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Antioxidants
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Mitochondrial Oxidative and Nitrosative Stress as a Therapeutic Target in...
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Mitochondrial Oxidative and Nitrosative Stress as a Therapeutic Target in Diseases II

A special issue of Antioxidants (ISSN 2076-3921).

Deadline for manuscript submissions: closed (10 October 2022) | Viewed by 21039

Special Issue Editors

Dr. Anna Colell

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Guest Editor
Department of Cell Death and Proliferation, Institut D'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), 08036 Barcelona, Spain
Interests: Alzheimer’s disease; cholesterol in neurodegeneration; mitochondria; mitochondrial oxidative stress; autophagy/mitophagy
Special Issues, Collections and Topics in MDPI journals
Dr. Montserrat Marí

E-Mail Website
Guest Editor
Department of Cell Death and Proliferation, Institut D'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), 08036 Barcelona, Spain
Interests: liver diseases; nafld; liver fibrosis; nkt cells; liver immunology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Although necessary for life, mitochondria are often essential for initiating apoptotic death and deciding cell fate under cellular stress. Recently, in addition to their role in cell death, mitochondria have been suggested to serve as signaling platforms critical for regulating autophagy and the inflammatory response. Mitochondrial oxidative/nitrosative stress has been reported to trigger autophagy by promoting autophagosome formation and induce the release of inflammatory cytokines through the activation of the NLRP3-inflammasome. Thus, it is becoming clear that mitochondria participate in many aspects of cell function, and evidence further suggests that mitochondria impairment is underlying many common human disorders. Consequently, new strategies are being sought to restore the mitochondrial function therapeutically.

Contributions to this Special Issue may cover research findings or review articles related to the role of mitochondrial oxidative stress and mitochondrial dysfunction in different pathological conditions ranging from cancer to neurodegenerative diseases, the mechanistic links between changes in mitochondria functionality and alterations of cellular processes such as autophagy and the inflammatory signaling pathways and its impact on cell viability, and the use of mitochondria-targeted molecules, including antioxidants, as therapeutic strategies for disease intervention.

Dr. Anna Colell
Dr. Montserrat Marí
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Mitochondrial oxidative stress
  • Autophagy
  • mitophagy
  • Inflammasome
  • Antioxidants
  • Mitochondrial dysfunction
  • Mitochondrial-targeted molecules
  • Disease

Related Special Issues

Published Papers (7 papers)

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Research

17 pages, 2423 KiB  
Article
Involvement of Mitochondrial Dysfunction in the Inflammatory Response in Human Mesothelial Cells from Peritoneal Dialysis Effluent
by Olalla Ramil-Gómez, Mirian López-Pardo, Jennifer Adriana Fernández-Rodríguez, Ana Rodríguez-Carmona, Teresa Pérez-López, Carlos Vaamonde-García, Miguel Pérez-Fontán and María José López-Armada
Antioxidants 2022, 11(11), 2184; https://doi.org/10.3390/antiox11112184 - 04 Nov 2022
Cited by 3 | Viewed by 1691
Abstract
Recent studies have related mitochondrial impairment with peritoneal membrane damage during peritoneal dialysis (PD) therapy. Here, we assessed the involvement of mitochondrial dysfunction in the inflammatory response in human mesothelial cells, a hallmark in the pathogenesis of PD-related peritoneal membrane damage. Our ex [...] Read more.
Recent studies have related mitochondrial impairment with peritoneal membrane damage during peritoneal dialysis (PD) therapy. Here, we assessed the involvement of mitochondrial dysfunction in the inflammatory response in human mesothelial cells, a hallmark in the pathogenesis of PD-related peritoneal membrane damage. Our ex vivo studies showed that IL-1β causes a drop in the mitochondrial membrane potential in cells from peritoneal effluent. Moreover, when mitochondrial damage was induced by inhibitors of mitochondrial function, a low-grade inflammatory response was generated. Interestingly, mitochondrial damage sensitized mesothelial cells, causing a significant increase in the inflammatory response induced by cytokines, in which ROS generation and NF-κB activation appear to be involved, since inflammation was counteracted by both mitoTEMPO (mitochondrial ROS scavenger) and BAY-117085 (NF-κB inhibitor). Furthermore, the natural anti-inflammatory antioxidant resveratrol significantly attenuated the inflammatory response, by reversing the decline in mitochondrial membrane potential and decreasing the expression of IL-8, COX-2 and PGE2 caused by IL-1β. These findings suggest that IL-1β regulates mitochondrial function in mesothelial cells and that mitochondrial dysfunction could induce an inflammatory scenario that sensitizes these cells, causing significant amplification of the inflammatory response induced by cytokines. Resveratrol may represent a promising strategy in controlling the mesothelial inflammatory response to PD. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative and Nitrosative Stress as a Therapeutic Target in Diseases II)
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19 pages, 15018 KiB  
Article
Antioral Cancer Effects by the Nitrated [6,6,6]Tricycles Compound (SK1) In Vitro
by Yan-Ning Chen, Chieh-Kai Chan, Ching-Yu Yen, Jun-Ping Shiau, Meng-Yang Chang, Cheng-Chung Wang, Jiiang-Huei Jeng, Jen-Yang Tang and Hsueh-Wei Chang
Antioxidants 2022, 11(10), 2072; https://doi.org/10.3390/antiox11102072 - 20 Oct 2022
Cited by 5 | Viewed by 1392
Abstract
A novel nitrated [6,6,6]tricycles-derived compound containing nitro, methoxy, and ispropyloxy groups, namely SK1, was developed in our previous report. However, the anticancer effects of SK1 were not assessed. Moreover, SK1 contains two nitro groups (NO2) and one nitrogen-oxygen (N-O) bond exhibiting [...] Read more.
A novel nitrated [6,6,6]tricycles-derived compound containing nitro, methoxy, and ispropyloxy groups, namely SK1, was developed in our previous report. However, the anticancer effects of SK1 were not assessed. Moreover, SK1 contains two nitro groups (NO2) and one nitrogen-oxygen (N-O) bond exhibiting the potential for oxidative stress generation, but this was not examined. The present study aimed to evaluate the antiproliferation effects and oxidative stress and its associated responses between oral cancer and normal cells. Based on the MTS assay, SK1 demonstrated more antiproliferation ability in oral cancer cells than normal cells, reversed by N-acetylcysteine. This suggests that SK1 causes antiproliferation effects preferentially in an oxidative stress-dependent manner. The oxidative stress-associated responses were further validated, showing higher ROS/MitoSOX burst, MMP, and GSH depletion in oral cancer cells than in normal cells. Meanwhile, SK1 caused oxidative stress-causing apoptosis, such as caspases 3/8/9, and DNA damages, such as γH2AX and 8-OHdG, to a greater extent in oral cancer cells than in normal cells. Siilar to cell viability, these oxidative stress responses were partially diminished by NAC, indicating that SK1 promoted oxidative stress-dependent responses. In conclusion, SK1 exerts oxidative stress, apoptosis, and DNA damage to a greater extent to oral cancer cells than in normal cells. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative and Nitrosative Stress as a Therapeutic Target in Diseases II)
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16 pages, 1936 KiB  
Article
Decreased Levels of GSH Are Associated with Platinum Resistance in High-Grade Serous Ovarian Cancer
by Daniela Criscuolo, Rosario Avolio, Matteo Parri, Simona Romano, Paola Chiarugi, Danilo Swann Matassa and Franca Esposito
Antioxidants 2022, 11(8), 1544; https://doi.org/10.3390/antiox11081544 - 10 Aug 2022
Cited by 10 | Viewed by 2315
Abstract
High-grade serous ovarian cancer (HGSOC) is the most common and aggressive OC histotype. Although initially sensitive to standard platinum-based chemotherapy, most HGSOC patients relapse and become chemoresistant. We have previously demonstrated that platinum resistance is driven by a metabolic shift toward oxidative phosphorylation [...] Read more.
High-grade serous ovarian cancer (HGSOC) is the most common and aggressive OC histotype. Although initially sensitive to standard platinum-based chemotherapy, most HGSOC patients relapse and become chemoresistant. We have previously demonstrated that platinum resistance is driven by a metabolic shift toward oxidative phosphorylation via activation of an inflammatory response, accompanied by reduced cholesterol biosynthesis and increased uptake of exogenous cholesterol. To better understand metabolic remodeling in OC, herein we performed an untargeted metabolomic analysis, which surprisingly showed decreased reduced glutathione (GSH) levels in resistant cells. Accordingly, we found reduced levels of enzymes involved in GSH synthesis and recycling, and compensatory increased expression of thioredoxin reductase. Cisplatin treatment caused an increase of reduced GSH, possibly due to direct binding hindering its oxidation, and consequent accumulation of reactive oxygen species. Notably, expression of the cysteine-glutamate antiporter xCT, which is crucial for GSH synthesis, directly correlates with post-progression survival of HGSOC patients, and is significantly reduced in patients not responding to platinum-based therapy. Overall, our data suggest that cisplatin treatment could positively select cancer cells which are independent from GSH for the maintenance of redox balance, and thus less sensitive to cisplatin-induced oxidative stress, opening new scenarios for the GSH pathway as a therapeutic target in HGSOC. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative and Nitrosative Stress as a Therapeutic Target in Diseases II)
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22 pages, 5017 KiB  
Article
Mitochondrial-Targeted Therapies Require Mitophagy to Prevent Oxidative Stress Induced by SOD2 Inactivation in Hypertrophied Cardiomyocytes
by Victoriane Peugnet, Maggy Chwastyniak, Paul Mulder, Steve Lancel, Laurent Bultot, Natacha Fourny, Edith Renguet, Heiko Bugger, Olivia Beseme, Anne Loyens, Wilfried Heyse, Vincent Richard, Philippe Amouyel, Luc Bertrand, Florence Pinet and Emilie Dubois-Deruy
Antioxidants 2022, 11(4), 723; https://doi.org/10.3390/antiox11040723 - 06 Apr 2022
Cited by 7 | Viewed by 2990
Abstract
Heart failure, mostly associated with cardiac hypertrophy, is a major cause of illness and death. Oxidative stress causes accumulation of reactive oxygen species (ROS), leading to mitochondrial dysfunction, suggesting that mitochondria-targeted therapies could be effective in this context. The purpose of this work [...] Read more.
Heart failure, mostly associated with cardiac hypertrophy, is a major cause of illness and death. Oxidative stress causes accumulation of reactive oxygen species (ROS), leading to mitochondrial dysfunction, suggesting that mitochondria-targeted therapies could be effective in this context. The purpose of this work was to determine whether mitochondria-targeted therapies could improve cardiac hypertrophy induced by mitochondrial ROS. We used neonatal (NCMs) and adult (ACMs) rat cardiomyocytes hypertrophied by isoproterenol (Iso) to induce mitochondrial ROS. A decreased interaction between sirtuin 3 and superoxide dismutase 2 (SOD2) induced SOD2 acetylation on lysine 68 and inactivation, leading to mitochondrial oxidative stress and dysfunction and hypertrophy after 24 h of Iso treatment. To counteract these mechanisms, we evaluated the impact of the mitochondria-targeted antioxidant mitoquinone (MitoQ). MitoQ decreased mitochondrial ROS and hypertrophy in Iso-treated NCMs and ACMs but altered mitochondrial structure and function by decreasing mitochondrial respiration and mitophagy. The same decrease in mitophagy was found in human cardiomyocytes but not in fibroblasts, suggesting a cardiomyocyte-specific deleterious effect of MitoQ. Our data showed the importance of mitochondrial oxidative stress in the development of cardiomyocyte hypertrophy. We observed that targeting mitochondria by MitoQ in cardiomyocytes impaired the metabolism through defective mitophagy, leading to accumulation of deficient mitochondria. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative and Nitrosative Stress as a Therapeutic Target in Diseases II)
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21 pages, 11280 KiB  
Article
LDHB Deficiency Promotes Mitochondrial Dysfunction Mediated Oxidative Stress and Neurodegeneration in Adult Mouse Brain
by Jun Sung Park, Kamran Saeed, Myeung Hoon Jo, Min Woo Kim, Hyeon Jin Lee, Chan-Bae Park, Gwang Lee and Myeong Ok Kim
Antioxidants 2022, 11(2), 261; https://doi.org/10.3390/antiox11020261 - 28 Jan 2022
Cited by 11 | Viewed by 3642
Abstract
Age-related decline in mitochondrial function and oxidative stress plays a critical role in neurodegeneration. Lactate dehydrogenase-B (LDHB) is a glycolytic enzyme that catalyzes the conversion of lactate, an important brain energy substrate, into pyruvate. It has been reported that the LDHB pattern changes [...] Read more.
Age-related decline in mitochondrial function and oxidative stress plays a critical role in neurodegeneration. Lactate dehydrogenase-B (LDHB) is a glycolytic enzyme that catalyzes the conversion of lactate, an important brain energy substrate, into pyruvate. It has been reported that the LDHB pattern changes in the brain during ageing. Yet very little is known about the effect of LDHB deficiency on brain pathology. Here, we have used Ldhb knockout (Ldhb−/−) mice to test the hypothesis that LDHB deficiency plays an important role in oxidative stress-mediated neuroinflammation and neurodegeneration. LDHB knockout (Ldhb−/−) mice were generated by the ablation of the Ldhb gene using the Cre/loxP-recombination system in the C57BL/6 genetic background. The Ldhb−/− mice were treated with either osmotin (15 μg/g of the body; intraperitoneally) or vehicle twice a week for 5-weeks. After behavior assessments, the mice were sacrificed, and the cortical and hippocampal brain regions were analyzed through biochemical and morphological analysis. Ldhb−/− mice displayed enhanced reactive oxygen species (ROS) and lipid peroxidation (LPO) production, and they revealed depleted stores of cellular ATP, GSH:GSSG enzyme ratio, and downregulated expression of Nrf2 and HO-1 proteins, when compared to WT littermates. Importantly, the Ldhb−/− mice showed upregulated expression of apoptosis mediators (Bax, Cytochrome C, and caspase-3), and revealed impaired p-AMPK/SIRT1/PGC-1alpha signaling. Moreover, LDHB deficiency-induced gliosis increased the production of inflammatory mediators (TNF-α, Nf-ĸB, and NOS2), and revealed cognitive deficits. Treatment with osmotin, an adipoR1 natural agonist, significantly increased cellular ATP production by increasing mitochondrial function and attenuated oxidative stress, neuroinflammation, and neuronal apoptosis, probably, by upregulating p-AMPK/SIRT1/PGC-1alpha signaling in Ldhb−/− mice. In brief, LDHB deficiency may lead to brain oxidative stress-mediated progression of neurodegeneration via regulating p-AMPK/SIRT1/PGC-1alpha signaling, while osmotin could improve mitochondrial functions, abrogate oxidative stress and alleviate neuroinflammation and neurodegeneration in adult Ldhb−/− mice. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative and Nitrosative Stress as a Therapeutic Target in Diseases II)
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14 pages, 4395 KiB  
Article
Antioxidants Threaten Multikinase Inhibitor Efficacy against Liver Cancer by Blocking Mitochondrial Reactive Oxygen Species
by Blanca Cucarull, Anna Tutusaus, Tania Hernáez-Alsina, Pablo García de Frutos, María Reig, Anna Colell, Montserrat Marí and Albert Morales
Antioxidants 2021, 10(9), 1336; https://doi.org/10.3390/antiox10091336 - 24 Aug 2021
Cited by 14 | Viewed by 3914
Abstract
Sorafenib and regorafenib, multikinase inhibitors (MKIs) used as standard chemotherapeutic agents for hepatocellular carcinoma (HCC), generate reactive oxygen species (ROS) during cancer treatment. Antioxidant supplements are becoming popular additions to our diet, particularly glutathione derivatives and mitochondrial-directed compounds. To address their possible interference [...] Read more.
Sorafenib and regorafenib, multikinase inhibitors (MKIs) used as standard chemotherapeutic agents for hepatocellular carcinoma (HCC), generate reactive oxygen species (ROS) during cancer treatment. Antioxidant supplements are becoming popular additions to our diet, particularly glutathione derivatives and mitochondrial-directed compounds. To address their possible interference during HCC chemotherapy, we analyzed the effect of common antioxidants using hepatoma cell lines and tumor spheroids. In liver cancer cell lines, sorafenib and regorafenib induced mitochondrial ROS production and potent cell death after glutathione depletion. In contrast, cabozantinib only exhibited oxidative cell death in specific HCC cell lines. After sorafenib and regorafenib administration, antioxidants such as glutathione methyl ester and the superoxide scavenger MnTBAP decreased cell death and ROS production, precluding the MKI activity against hepatoma cells. Interestingly, sorafenib-induced mitochondrial damage caused PINK/Parkin-dependent mitophagy stimulation, altered by increased ROS production. Finally, in sorafenib-treated tumor spheroids, while ROS induction reduced tumor growth, antioxidant treatments favored tumor development. In conclusion, the anti-tumor activity of specific MKIs, such as regorafenib and sorafenib, is altered by the cellular redox status, suggesting that uncontrolled antioxidant intake during HCC treatment should be avoided or only endorsed to diminish chemotherapy-induced side effects, always under medical scrutiny. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative and Nitrosative Stress as a Therapeutic Target in Diseases II)
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15 pages, 2217 KiB  
Communication
Erythropoietin Gene Therapy Delays Retinal Degeneration Resulting from Oxidative Stress in the Retinal Pigment Epithelium
by Manas R. Biswal, Zhaoyao Wang, Ryan J. Paulson, Rukshana R. Uddin, Yao Tong, Ping Zhu, Hong Li and Alfred S. Lewin
Antioxidants 2021, 10(6), 842; https://doi.org/10.3390/antiox10060842 - 25 May 2021
Cited by 8 | Viewed by 3574
Abstract
Erythropoietin (EPO) plays an important role in erythropoiesis by its action in blocking apoptosis of progenitor cells and protects both photoreceptors and retinal ganglion cells from induced or inherited degeneration. A modified form of EPO, EPO-R76E has attenuated erythropoietic activity but is effective [...] Read more.
Erythropoietin (EPO) plays an important role in erythropoiesis by its action in blocking apoptosis of progenitor cells and protects both photoreceptors and retinal ganglion cells from induced or inherited degeneration. A modified form of EPO, EPO-R76E has attenuated erythropoietic activity but is effective in inhibiting apoptosis, oxidative stress, and inflammation in several models of retinal degeneration. In this study, we used recombinant Adeno Associated Virus (AAV) to provide long-term sustained delivery of EPO-R76E and demonstrated its effects in a mouse model of dry-AMD in which retinal degeneration is induced by oxidative stress in the retinal pigment epithelial (RPE) cells. Experimental vector AAV-EPO-R76E and control vector AAV-GFP were packaged into serotype-1 (AAV1) to enable RPE selective expression. RPE oxidative stress-mediated retinal degeneration was induced by exon specific deletion of the protective enzyme MnSOD (encoded by Sod2) by cre/lox mechanism. Experimental mice received subretinal injection of AAV-EPO-R76E in the right eye and AAV-GFP in the left eye. Western blotting of RPE/choroid protein samples from AAV-EPO-R76E injected eyes showed RPE specific EPO expression. Retinal function was monitored by electroretinography (ERG). EPO-R76E over-expression in RPE delayed the retinal degeneration as measured by light microscopy in RPE specific Sod2 knockout mice. Delivery of EPO-R76E vector can be used as a tool to prevent retinal degeneration induced by RPE oxidative stress, which is implicated as a potential cause of Age-Related Macular Degeneration. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative and Nitrosative Stress as a Therapeutic Target in Diseases II)
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