after an initial host response to an infection becomes amplified and dysregulated, which leads to circu-
latory changes and septic shock. The most common consequences are impaired vascular permeability, cardiac malfunc-
tion, and mitochondrial dysfunction leading to impaired respiration [4]. The pathogenesis of sepsis-induced myocardial
injury remains unclear, but the mitochondrial dysfunction of myocardial cells plays a very important role in the patho-
physiological mechanism [5]; oxidants and antioxidants also play a key role. Normally, there is a balance between the ox-
idant and antioxidant systems in the body; oxidative stress occurs when oxidant levels exceed those of antioxidants, which
contributes to the septic process and may lead to organ damage. The inflammatory response and persistent oxidative

Received on April 25, 2018 Accepted on May 8, 2018

Correspondence to: Cuk-Seong Kim, Department of Physiology, Chungnam National University School of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Korea
Tel: +82-42-580-8219, Fax: +82-42-585-8440, E-mail: cskim@cnu.ac.kr
*These authors contributed equally to this work.
*No potential conflict of interest relevant to this article was reported.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/
licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright ⓒ 2018 The Korean Society of Critical Care Medicine
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66 Acute and Critical Care: Vol. 33, No. 2, May 2018

stress seen during sepsis-induced organ failure induce membrane consists of five OXPHOS complexes (I–V). Elec-
changes in the mitochondria that ultimately lead to mito- trons are transferred from complex I to II–IV, leading to
chondrial dysfunction and cell death. The generally accept- adenosine triphosphate (ATP) generation in complex V
ed theory is that sepsis represents an uncontrolled inflam- (ATP synthase). When there is a defective reduction of O2
matory response to a pathogen [6]. While numerous studies to H2O2, it results in an excess generation of superoxide
have been performed using anti-inflammatory agents, most usually at the complex IV of the electron transport chain
have failed to identify any beneficial effect and thus have [12]. Superoxide is usually converted to hydrogen perox-
called into question the aforementioned hypothesis of hy- ide (H 2O 2) by manganese-containing superoxide dis-
per-inflammation [7-10]. mutase (Mn-SOD) and thereafter to H2O by catalase
The protocol followed in the treatment of sepsis or he- (CAT). The various markers of oxidative stress involved
modynamic collapse is not consistent among studies. How- in the process of sepsis are an increased SOD/CAT ratio,
ever, general guidelines recommend early goal-directed which results in the accumulation of H2O2 in cells [13-
therapy and supportive measures for hemodynamic col- 17], decreased level of glutathione, increased level of
lapse. Until recently, therapies focused on addressing mac- malondialdehyde, and an increase in protein carbonyl
rocirculatory failure, which often exhibits decreased car- groups. Thus, any changes in the SOD:CAT ratio, like an
diac output or decreased mean arterial pressure. However, inhibition of CAT or an overexpression of SOD, will lead
immunohistochemical analyses have revealed that apop- to an increase in the oxidative stress levels and morbidity
tosis is not widespread in sepsis, suggesting that mecha- in sepsis [18]. Selenium-containing glutathione peroxi-
nisms other than cell death are responsible for the condi- dase also plays a role in the catalytic conversion of H2O2
tion’s associated mortality [11]. A growing body of evidence to water (H2O) [19,20].
indicates that the pathogenesis of sepsis involves an inabil- As O2 is the final receptor of electrons in the electron
ity of the cell to consume oxygen. Since mitochondrial mo- transport chain, measurement of oxygen consumption is a
lecular oxygen (O2) consumption accounts for 90% of the good option to assess mitochondrial function. The pe-
body’s O2 usage, impaired O2 utilization and mitochon- ripheral blood of septic patients show normal PO2 levels
drial dysfunction may play a key role in the pathogenesis even though the oxygen consumption by cells might be
of sepsis. Additionally, excessive oxidative stress is a fea- reduced [21,22]. This phenomenon, known as “cytopath-
ture of sepsis, and redox homeostasis may therefore be ic hypoxia,” is a condition when the septic cells are un-
involved; consequently, therapies targeting redox abnor- able to utilize oxygen [23,24]. It was previously demon-
malities could be useful for improving the management of strated that, during sepsis, cellular energetic failure due to
septic patients. mitochondrial dysfunction is the main reason for poorer
outcomes of critically ill patients [25]; improving mito-
chondrion biogenesis may lead to increased patient sur-
INVOLVEMENT OF MITOCHONDRIAL vival [26]. The pathological effects of mitochondrial
DYSFUNCTION IN SEPSIS dysfunction result from the excessive production of ROS,
PATHOGENESIS ATP depletion, the release of proapoptotic proteins, and a
disturbance in Ca2+ homeostasis [27]. Cells also show in-
The mitochondrion serves as the central source of reac- flammatory responses that are triggered by oxidative
tive oxygen species (ROS) in normal physiological con- stress via the activation of redox pathways. A rise in the
ditions. Oxidative phosphorylation (OXPHOS) takes place levels of intracellular adhesion molecules I and IV, along
in the inner mitochondrial membrane. The mitochondrial with elevation of monocyte chemotactic protein 1 are
electron transport chain present in the inner mitochondrial considered as important inflammatory markers of sepsis.

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 Harsha Nagar, et al. Role of Mitochondrial Oxidative Stress in Sepsis 67

Phosphorylated and transcriptionally active nuclear fac- inate the overproduction of ROS and prevent damage to
tor-kappa B (NF-κB) levels also increase, along with the mitochondria. SOD converts the superoxide radical
those of circulating inflammatory mediators, such as cy- and the singlet oxygen radical to H2O2 and O2, respective-
tokines, in patients with sepsis. ly, and serves as the first line of antioxidant defense in bi-
ological systems. The level of SOD in plasma is significant-
ly decreased in patients with severe sepsis [28]. Macarthur
TARGETING ANTIOXIDANTS TO et al. [29] reported that intravenous infusion of the SOD
MITOCHONDRIA mimetic M40401 protected against hypotension, decreased
inflammatory cytokines, and improved mortality in a rat
Although moderate levels of ROS are required for prop- model of septic shock. The upregulation of SOD2 induced
er cell function, particularly in immune cells, excessive by insulin also protected against mitochondrial oxidative
mitochondrial oxidative stress is the main cause of a num- stress in a septic acute kidney injury rat model [30]. These
ber of cell pathologies, including sepsis. Therefore, tar- studies suggest that SOD regulation could have therapeu-
geting antioxidants to mitochondria can be a useful thera- tic value in sepsis. Apart from SOD, glutathione is the most
peutic method for treating sepsis. Strategies to deliver abundant water-soluble antioxidant; it plays an important
antioxidants to mitochondria or accelerate ROS scaveng- role in maintaining redox homeostasis and is synthesized
ing by antioxidants augment the capacity of the antioxi- in the cytoplasm and then transported into the mitochon-
dant defenses of mitochondria by increasing the expres- dria. N-acetylcysteine is a hydrophilic antioxidant that el-
sion of endogenous antioxidant enzymes (Figure 1). evates glutathione level. Glutathione peroxidase catalyz-
es the conversion of H2O2 into water. CAT also catalyzes
Elevating Endogenous Antioxidant Protein Levels the breakdown of H2O2. There are several other enzymes
The main antioxidant proteins, including SOD, gluta- and small molecules that act as scavengers and comprise
thione, CAT, thioredoxin, and peroxiredoxin, regulate the the antioxidant defense system, such as ascorbic acid
redox balance in mitochondria. Therefore, increasing these (Table 1).
endogenous mitochondrial antioxidant proteins can elim-

Figure 1. Overview of the process of drawing antioxidants and reactive oxygen species (ROS) to mitochondria in sepsis. ROS production with-
in the mitochondria destroys the redox system so that the existing antioxidants are insufficient to eliminate any overproduced ROS. Delivering
antioxidants to the mitochondria and scavenging ROS are beneficial aspects of sepsis treatment. SOD: superoxide dismutase; GSH: glutathi-
one; MnSOD: manganese-containing superoxide dismutase; TEMPOL: 4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-oxyl; MitoQ: 10-(6’-ubiqui-
nonyl)decyltriphenylphosphonium bromide; MitoVitE: mitochondria-targeted antioxidant.

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68 Acute and Critical Care: Vol. 33, No. 2, May 2018

Table 1. Summary of antioxidants and their effects

Antioxidant (endogenous component) Diet-derived component Mechanism of action
Glutathione peroxidase Tocopherols and tocotrienols (vitamin E) H2O2 to H2O
Superoxide dismutase (Mn-, Zn-, or Cu-dependent) Vitamin A and carotenoids (β-carotene, lycopene, lutein, etc.) O2− to O2
Catalase Ascorbate (vitamin C, those species lacking synthetic capacity, H2O2 to H2O and O2
e.g., human)
Glutathione Tocopherols and tocotrienols (vitamin E) Antioxidant scavenger, DNA repair, cofactor for
enzymes
Ascorbic acid Selenium, zinc, manganese, copper, phytochemicals with Acts against oxidation of lipids, proteins, and
antioxidant activity DNA

Lipophilic Cation Conjugation with Small philic cation conjugates.

Molecule: MitoQ
The most widely used strategy to transport small mole- Mitochondria-Targeted ROS Scavengers:
cules to the mitochondria in vivo is by conjugation of an Hemigramicidin-TEMPOL
antioxidant to a lipophilic cation [31,32]. The construc- The mechanism of 4-hydroxy-2,2,6,6,-tetramethylpiper-
tion of a lipophilic cation allows it to pass through mem- idine-1-oxyl (TEMPOL) in the elimination of oxidative
branes easily and gather in the mitochondrial matrix with- stress is as follows: TEMPOL limits formation of the high-
out a carrier. 10-(6’-ubiquinonyl)decyltriphenylphosphonium ly toxic hydroxyl radical from H2O2 and removes the su-
bromide (MitoQ; ubiquinone attached to the lipophilic tri- peroxide anion. There are two portions in TEMPOL (the
phenylphosphonium cation) has been used to protect cells targeting portion and the ROS-scavenging portion), which
from oxidative damage and apoptosis by activating ubi- have been extensively demonstrated to be effective cyto-
quinol and therefore restoring its antioxidant efficacy in the protectors in different oxidative stress models [40,41].
respiratory chain [33,34]. Lowes et al. [35] first reported XJB-5-131, one of the hemigramicidin-TEMPOL conju-
that MitoQ suppressed proinflammatory cytokine levels gates, ameliorated intestinal mucosal injury and prolonged
and increased anti-inflammatory cytokine levels in sepsis survival in a rat model of hemorrhagic shock and had a
models, both in vitro and in vivo. Studies in humans have greater effect than non-targeted TEMPOL [42,43]. In ce-
shown that MitoQ exerts antioxidant and anti-inflamma- cal ligation and puncture murine models of sepsis, Mito-
tory effects on the leukocytes of type 2 diabetes patients TEMPOL attenuated sepsis-induced acute kidney injury,
by decreasing ROS production and tumor necrosis factor decreased mitochondrial superoxide levels, improved re-
alpha via suppression of NF-κB activation [36]. Another nal microcirculation and the glomerular filtration rate,
study revealed that administration of MitoQ impeded en- and significantly increased the rate of survival [44].
dotoxin-induced cardiac dysfunction in a rat model of sep-
sis [37]. Assessment of MitoQ in a human phase II Parkin- Other Methods: Melatonin and Lipoic Acid
son disease trial confirmed that it is safe to administer to Melatonin, a potent antioxidant, has a higher concen-
patients [38]. Nevertheless, MitoQ has not been utilized in tration in the mitochondria than in other cellular organ-
clinical studies on sepsis. Other compounds conjugated to elles. Melatonin reduces oxidative stress by scavenging
the triphenylphosphonium cation, such as vitamin E, per- endogenous free radicals, such as the hydroxyl radical,
oxidase, or ebselen, also have an effect on the elimination of H2O2, peroxynitrite anion, and nitric oxide [45]. Several
mitochondrial oxidative stress [39]. Further human studies animal studies have demonstrated that melatonin attenu-
will be required to demonstrate a beneficial effect of lipo- ates mitochondrial dysfunction in septic mice [46] and

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 Harsha Nagar, et al. Role of Mitochondrial Oxidative Stress in Sepsis 69

peritonitis-induced septic shock in rats [47]. Clinical stud- Acknowledgments

ies have indicated that melatonin exerts beneficial effects This work was supported by the research fund of Chun-
in humans. Gitto et al. [48] showed that melatonin admin- gnam National University, Daejeon, Korea.
istration reduced the septic newborn death rate by decreas-
ing the concentrations of lipid peroxidation products. In
another study, melatonin had beneficial effects on sepsis- ORCID
induced mitochondrial dysfunction, oxidative stress, and
cytokine responses [49]. Alpha-lipoic acid is another met- Harsha Nagar https://orcid.org/0000-0002-2879-0118
abolic antioxidant; its reduced form, dihydrolipoic acid, Shuyu Piao https://orcid.org/0000-0003-4250-6491
plays an important role in mitochondrial dehydrogenase Cuk-Seong Kim https://orcid.org/0000-0001-7647-6089
reactions; directly scavenges ROS, such as superoxide
radicals, hydroxyl radicals, and peroxyl radicals; and ex-
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