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Oxidative Stress and Mitochondrial Dysfunction in Disease

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (20 October 2022) | Viewed by 25781

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Dr. Claudia von Montfort

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Guest Editor

Heinrich-Heine-University, Medical Faculty, Institute of Biochemistry & Molecular Biology I, Universitaetsstr. 1, 40225 Duesseldorf, Germany
Interests: redox biology; ROS; cancer; antioxidants; melanoma

Prof. Dr. Peter Brenneisen

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Institute of Biochemistry & Molecular Biology I, Medical Faculty, Heinrich-Heine-University, Universitaetsstr. 1, 40225 Duesseldorf, Germany
Interests: cancer; tumor-stroma interactions; reactive oxygen species (ROS); oxidative stress; redox signaling; antioxidants; nanoparticle; nanotherapy/nanomedicine

Special Issue Information

Dear Colleagues,

It has been established that many diseases are caused, or at least accompanied, by an imbalance between pro-oxidants and antioxidants towards pro-oxidants, the so-called oxidative distress. Cause or consequence of such distress is often a mitochondrial dysfunction, displayed in the beginning by a loss of mitochondrial membrane potential and a decrease in ATP production. While an increase in antioxidants and/or antioxidative enzymes finally may maintain a cell’s homeostasis by lowering an increased level of reactive oxygen species (ROS), certain redox-active compounds can be employed to specifically exert a tolerable ROS threshold and thereby induce cell death in, e.g., cancer cells and, in the best case scenario, do not even affect normal (healthy) cells. The mechanisms by which this is achieved may vary from activating certain cellular signaling pathways, including apoptosis and/or autophagy, to redox regulation through reversible oxidation of thiol proteins, affecting not only the regulation of cell death but also metabolic pathways.

We invite you to submit your latest research findings or a review article to this Special Issue, which will bring together current research concerning both oxidants and antioxidants and their role in combatting cancer and other diseases. This research can include both in vitro and in vivo studies relating to any of the following topics: oxidative stress; antioxidants; redox-active compounds, mitochondrial dysfunction; cancer and the role of oxidative stress in signaling, cell metabolism, cellular stress and disease.

We look forward to your contribution.

Dr. Claudia von Montfort
Prof. Dr. Peter Brenneisen
Guest Editors

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Keywords

Oxidative stress
Antioxidants
Redox-active compounds
Redox regulation

Published Papers (9 papers)

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Research

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19 pages, 3863 KiB

Open AccessArticle

The Hepatic Mitochondrial Alterations Exacerbate Meta-Inflammation in Autism Spectrum Disorders

by Giovanna Trinchese, Fabiano Cimmino, Gina Cavaliere, Angela Catapano, Chiara Fogliano, Adriano Lama, Claudio Pirozzi, Claudia Cristiano, Roberto Russo, Lidia Petrella, Rosaria Meli, Giuseppina Mattace Raso, Marianna Crispino, Bice Avallone and Maria Pina Mollica

Antioxidants 2022, 11(10), 1990; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11101990 - 07 Oct 2022

Cited by 10 | Viewed by 2091

Abstract

The role of the liver in autism spectrum disorders (ASD), developmental disabilities characterized by impairments in social interactions and repetitive behavioral patterns, has been poorly investigated. In ASD, it has been shown a dysregulation of gut–brain crosstalk, a communication system able to influence metabolic homeostasis, as well as brain development, mood and cognitive functions. The liver, with its key role in inflammatory and metabolic states, represents the crucial metabolic organ in this crosstalk. Indeed, through the portal vein, the liver receives not only nutrients but also numerous factors derived from the gut and visceral adipose tissue, which modulate metabolism and hepatic mitochondrial functions. Here, we investigated, in an animal model of ASD (BTBR mice), the involvement of hepatic mitochondria in the regulation of inflammatory state and liver damage. We observed increased inflammation and oxidative stress linked to hepatic mitochondrial dysfunction, steatotic hepatocytes, and marked mitochondrial fission in BTBR mice. Our preliminary study provides a better understanding of the pathophysiology of ASD and could open the way to identifying hepatic mitochondria as targets for innovative therapeutic strategies for the disease. Full article

(This article belongs to the Special Issue Oxidative Stress and Mitochondrial Dysfunction in Disease)

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16 pages, 1727 KiB

Open AccessArticle

Artemisinin Targets Transcription Factor PDR1 and Impairs Candida glabrata Mitochondrial Function

by Pan Zhu, Chaoping Yue, Xin Zeng and Xiulai Chen

Antioxidants 2022, 11(10), 1855; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11101855 - 20 Sep 2022

Cited by 6 | Viewed by 1808

Abstract

A limited number of antifungal drugs, the side-effect of clinical drugs and the emergence of resistance create an urgent need for new antifungal treatment agents. High-throughput drug screening and in-depth drug action mechanism analyzation are needed to address this problem. In this study, we identified that artemisinin and its derivatives possessed antifungal activity through a high-throughput screening of the FDA-approved drug library. Subsequently, drug-resistant strains construction, a molecular dynamics simulation and a transcription level analysis were used to investigate artemisinin’s action mechanism in Candida glabrata. Transcription factor pleiotropic drug resistance 1 (PDR1) was an important determinant of artemisinin’s sensitivity by regulating the drug efflux pump and ergosterol biosynthesis pathway, leading to mitochondrial dysfunction. This dysfunction was shown by a depolarization of the mitochondrial membrane potential, an enhancement of the mitochondrial membrane viscosity and an upregulation of the intracellular ROS level in fungi. The discovery shed new light on the development of antifungal agents and understanding artemisinin’s action mechanism. Full article

(This article belongs to the Special Issue Oxidative Stress and Mitochondrial Dysfunction in Disease)

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16 pages, 3569 KiB

Open AccessArticle

Sinularin Induces Oxidative Stress-Mediated Apoptosis and Mitochondrial Dysfunction, and Inhibits Angiogenesis in Glioblastoma Cells

by Shih-Yuan Hsu, Zhi-Hong Wen, Po-Chang Shih, Hsiao-Mei Kuo, Sung-Chun Lin, Hsin-Tzu Liu, Yi-Hsin Lee, Yi-Jen Wang, Wu-Fu Chen and Nan-Fu Chen

Antioxidants 2022, 11(8), 1433; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11081433 - 23 Jul 2022

Cited by 7 | Viewed by 2132

Abstract

Glioblastoma multiforme (GBM) is a cancer of largely unknown cause that leads to a 5-year survival rate of approximately 7% in the United States. Current treatment strategies are not effective, indicating a strong need for the development of novel therapies. In this study, the outcomes of sinularin, a marine-derived product, were evaluated against GBM. Our cellular studies using GBM cells revealed that sinularin induces cell death. The measured half maximal inhibitory concentrations (IC₅₀) values ranged from 30 to 6 μM at 24–72 h. Cell death was induced via the generation of ROS leading to mitochondria-mediated apoptosis. This was evidenced by annexin V/propidium iodine staining and an upregulation of cleaved forms of the pro-apoptotic proteins caspase 9, 3, and PARP, and supported by CellROX^TM Green, MitoSOX^TM Red, and CM-H₂DCFDA staining methods. In addition, we observed a downregulation of the antioxidant enzymes SOD1/2 and thioredoxin. Upon treatment with sinularin at the ~IC₅₀ concentration, mitochondrial respiration capacities were significantly reduced, as shown by measuring the oxygen consumption rates and enzymatic complexes of oxidative phosphorylation. Intriguingly, sinularin significantly inhibited indicators of angiogenesis such as vessel tube formation, cell migration, and cell mobility in human umbilical vein endothelial cells or the fusion cell line EA.Hy926. Lastly, in a transgenic zebrafish model, intersegmental vessel formation was also significantly inhibited by sinularin treatment. These findings indicate that sinularin exerts anti-brain cancer properties that include apoptosis induction but also antiangiogenesis. Full article

(This article belongs to the Special Issue Oxidative Stress and Mitochondrial Dysfunction in Disease)

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15 pages, 3914 KiB

Open AccessArticle

Hydroxytyrosol Promotes the Mitochondrial Function through Activating Mitophagy

by Yanzou Dong, Manhan Yu, Youlin Wu, Tian Xia, Ling Wang, Kai Song, Chunxiao Zhang, Kangle Lu and Samad Rahimnejad

Antioxidants 2022, 11(5), 893; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11050893 - 30 Apr 2022

Cited by 25 | Viewed by 3260

Abstract

Emerging evidence suggests that mitochondrial dysfunction mediates the pathogenesis for non-alcoholic fatty liver disease (NAFLD). Hydroxytyrosol (HT) is a key component of extra virgin olive oil which can exert beneficial effects on NAFLD through modulating mitochondria. However, the mechanism of the impacts of HT still remains elusive. Thus, an in vivo and a series of in vitro experiments were carried out to examine the impacts of hydroxytyrosol (HT) on lipid metabolism and mitochondrial function in fish. For the in vivo experiment, two diets were produced to contain 10% and 16% fat as normal-fat and high-fat diets (NFD and HFD) and two additional diets were prepared by supplementing 200 mg/kg of HT to the NFD and HFD. The test diets were fed to triplicate groups of spotted seabass (Lateolabrax maculatus) juveniles for 8 weeks. The results showed that feeding HFD leads to increased fat deposition in the liver and induces oxidative stress, both of which were ameliorated by HT application. Furthermore, transmission electron microscopy revealed that HFD destroyed mitochondrial cristae and matrix and induced severe hydropic phenotype, while HT administration relieved these alterations. The results of in vitro studies using zebrafish liver cell line (ZFL) showed that HT promotes mitochondrial function and activates PINK1-mediated mitophagy. These beneficial effects of HT disappeared when the cells were treated with cyclosporin A (Csa) as a mitophagy inhibitor. Moreover, the PINK1-mediated mitophagy activation by HT was blocked when compound C (CC) was used as an AMPK inhibitor. In conclusion, our findings demonstrated that HT alleviates fat accumulation, oxidative stress and mitochondrial dysfunction, and its effects are deemed to be mediated via activating mitophagy through the AMPK/PINK1 pathway. Full article

(This article belongs to the Special Issue Oxidative Stress and Mitochondrial Dysfunction in Disease)

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18 pages, 1790 KiB

Open AccessArticle

Enzymatic Depletion of Mitochondrial Inorganic Polyphosphate (polyP) Increases the Generation of Reactive Oxygen Species (ROS) and the Activity of the Pentose Phosphate Pathway (PPP) in Mammalian Cells

by Vedangi Hambardikar, Mariona Guitart-Mampel, Ernest R. Scoma, Pedro Urquiza, Gowda G. A. Nagana, Daniel Raftery, John A. Collins and Maria E. Solesio

Antioxidants 2022, 11(4), 685; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11040685 - 31 Mar 2022

Cited by 16 | Viewed by 2400

Abstract

Inorganic polyphosphate (polyP) is an ancient biopolymer that is well preserved throughout evolution and present in all studied organisms. In mammals, it shows a high co-localization with mitochondria, and it has been demonstrated to be involved in the homeostasis of key processes within the organelle, including mitochondrial bioenergetics. However, the exact extent of the effects of polyP on the regulation of cellular bioenergetics, as well as the mechanisms explaining these effects, still remain poorly understood. Here, using HEK293 mammalian cells under Wild-type (Wt) and MitoPPX (cells enzymatically depleted of mitochondrial polyP) conditions, we show that depletion of polyP within mitochondria increased oxidative stress conditions. This is characterized by enhanced mitochondrial O₂⁻ and intracellular H₂O₂ levels, which may be a consequence of the dysregulation of oxidative phosphorylation (OXPHOS) that we have demonstrated in MitoPPX cells in our previous work. These findings were associated with an increase in basal peroxiredoxin-1 (Prx1), superoxide dismutase-2 (SOD2), and thioredoxin (Trx) antioxidant protein levels. Using ¹³C-NMR and immunoblotting, we assayed the status of glycolysis and the pentose phosphate pathway (PPP) in Wt and MitoPPX cells. Our results show that MitoPPX cells display a significant increase in the activity of the PPP and an increase in the protein levels of transaldolase (TAL), which is a crucial component of the non-oxidative phase of the PPP and is involved in the regulation of oxidative stress. In addition, we observed a trend towards increased glycolysis in MitoPPX cells, which corroborates our prior work. Here, for the first time, we show the crucial role played by mitochondrial polyP in the regulation of mammalian redox homeostasis. Moreover, we demonstrate a significant effect of mitochondrial polyP on the regulation of global cellular bioenergetics in these cells. Full article

(This article belongs to the Special Issue Oxidative Stress and Mitochondrial Dysfunction in Disease)

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15 pages, 1970 KiB

Open AccessArticle

Combined Treatment with Herbal Medicine and Drug Ameliorates Inflammation and Metabolic Abnormalities in the Liver of an Amyotrophic Lateral Sclerosis Mouse Model

by Hee Ra Park and Eun Jin Yang

Antioxidants 2022, 11(1), 173; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11010173 - 17 Jan 2022

Cited by 5 | Viewed by 2215

Abstract

To date, no effective drugs exist for amyotrophic lateral sclerosis (ALS), although riluzole (RZ) and edaravone have been approved for treatment. We previously reported that Bojungikgi-tang (BJIGT) improved motor activity through anti-inflammatory effects in the muscle and spinal cord of hSOD1^G93A mice. Therefore, whether combined treatment with BJIGT and RZ synergistically affects liver function in hSOD1^G93A mice was investigated. Two-month-old male hSOD1^G93A mice were treated with BJIGT (1 mg/g) and RZ (8 μg/g) administered orally for 5 weeks. Drug metabolism and liver function tests of serum and liver homogenates were conducted. mRNA expression levels of cytochrome P450 (CYP) isozymes, inflammatory cytokines, metabolic factors, and mitochondrial oxidative phosphorylation (OXPHOS) subunits were examined using qPCR and Western blotting. Combined administration of BJIGT and RZ did not alter mRNA expression levels of drug-metabolism-related isozymes (CYP1A2 and CYP3A4) but significantly decreased the activity of liver-function-related enzymes (AST, ALT, ALP, and LDH). Increased expression of inflammatory cytokines (IL-1β, TNF-α, and IL-6) and of intracellular stress-related proteins (Bax, AMPKα, JNK, and p38) was reduced by the combined treatment in hSOD1^G93A mice compared to that in control mice. Combined administration reduced the mRNA expression of metabolism-related factors and the expression of OXPHOS subunits. Elevated ATP levels and mitochondrial-fusion-associated protein were decreased after co-administration. Co-administration of BJIGT and RZ did not cause liver damage or toxicity but rather restored liver function in hSOD1^G93A mice. This suggests that this combination can be considered a candidate therapeutic agent for ALS. Full article

(This article belongs to the Special Issue Oxidative Stress and Mitochondrial Dysfunction in Disease)

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15 pages, 1777 KiB

Open AccessArticle

Selenoprotein T Protects Endothelial Cells against Lipopolysaccharide-Induced Activation and Apoptosis

by Dennis Merk, Johannes Ptok, Philipp Jakobs, Florian von Ameln, Jan Greulich, Pia Kluge, Kathrin Semperowitsch, Olaf Eckermann, Heiner Schaal, Niloofar Ale-Agha, Joachim Altschmied and Judith Haendeler

Antioxidants 2021, 10(9), 1427; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10091427 - 07 Sep 2021

Cited by 5 | Viewed by 2239

Abstract

Sepsis is an exaggerated immune response upon infection with lipopolysaccharide (LPS) as the main causative agent. LPS-induced activation and apoptosis of endothelial cells (EC) can lead to organ dysfunction and finally organ failure. We previously demonstrated that the first twenty amino acids of the Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APEX1) are sufficient to inhibit EC apoptosis. To identify genes whose regulation by LPS is affected by this N-terminal APEX1 peptide, EC were transduced with an expression vector for the APEX1 peptide or an empty control vector and treated with LPS. Following RNA deep sequencing, genes upregulated in LPS-treated EC expressing the APEX1 peptide were identified bioinformatically. Selected candidates were validated by semi-quantitative real time PCR, a promising one was Selenoprotein T (SELENOT). For functional analyses, an expression vector for SELENOT was generated. To study the effect of SELENOT expression on LPS-induced EC activation and apoptosis, the SELENOT vector was transfected in EC. Immunostaining showed that SELENOT was expressed and localized in the ER. EC transfected with the SELENOT plasmid showed no activation and reduced apoptosis induced by LPS. SELENOT as well as APEX1(1-20) can protect EC against activation and apoptosis and could provide new therapeutic approaches in the treatment of sepsis. Full article

(This article belongs to the Special Issue Oxidative Stress and Mitochondrial Dysfunction in Disease)

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Review

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19 pages, 928 KiB

Open AccessReview

Is Mitochondrial Oxidative Stress a Viable Therapeutic Target in Preeclampsia?

by Ramana Vaka, Evangeline Deer and Babbette LaMarca

Antioxidants 2022, 11(2), 210; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11020210 - 22 Jan 2022

Cited by 7 | Viewed by 3203

Abstract

Despite considerable research efforts over the past few decades, the pathology of preeclampsia (PE) remains poorly understood with no new FDA-approved treatments. There is a substantial amount of work being conducted by investigators around the world to identify targets to develop therapies for PE. Oxidative stress has been identified as one of the crucial players in pathogenesis of PE and has garnered a great deal of attention by several research groups including ours. While antioxidants have shown therapeutic benefit in preclinical models of PE, the clinical trials evaluating antioxidants (vitamin E and vitamin C) were found to be disappointing. Although the idea behind contribution of mitochondrial oxidative stress in PE is not new, recent years have seen an enormous interest in exploring mitochondrial oxidative stress as an important pathological mediator in PE. We and others using animals, cell models, and preeclamptic patient samples have shown the evidence for placental, renal, and endothelial cell mitochondrial oxidative stress, and its significance in PE. These studies offer promising results; however, the important and relevant question is can we translate these results into clinical efficacy in treating PE. Hence, the purpose of this review is to review the existing literature and offer our insights on the potential of mitochondrial antioxidants in treating PE. Full article

(This article belongs to the Special Issue Oxidative Stress and Mitochondrial Dysfunction in Disease)

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Other

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13 pages, 710 KiB

Open AccessPerspective

Role of Iron in Aging Related Diseases

by William J. Chen, George P. Kung and Jaya P. Gnana-Prakasam

Antioxidants 2022, 11(5), 865; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11050865 - 28 Apr 2022

Cited by 12 | Viewed by 4994

Abstract

Iron progressively accumulates with age and can be further exacerbated by dietary iron intake, genetic factors, and repeated blood transfusions. While iron plays a vital role in various physiological processes within the human body, its accumulation contributes to cellular aging in several species. In its free form, iron can initiate the formation of free radicals at a cellular level and contribute to systemic disorders. This is most evident in high iron conditions such as hereditary hemochromatosis, when accumulation of iron contributes to the development of arthritis, cirrhosis, or cardiomyopathy. A growing body of research has further identified iron’s contributory effects in neurodegenerative diseases, ocular disorders, cancer, diabetes, endocrine dysfunction, and cardiovascular diseases. Reducing iron levels by repeated phlebotomy, iron chelation, and dietary restriction are the common therapeutic considerations to prevent iron toxicity. Chelators such as deferoxamine, deferiprone, and deferasirox have become the standard of care in managing iron overload conditions with other potential applications in cancer and cardiotoxicity. In certain animal models, drugs with iron chelating ability have been found to promote health and even extend lifespan. As we further explore the role of iron in the aging process, iron chelators will likely play an increasingly important role in our health. Full article

(This article belongs to the Special Issue Oxidative Stress and Mitochondrial Dysfunction in Disease)

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