Antioxidants

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14 pages, 2505 KiB

Open AccessArticle

Mitochondrial Dysfunction Plays a Relevant Role in Pathophysiology of Peritoneal Membrane Damage Induced by Peritoneal Dialysis

by Olalla Ramil-Gómez, Ana Rodríguez-Carmona, Jennifer Adriana Fernández-Rodríguez, Miguel Pérez-Fontán, Tamara Ferreiro-Hermida, Mirian López-Pardo, Teresa Pérez-López and María J. López-Armada

Antioxidants 2021, 10(3), 447; https://doi.org/10.3390/antiox10030447 - 13 Mar 2021

Cited by 9 | Viewed by 1793

Abstract

Preservation of the peritoneal membrane is an essential determinant of the long-term outcome of peritoneal dialysis (PD). Epithelial-to-mesenchymal transition (EMT) plays a central role in the pathogenesis of PD-related peritoneal membrane injury. We hypothesized that mitochondria may be implicated in the mechanisms that [...] Read more.

Preservation of the peritoneal membrane is an essential determinant of the long-term outcome of peritoneal dialysis (PD). Epithelial-to-mesenchymal transition (EMT) plays a central role in the pathogenesis of PD-related peritoneal membrane injury. We hypothesized that mitochondria may be implicated in the mechanisms that initiate and sustain peritoneal membrane damage in this setting. Hence, we carried out ex vivo studies of effluent-derived human mesothelial cells, which disclosed a significant increase in mitochondrial reactive oxygen species (mtROS) production and a loss of mitochondrial membrane potential in mesothelial cells with a fibroblast phenotype, compared to those preserving an epithelial morphology. In addition, in vitro studies of omentum-derived mesothelial cells identified mtROS as mediators of the EMT process as mitoTEMPO, a selective mtROS scavenger, reduced fibronectin protein expression induced by TGF-ß1. Moreover, we quantified mitochondrial DNA (mtDNA) levels in the supernatant of effluent PD solutions, disclosing a direct correlation with small solute transport characteristics (as estimated from the ratio dialysate/plasma of creatinine at 240 min), and an inverse correlation with peritoneal ultrafiltration. These results suggest that mitochondria are involved in the EMT that human peritoneal mesothelial cells suffer in the course of PD therapy. The level of mtDNA in the effluent dialysate of PD patients could perform as a biomarker of PD-induced damage to the peritoneal membrane. Full article

(This article belongs to the Special Issue Mitochondrial Reactive Oxygen Species)

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18 pages, 5542 KiB

Open AccessArticle

Methylene Blue Bridges the Inhibition and Produces Unusual Respiratory Changes in Complex III-Inhibited Mitochondria. Studies on Rats, Mice and Guinea Pigs

by Gergely Sváb, Márton Kokas, Ildikó Sipos, Attila Ambrus and László Tretter

Antioxidants 2021, 10(2), 305; https://doi.org/10.3390/antiox10020305 - 16 Feb 2021

Cited by 6 | Viewed by 3584

Abstract

Methylene blue (MB) is used in human therapy in various pathological conditions. Its effects in neurodegenerative disease models are promising. MB acts on multiple cellular targets and mechanisms, but many of its potential beneficial effects are ascribed to be mitochondrial. According to the [...] Read more.

Methylene blue (MB) is used in human therapy in various pathological conditions. Its effects in neurodegenerative disease models are promising. MB acts on multiple cellular targets and mechanisms, but many of its potential beneficial effects are ascribed to be mitochondrial. According to the “alternative electron transport” hypothesis, MB is capable of donating electrons to cytochrome c bypassing complex I and III. As a consequence of this, the deleterious effects of the inhibitors of complex I and III can be ameliorated by MB. Recently, the beneficial effects of MB exerted on complex III-inhibited mitochondria were debated. In the present contribution, several pieces of evidence are provided towards that MB is able to reduce cytochrome c and improve bioenergetic parameters, like respiration and membrane potential, in mitochondria treated with complex III inhibitors, either antimycin or myxothiazol. These conclusions were drawn from measurements for mitochondrial oxygen consumption, membrane potential, NAD(P)H steady state, MB uptake and MB-cytochrome c oxidoreduction. In the presence of MB and complex III inhibitors, unusual respiratory reactions, like decreased oxygen consumption as a response to ADP addition as well as stimulation of respiration upon administration of inhibitors of ATP synthase or ANT, were observed. Qualitatively identical results were obtained in three rodent species. The actual metabolic status of mitochondria is well reflected in the distribution of MB amongst various compartments of this organelle. Full article

(This article belongs to the Special Issue Mitochondrial Reactive Oxygen Species)

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17 pages, 2664 KiB

Open AccessArticle

Propagation of Mitochondria-Derived Reactive Oxygen Species within the Dipodascus magnusii Cells

by Anton G. Rogov, Tatiana N. Goleva, Khoren K. Epremyan, Igor I. Kireev and Renata A. Zvyagilskaya

Antioxidants 2021, 10(1), 120; https://doi.org/10.3390/antiox10010120 - 15 Jan 2021

Cited by 9 | Viewed by 3189

Abstract

Mitochondria are considered to be the main source of reactive oxygen species (ROS) in the cell. It was shown that in cardiac myocytes exposed to excessive oxidative stress, ROS-induced ROS release is triggered. However, cardiac myocytes have a network of densely packed organelles [...] Read more.

Mitochondria are considered to be the main source of reactive oxygen species (ROS) in the cell. It was shown that in cardiac myocytes exposed to excessive oxidative stress, ROS-induced ROS release is triggered. However, cardiac myocytes have a network of densely packed organelles that do not move, which is not typical for the majority of eukaryotic cells. The purpose of this study was to trace the spatiotemporal development (propagation) of prooxidant-induced oxidative stress and its interplay with mitochondrial dynamics. We used Dipodascus magnusii yeast cells as a model, as they have advantages over other models, including a uniquely large size, mitochondria that are easy to visualize and freely moving, an ability to vigorously grow on well-defined low-cost substrates, and high responsibility. It was shown that prooxidant-induced oxidative stress was initiated in mitochondria, far preceding the appearance of generalized oxidative stress in the whole cell. For yeasts, these findings were obtained for the first time. Preincubation of yeast cells with SkQ1, a mitochondria-addressed antioxidant, substantially diminished production of mitochondrial ROS, while only slightly alleviating the generalized oxidative stress. This was expected, but had not yet been shown. Importantly, mitochondrial fragmentation was found to be primarily induced by mitochondrial ROS preceding the generalized oxidative stress development. Full article

(This article belongs to the Special Issue Mitochondrial Reactive Oxygen Species)

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19 pages, 3203 KiB

Open AccessArticle

Eukarion-134 Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Dysfunction in Human Skeletal Muscle Cells

by Anastasia Thoma, Max Lyon, Nasser Al-Shanti, Gareth A. Nye, Robert G. Cooper and Adam P. Lightfoot

Antioxidants 2020, 9(8), 710; https://doi.org/10.3390/antiox9080710 - 5 Aug 2020

Cited by 8 | Viewed by 3842

Abstract

Maladaptive endoplasmic reticulum (ER) stress is associated with modified reactive oxygen species (ROS) generation and mitochondrial abnormalities; and is postulated as a potential mechanism involved in muscle weakness in myositis, an acquired autoimmune neuromuscular disease. This study investigates the impact of ROS generation [...] Read more.

Maladaptive endoplasmic reticulum (ER) stress is associated with modified reactive oxygen species (ROS) generation and mitochondrial abnormalities; and is postulated as a potential mechanism involved in muscle weakness in myositis, an acquired autoimmune neuromuscular disease. This study investigates the impact of ROS generation in an in vitro model of ER stress in skeletal muscle, using the ER stress inducer tunicamycin (24 h) in the presence or absence of a superoxide dismutase/catalase mimetic Eukarion (EUK)-134. Tunicamycin induced maladaptive ER stress, which was mitigated by EUK-134 at the transcriptional level. ER stress promoted mitochondrial dysfunction, described by substantial loss of mitochondrial membrane potential, as well as a reduction in respiratory control ratio, reserve capacity, phosphorylating respiration, and coupling efficiency, which was ameliorated by EUK-134. Tunicamycin induced ROS-mediated biogenesis and fusion of mitochondria, which, however, had high propensity of fragmentation, accompanied by upregulated mRNA levels of fission-related markers. Increased cellular ROS generation was observed under ER stress that was prevented by EUK-134, even though no changes in mitochondrial superoxide were noticeable. These findings suggest that targeting ROS generation using EUK-134 can amend aspects of ER stress-induced changes in mitochondrial dynamics and function, and therefore, in instances of chronic ER stress, such as in myositis, quenching ROS generation may be a promising therapy for muscle weakness and dysfunction. Full article

(This article belongs to the Special Issue Mitochondrial Reactive Oxygen Species)

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16 pages, 3986 KiB

Open AccessArticle

Mitochondrial ROS Induce Partial Dedifferentiation of Human Mesothelioma via Upregulation of NANOG

by Filip Sedlic, Fran Seiwerth, Ana Sepac, Suncana Sikiric, Marina Cindric, Marija Milavic, Lovorka Batelja Vuletic, Marko Jakopovic and Sven Seiwerth

Antioxidants 2020, 9(7), 606; https://doi.org/10.3390/antiox9070606 - 10 Jul 2020

Cited by 8 | Viewed by 2705

Abstract

The expression of pluripotency factors is a key regulator of tumor differentiation status and cancer stem cells. The purpose of this study was to examine the expression of pluripotency factors and differentiation status of human mesothelioma and the role of mitochondria in their [...] Read more.

The expression of pluripotency factors is a key regulator of tumor differentiation status and cancer stem cells. The purpose of this study was to examine the expression of pluripotency factors and differentiation status of human mesothelioma and the role of mitochondria in their regulation. We tested the expression of OCT4/POU5F1, NANOG, SOX2, PI3K-AKT pathway and BCL2 genes and proteins in 65 samples of human mesothelioma and 19 samples of normal mesothelium. Mitochondrial membrane potential, reactive oxygen species (ROS) generation and expression of pluripotency factors were also tested in human mesothelioma cell line. Human mesothelium and mesothelioma expressed SOX2, NANOG, PI3K and AKT genes and proteins and POU5F1 gene, whereby NANOG, SOX2 and phosphorylated (activated) AKT were upregulated in mesothelioma. NANOG protein expression was elevated in less differentiated samples of human mesothelioma. The expression of genes of PI3K-AKT pathway correlated with pluripotency factor genes. Mesothelioma cells had functional, but depolarized mitochondria with large capacity to generate ROS. Mitochondrial ROS upregulated NANOG and mitoTEMPO abrogated it. In conclusion, human mesothelioma displays enhanced expression of NANOG, SOX2 and phosphorylated AKT proteins, while elevated NANOG expression correlates with poor differentiation of human mesothelioma. Mitochondria of mesothelioma cells have a large capacity to form ROS and thereby upregulate NANOG, leading to dedifferentiation of mesothelioma. Full article

(This article belongs to the Special Issue Mitochondrial Reactive Oxygen Species)

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Review

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19 pages, 3300 KiB

Open AccessReview

Power Failure of Mitochondria and Oxidative Stress in Neurodegeneration and Its Computational Models

by JunHyuk Woo, Hyesun Cho, YunHee Seol, Soon Ho Kim, Chanhyeok Park, Ali Yousefian-Jazi, Seung Jae Hyeon, Junghee Lee and Hoon Ryu

Antioxidants 2021, 10(2), 229; https://doi.org/10.3390/antiox10020229 - 3 Feb 2021

Cited by 17 | Viewed by 4520

Abstract

The brain needs more energy than other organs in the body. Mitochondria are the generator of vital power in the living organism. Not only do mitochondria sense signals from the outside of a cell, but they also orchestrate the cascade of subcellular events [...] Read more.

The brain needs more energy than other organs in the body. Mitochondria are the generator of vital power in the living organism. Not only do mitochondria sense signals from the outside of a cell, but they also orchestrate the cascade of subcellular events by supplying adenosine-5′-triphosphate (ATP), the biochemical energy. It is known that impaired mitochondrial function and oxidative stress contribute or lead to neuronal damage and degeneration of the brain. This mini-review focuses on addressing how mitochondrial dysfunction and oxidative stress are associated with the pathogenesis of neurodegenerative disorders including Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and Parkinson’s disease. In addition, we discuss state-of-the-art computational models of mitochondrial functions in relation to oxidative stress and neurodegeneration. Together, a better understanding of brain disease-specific mitochondrial dysfunction and oxidative stress can pave the way to developing antioxidant therapeutic strategies to ameliorate neuronal activity and prevent neurodegeneration. Full article

(This article belongs to the Special Issue Mitochondrial Reactive Oxygen Species)

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25 pages, 2222 KiB

Open AccessReview

Targeted Antioxidants in Exercise-Induced Mitochondrial Oxidative Stress: Emphasis on DNA Damage

by Josh Williamson and Gareth Davison

Antioxidants 2020, 9(11), 1142; https://doi.org/10.3390/antiox9111142 - 17 Nov 2020

Cited by 21 | Viewed by 3900

Abstract

Exercise simultaneously incites beneficial (e.g., signal) and harming (e.g., damage to macromolecules) effects, likely through the generation of reactive oxygen and nitrogen species (RONS) and downstream changes to redox homeostasis. Given the link between nuclear DNA damage and human longevity/pathology, research attempting to [...] Read more.

Exercise simultaneously incites beneficial (e.g., signal) and harming (e.g., damage to macromolecules) effects, likely through the generation of reactive oxygen and nitrogen species (RONS) and downstream changes to redox homeostasis. Given the link between nuclear DNA damage and human longevity/pathology, research attempting to modulate DNA damage and restore redox homeostasis through non-selective pleiotropic antioxidants has yielded mixed results. Furthermore, until recently the role of oxidative modifications to mitochondrial DNA (mtDNA) in the context of exercising humans has largely been ignored. The development of antioxidant compounds which specifically target the mitochondria has unveiled a number of exciting avenues of exploration which allow for more precise discernment of the pathways involved with the generation of RONS and mitochondrial oxidative stress. Thus, the primary function of this review, and indeed its novel feature, is to highlight the potential roles of mitochondria-targeted antioxidants on perturbations to mitochondrial oxidative stress and the implications for exercise, with special focus on mtDNA damage. A brief synopsis of the current literature addressing the sources of mitochondrial superoxide and hydrogen peroxide, and available mitochondria-targeted antioxidants is also discussed. Full article

(This article belongs to the Special Issue Mitochondrial Reactive Oxygen Species)

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31 pages, 3230 KiB

Open AccessReview

Mechanisms of Mitochondrial ROS Production in Assisted Reproduction: The Known, the Unknown, and the Intriguing

by James N. Cobley

Antioxidants 2020, 9(10), 933; https://doi.org/10.3390/antiox9100933 - 29 Sep 2020

Cited by 32 | Viewed by 5259

Abstract

The consensus that assisted reproduction technologies (ART), like in vitro fertilization, to induce oxidative stress (i.e., the known) belies how oocyte/zygote mitochondria—a major presumptive oxidative stressor—produce reactive oxygen species (ROS) with ART being unknown. Unravelling how oocyte/zygote mitochondria produce ROS is important for [...] Read more.

The consensus that assisted reproduction technologies (ART), like in vitro fertilization, to induce oxidative stress (i.e., the known) belies how oocyte/zygote mitochondria—a major presumptive oxidative stressor—produce reactive oxygen species (ROS) with ART being unknown. Unravelling how oocyte/zygote mitochondria produce ROS is important for disambiguating the molecular basis of ART-induced oxidative stress and, therefore, to rationally target it (e.g., using site-specific mitochondria-targeted antioxidants). I review the known mechanisms of ROS production in somatic mitochondria to critique how oocyte/zygote mitochondria may produce ROS (i.e., the unknown). Several plausible site- and mode-defined mitochondrial ROS production mechanisms in ART are proposed. For example, complex I catalyzed reverse electron transfer-mediated ROS production is conceivable when oocytes are initially extracted due to at least a 10% increase in molecular dioxygen exposure (i.e., the intriguing). To address the term oxidative stress being used without recourse to the underlying chemistry, I use the species-specific spectrum of biologically feasible reactions to define plausible oxidative stress mechanisms in ART. Intriguingly, mitochondrial ROS-derived redox signals could regulate embryonic development (i.e., their production could be beneficial). Their potential beneficial role raises the clinical challenge of attenuating oxidative damage while simultaneously preserving redox signaling. This discourse sets the stage to unravel how mitochondria produce ROS in ART, and their biological roles from oxidative damage to redox signaling. Full article

(This article belongs to the Special Issue Mitochondrial Reactive Oxygen Species)

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