Special Issue "Oxidative Stress and Mitochondria"

Guest Editor
Prof. Dr. Daret K. St. Clair
Graduate Center for Toxicology, 1095 V.A. Drive, 306 Health Sciences Research Building, Lexington, KY 40536-0305, USA
Website: http://www.mc.uky.edu/toxicology/faculty/stclair.asp
E-Mail: dstcl00@uky.edu
Phone: +1 859 257 3956
Fax: +1 859 323 1059

Guest Editor
Dr. Aaron K. Holley
Graduate Center for Toxicology, 1095 V.A. Drive, 448 Health Sciences Research Building, Lexington, KY 40536-0305, USA
E-Mail: aaron.holley@uky.edu

Dear Colleagues,

Mitochondria are important sites for a variety of cellular processes, including amino acid and fatty acid metabolism, the citric acid cycle, nitrogen metabolism, and oxidative phosphorylation to produce ATP.  Mitochondria are also an important source of reactive oxygen species (ROS).  Myriad enzyme systems within mitochondria contribute to ROS production.  Superoxide radicals can be produced by complexes I and III of the electron transport chain, the cytochrome P450 family of enzymes localized to mitochondria, and the release of free iron cations from the catalytic centers of iron-sulfur centers of various enzymes, such as aconitase, which, are susceptible to attack by superoxide radicals. Through these processes, mitochondria also produce hydrogen peroxide from superoxide radical dismutation, the hydroxyl radical through the iron-catalyzed Haber-Weiss reaction, and the highly reactive peroxynitrite molecule (ONOO^-) from the interaction between superoxide radicals with nitric oxide, an uncharged radical synthesized by nitric oxide synthase (NOS).

Under normal conditions ROS are important for regulation of various cellular processes including metabolic cell signaling. Mitochondria communicate with other organelles of the cell, such as the nucleus, through a process called retrograde signaling to maintain cellular homeostasis and adapt to changing metabolic requirements of the cell. It is well documented that ROS contribute significantly to the regulation of the activity of various signal transduction pathways and transcription factors.  For example, various members of the MAP kinase pathway are activated by ROS.  ROS play a role in growth factor receptor activation through oxidative deactivation of protein tyrosine phosphatases that maintain the growth factor receptors in an inactive state.  Multiple transcription factors, including NF-κB, AP-1, HIF-1, and p53, are sensitive to ROS.  Altered activation of these signaling pathways and transcription factors results in changes in gene expression and initiation of different cellular events, including cell proliferation, senescence, apoptosis, angiogenesis, and autophagy.

While ROS are important for normal cellular activities, aberrant production of ROS, or diminished capacity to scavenge excessive ROS, leads to an imbalance in the redox environment of the cell. Myriad ROS-scavenging enzyme systems are in place to detoxify mitochondrial ROS.  Manganese superoxide dismutase (MnSOD) is the major ROS scavenger of the cell, catalyzing the dismutation of superoxide radicals to hydrogen peroxide and molecular oxygen.  Hydrogen peroxide, a non-radical ROS, is detoxified by multiple enzymes in mitochondria, including glutathione peroxidase, peroxiredoxin, as well as glutathione and protein thiols.  The presence of these molecules in regulation of mitochondria-centered signaling has yet to be fully investigated. The disparity from normal ROS levels can cause damage of lipids, proteins, and DNA, all of which contribute to the development of various pathologies, including age-related ailments, neurological disorders, cardiovascular diseases, diabetes, and cancer.

Because of the omnipresence of ROS in cells and contribution of mitochondria in the production and removal of cellular ROS, a greater understanding of oxidative stress in mitochondria, under both normal and disease-causing conditions, and the involvement of mitochondrial ROS in global regulation of gene expression can illuminate the contribution of mitochondria in the development of disease and may lead to the advancement of new and novel therapeutic modalities that exploit mitochondria in treating many maladies.

Daret K. St. Clair
Guest Editor

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• mitochondria
• reactive oxygen species
• antioxidant enzymes
• redox regulation
• oxidative stress
• retrograde signaling
• cell signaling

Type of Paper: Article
Title: Impaired Mitochondrial Respiratory Functions and Oxidative Stress in Streptozotocin-Induced Diabetic Rats
Authors: Haider Raza¹, Subbuswamy K. Prabu², Annie John¹ and Narayan G. Avadhani²
Affiliations: ¹ Department of Biochemistry, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates;
E-Mail: H.Raza@uaeu.ac.ae (H.R.)
² Animal Biology, School of Veterinary Medicine, 3800 Spruce Street, University of Pennsylvania, Philadelphia 19104, USA;
E-Mail: narayan@vet.upenn.edu (N.G.A.)
Abstract: We have previously shown a tissue-specific increase in oxidative stress in early stages of streptozotocin (STZ)-induced diabetes in rats. In this study, we investigated the oxidative stress and mitochondrial functions in rats with chronic diabetes (>15 mM blood glucose for 8 weeks) in the pancreas and other tissues. We show that increased oxidative stress in chronic diabetes is associated with altered mitochondrial respiratory and redox functions. Increased production of reactive oxygen and nitrogen species (ROS and RNS respectively) were observed in different tissues after STZ treatment. Oxidative protein carbonylation was increased in different tissues with maximum effect in the pancreas of diabetic rats. Mitochondrial cytochrome c oxidase (CcO, complex IV) and ubiquinol: cytochrome c oxidoreductase (complex III) activities were decreased while the activities of NADH:ubiquinone oxidoreductase (complex I) and succinate:ubiquinone oxidoreductase (complex II) were increased in STZ treated rats. The mitochondrial aconitase activity, a ROS sensitive metabolic enzyme, was significantly inhibited in the diabetic rat tissues. The increased level of mitochondrial nitric oxide synthase was also observed in the tissues after STZ treatment. These results suggest that mitochondrial respiratory complexes may play critical roles in ROS/RNS homeostasis and oxidative stress related changes in type 1 diabetes. The altered respiratory and redox mitochondrial functions may have implications in the etiology of diabetes and its complications.
Keywords: diabetes; oxidative stress; mitochondrial respiratory functions; ROS; NO; protein carbonylation
Abbreviations Used: CcO: cytochrome c oxidase; DCF-DA: 2’,7’-dichlorofluorescein diacetate; DNPH: 2,4’-dinitrophenylhydrazine; NO: nitric oxide; NOS: nitric oxide synthase; ROS: reactive oxygen species; STZ: streptozotocin; SDSPAGE: sodium dodecylsulphate polyacrylamide gel electrophoresis

Type of Paper: Review
Title: Oxidative Stress and Its Consequences in Human Cells with Mitochondrial Dysfunction and Redox Therapy for Diseases with Mitochondrial Disorder
Authors: Yin-Chiu Chen, Shi-Bei Wu, Yu-Ting Wu and Yau-Huei Wei
Affiliation: Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, and Department of Medicine, Mackay Medical College, Taipei 252, Taiwan; E-Mail: joeman@mmc.edu.tw (Y.-H.W.)
Abstract: Pathogenic mtDNA mutations contribute to the decline of mitochondrial function, which results in not only decreased efficiency in the production of ATP but also increased generation of reactive oxygen species (ROS) in the mitochondria of affected tissues of patients with mitochondrial disorders. Long-term exposure of human cells to ROS results in the decrease of their capacity to respond to oxidative stress, which in turn elicits more serious consequences of enhanced oxidative damage and cell death in affected cells. Recent studies by comparative cDNA microarray and 2D-proteomic techniques have identified several clusters of genes whose expression levels are changed in cells harboring a pathogenic mtDNA mutation. These studies have revealed that stress response proteins such as the antioxidant enzymes, DNA repair enzymes and mitochondrial proteases may play important roles in the pathophysiology of mitochondrial diseases. On the other hand, we observed that oxidative stress induced by respiratory inhibitors, hydrogen peroxide or menadione caused post-translational modification of proteins in mitochondria. The skin fibroblasts with mtDNA mutation-elicited oxidative stress displayed lower motility and abnormal distribution of mitochondria, which could be corrected by N-acetylcysteine (NAC), a precursor of glutathione. Antioxidants such as CoQ₁₀, NAC, lipoic acid and the SOD mimetic could restore the redox status of cells, which have been considered a feasible approach to develop novel treatments of diseases caused by mitochondrial disorders. Taken together, we suggest that mtDNA mutation-induced oxidative stress and its consequences are involved in the pathophysiology of mitochondrial diseases, and that redox therapy may help alleviate oxidative stress and oxidative damage in these patients.

Type of Paper: Review
Title: Iron: A Double-Edged Sword in Aging Research
Author: Jinze Xu
Affiliation: Research Fellow, Division of Biology of Aging, Department of Aging and Geriatrics, College of Medicine, University of Florida, Institute on Aging, USA; E-Mail: jxu@aging.ufl.edu
Abstract: Iron is the most abundant trace metal in the body. However, excess iron, by virtue of its ability to catalyze the formation of reactive oxygen species (ROS), may generate cellular and mitochondrial toxic stress, which contributes to aging and age-related disorders. Recent studies show that cellular and mitochondrial iron in brain and skeletal muscle increases with age, concomitant with lower hematological parameters and plasma iron, indicating that there is an age-related iron shift from functional, transport and storage compartments to nervous and skeletal muscle tissues. Thus, we will review important features, potential mechanisms, and interventions of iron dysregulation in aging research with a particular emphasis on its effects on oxidative stress and mitochondrial function.

Type of Paper: Article
Title: Resorcylidene Aminoguanidine (RAG) Improves Cardiac Mitochondrial Bioenergetics Impaired by Hyperglycaemia in a Model of Experimental Diabetes
Authors: M. Labieniec-Watala ¹, K. Siewiera ², K. Kochel ¹, S. Gierszewski ¹ and Z. Jozwiak ¹
Affiliations: ¹ Department of Thermobiology, University of Lodz, 141/143 Pomorska Street, 90-236 Lodz, Poland; E-Mail: magdalab@biol.uni.lodz.pl (M.L.-W.)
² Department of General Biophysics, University of Lodz, 141/143 Pomorska Street, 90-236 Lodz, Poland
Abstract: Introduction: Diabetes is associated with a mitochondrial dysfunction. Hyperglycaemia is also clearly recognized as the primary culprit in the pathogenesis of cardiac complications. In response to glycation and oxidative stress, cardiac mitochondria undergo cumulative alterations often leading to heart deterioration. There is a continuous search for innovative treatment strategies for protecting the heart mitochondria from destructive impact of diabetes. Aminoguanidine derivatives have been successfully used in animal model studies on the treatment of experimental diabetes, as well as the diabetes-driven dysfunctions of peripheral tissues and cells. Considerable attention has been paid particularly to b-resorcylidene aminoguanidine (RAG), often shown as the efficient anti-glycation and anti-oxidant agent in both animal studies and in vitro experiments. Aim/hypothesis: The aim of the present study was to test the hypothesis that RAG improves oxidative phosphorylation and electron transport capacity in mitochondria impaired by hyperglycaemia. Experimental design: Diabetes mellitus was induced in Wistar rats by a single intraperitoneal injection of streptozotocin (70 mg/kg body weight). The rats were weighed weekly and sacrificed after 3 months of RAG supplementation at a dose of 40 mg/kg body weight/day. Additionally, the level of blood glucose was monitored once a week. Material: Heart mitochondria were isolated from healthy rats and rats with streptozotocin-diabetes. Method: Mitochondrial respiratory capacity was measured by high resolution respirometry with the OROBOROS Oxygraph-2k according to experimental protocol including respiratory substrates and inhibitors. Expected results: RAG protects the heart against diabetes-associated injury by improving the mitochondrial bioenergetics, thus suggesting a possible novel pharmacological strategy for cardio protection.

Type of Paper: Review
Title: Effect of Polyphenols on Oxidative Stress and Mitochondrial Dysfunction in Neuronal Death, Brain Edema and Cell Swelling in Cerebral Ischemia
Authors: Kiran S. Panickar and Richard A. Anderson
Affiliation: Diet, Genomics, & Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD 20705, USA; E-Mail: Kiran.panickar@ars.usda.gov (K.S.P.)
Abstract: Polyphenols are natural substances with variable phenolic structures and are elevated in vegetables, fruits, grains, bark, roots, tea, and wine. There are over 8000 polyphenolic structures identified in plants, but edible plants contain only several hundred polyphenolic structures. In addition to their anti-oxidant effects, select some polyphenols also have insulin-potentiating, anti-inflammatory, anti-carcinogenic, anti-viral, anti-ulcer, and anti-apoptotic properties. One important consequence of ischemia is neuronal death. Oxidative stress and mitochondrial dysfunction are implicated in its pathogenesis and may do so by activating mitochondria-associated cell death pathways. Another consequence of ischemia, that is possibly mediated by oxidative stress and mitochondrial dysfunction, is glial swelling, a component of cytotoxic brain edema. The purpose of this article is to review the current literature on the contribution of oxidative stress and mitochondrial dysfunction to neuronal death, cell swelling and brain edema in ischemia. A review of currently known mechanisms underlying neuronal death and edema/cell swelling will be undertaken and the potential of dietary polyphenols to reduce such neural damage will be critically reviewed.
Keywords: ischemia; oxidative stress; mitochondria; edema; glia

Type of Paper: Review
Title: Ghrelin Modulates Mitochondrial Function and Oxidative Stress in the Central Nervous System
Author: Zane B. Andrews
Affiliation: Department of Physiology, Monash University, Wellington Rd, Clayton, Victoria, Australia; E-Mail: Zane.andrews@monash.edu
Abstract: Recent evidence indicates that the peripheral hormone ghrelin has a significant impact on mitochondrial function and oxidative stress in the central nervous system (CNS). In this review, we highlight recent mechanistic advances that illustrate the role for ghrelin in mitochondrial function. We focus on describing the 1) mitochondrial mechanisms through which ghrelin stimulates feeding in the CNS; 2) mitochondrial and anti-oxidative mechanisms through which ghrelin mediates neuroprotection. We hypothesize that ghrelin uses a novel uncoupling protein-2 mitochondrial pathway to buffer in vivo reactive oxygen species and mitochondrial biogenesis.

Type of Paper: Review
Title: Antioxidant Roles of Endogenous and Exogenously Administered Intermediate Metabolites in Hypoxia, Ischemia and Oxidative Stress
Author: Lawrence Litt
Affiliation: University of California San Francisco, 521 Parnassus Ave 0648, Room C455, SF, CA 94143-0648, USA; E-Mail: littl@anesthesia.ucsf.edu
Abstract: Aerobic metabolism occurs in a background of oxygen radicals and reactive oxygen species (ROS) that originate from the incomplete reduction of molecular oxygen in electron transfer reactions. The essential role of aerobic metabolism, the generation and consumption of ATP and other high energy phosphates, employs approximately 3,000 essential human metabolites that serve not only as substrates and products of associated chemical reactions, but also serve as antioxidants, neurotransmitters, osmolytes, and participants in ligand-based and other cellular signaling.  In hypoxia, ischemia, and oxidative stress, where pathological circumstances cause oxygen radicals to form at a rate greater than is possible for their consumption, changes in the composition of metabolite ensembles, or metabolomes, can be associated with specific physiological changes.  Metabolomics is a scientific discipline that focuses on quantifying dynamic metabolome responses, using multivariate analytical approaches derived from methods within genomics, a discipline that consolidated innovative analysis techniques for situations where the number of biomarkers (metabolites in our case) greatly exceeds the number of subjects. This review is focused on intra- and extracellular roles of cytosolic, mitochondrial, and redox metabolites in ameliorating and treating oxidative stress that is either primary or secondary to hypoxia-ischemia.  The first section reviews work in which each study focused on a small number of metabolites, including NAD/NADH, NADP/NADPH, pyruvate, ethylpyruvate, and fructose-1,6-bisphosphate.  The second section reviews certain classical multivariate statistical methods common in metabolomics research, such as Principal Component Analysis (PCA) and Projection to Least Squares Linear Discriminant Analysis (PLS-DA).  As well some promising contemporary approaches are reviewed, such as L-1 penalized regression (LASSO).  The third section discusses recent metabolomic studies of different pathological situations, emphasizing NMR spectroscopic metabolomic determinations.

Type of paper: Review
Title: Metal-Induced Oxidative Stress and Plant Mitochondria
Authors: Els Keunen, Tony Remans, Jaco Vangronsveld and Ann Cuypers
Affiliation: Centre for Environmental Sciences, Hasselt University, Agoralaan Building D, Diepenbeek, Belgium; E-Mails: els.keunen@uhasselt.be (E.K.); jaco.vangronsveld@uhasselt.be (J.V.); ann.cuypers@uhasselt.be (A.C.)
Abstract: A general status of oxidative stress in plants caused by elevated metal concentrations in the environment coincides with a constraint on mitochondrial electron transport, which enhances ROS accumulation at the mitochondrial level. As mitochondria are suggested to be involved in redox signalling under environmental stress conditions, mitochondrial ROS can initiate a signalling cascade mediating the overall stress response, i.e. damage versus adaptation. This review highlights our current understanding on metal-induced responses in plants, with focus on the production and detoxification of mitochondrial ROS. In addition, the potential involvement of retrograde signalling in these processes will be discussed.