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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "ROS, RNS and RSS".

Deadline for manuscript submissions: closed (15 April 2019) | Viewed by 60785

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Prof. Dr. Dmitry B. Zorov

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Guest Editor

A.N.Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119991, Russia
Interests: mitochondria; bioenergetics; redox; reactive opxygen species; ATP synthase; respiration; phosphorylation; membranes; kidney; brain; cell death; protection
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Egor Yu. Plotnikov

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Guest Editor

A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia
Interests: acute kidney injury; renal progenitor cells; mitochondria; mesenchymal stromal cells; inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mitochondria are believed to be the main reactive oxygen species (ROS) source in a wide spectrum of diseases and pathologies, from cardiovascular conditions like stroke and myocardiac infarction to Parkinson’s disease, Alzheimer’s disease, diabetes, and even cancer. This makes them promising targets for pharmaceutical intervention. Furthermore, ROS are essential signaling molecules needed for normal cell physiology, while excessive amounts of ROS should be targeted and neutralized.

Mitochondria-targeted antioxidants provide one of the means to at least partially solve this problem. Since they are directed to the major site of cellular ROS production, their side effects on “signaling ROS” are noticeably reduced, and their therapeutic concentrations could be much lower than those of general antioxidants.

Recently, several types of mitochondria-targeted antioxidants have been developed. Many of them are permeable ions which carry a lipophilic delocalized positive charge, while others have an SS-type mitochondria-targeting peptide, and some use channel-forming compounds to permeabilize the mitochondrial membrane. An antioxidant moiety is also different among these substances: they can carry ROS-scavenging compounds, iron chelators, and mitochondria-targeted antioxidant enzymes such as catalase.

Mitochondria-targeted antioxidants have already been shown to bear a therapeutic effect on Parkinson's and Alzheimer's diseases, type 2 diabetes, hypertension, sepsis, acute bacterial infection as well as diseases caused by xenobiotics, toxic chemicals or irradiation. However, we still need to clarify a number of issues: Should we specifically target mitochondria or not? Do we want to target the mitochondrial matrix or the membrane? What principle of ROS neutralization should be used? Whether we should target chemical or signaling effect of ROS. The purpose of this Special Issue is to bring together our current knowledge of the impact of mitochondria-targeted antioxidants on treatment of different pathologies and diseases. We would like to highlight on the future perspectives and challenges for such antioxidants to overcome their limitations in clinical practice as one of the most universal and promising approaches for treatment of diseases without hiding their adverse effects.

The editors of this Special Issue invite researchers in the field to contribute original research papers and review articles on the subject to this ambitious task.

Prof. Dr. Dmitry B. Zorov
Prof. Dr. Egor Yu. Plotnikov
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

mitochondria
reactive oxygen species
oxidative stress
aging
ischemia
inflammation

Published Papers (10 papers)

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Editorial

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6 pages, 182 KiB

Open AccessEditorial

Pros and Cons of Use of Mitochondria-Targeted Antioxidants

by Egor Y. Plotnikov and Dmitry B. Zorov

Antioxidants 2019, 8(8), 316; https://doi.org/10.3390/antiox8080316 - 17 Aug 2019

Cited by 22 | Viewed by 4541

Abstract

Mitochondrial targeting is a novel strategy, which addresses pathologies originating from mitochondrial dysfunction. Here, one of the most potent therapeutics arises from the group of mitochondria-targeted antioxidants, which specifically quench mitochondrial reactive oxygen species (ROS). They show very high efficacy in the treatment of a diverse array of pathologies encountered in this Special Issue of Antioxidants. However, despite very encouraging results in the use of mitochondria-targeted antioxidants, the mechanistic principle of delivering these agents is, to some extent, counterproductive to the goal of selectively treating a population of damaged mitochondria. The main problem that arises is that injured mitochondria may carry a lower membrane potential when compared with normal ones and as a result, injured mitochondria are capable of taking up less therapeutic antioxidants than healthy mitochondria. Another problem is that the intracellular activity of mitochondrial ROS differs from cytosolic ROS in that they carry specific intracellular functions which are maintained at a delicate equilibrium and which may be disturbed under careless use of antioxidant doses. Consequently, understanding the overall benefit of targeting dysfunctional mitochondria in pathological tissue requires furthering the development of alternative techniques to target mitochondria. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Antioxidants)

Research

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15 pages, 3101 KiB

Open AccessArticle

Melatonin Prevents Oxidative Stress-Induced Mitochondrial Dysfunction and Apoptosis in High Glucose-Treated Schwann Cells via Upregulation of Bcl2, NF-κB, mTOR, Wnt Signalling Pathways

by Yee Lian Tiong, Khuen Yen Ng, Rhun Yian Koh, Gnanajothy Ponnudurai and Soi Moi Chye

Antioxidants 2019, 8(7), 198; https://doi.org/10.3390/antiox8070198 - 26 Jun 2019

Cited by 48 | Viewed by 5090

Abstract

Neuropathy is a complication that affects more than 50% of long-standing diabetic patients. One of the causes of diabetes neuropathy (DN) is the apoptosis of Schwann cells due to prolonged exposure to high glucose and build-up of oxidative stress. Melatonin is a hormone that has a known antioxidant property. In this study, we investigated the protective effect of melatonin on high glucose-induced Schwann cells’ apoptosis. Our results revealed that high glucose promoted apoptosis via mitochondrial-related oxidative stress and downregulated Bcl-2 family proteins in Schwann cells. In this signalling pathway, Bcl-2, Bcl-XL and Mcl-1 proteins were down-regulated while p-BAD and Puma proteins were up-regulated by high glucose treatment. Besides, we also proved that high glucose promoted apoptosis in Schwann cells through decreasing the p-NF-κB in the NF-κB signalling pathway. Key regulators of mTOR signalling pathway such as p-mTOR, Rictor and Raptor were also down-regulated after high glucose treatment. Additionally, high glucose treatment also decreased the Wnt signalling pathway downstream proteins (Wnt 5a/b, p-Lrp6 and Axin). Our results showed that melatonin treatment significantly inhibited high glucose-induced ROS generation, restored mitochondrial membrane potential and inhibited high glucose-induced apoptosis in Schwann cells. Furthermore, melatonin reversed the alterations of protein expression caused by high glucose treatment. Our results concluded that melatonin alleviates high glucose-induced apoptosis in Schwann cells through mitigating mitochondrial-related oxidative stress and the alterations of Bcl-2, NF-κB, mTOR and Wnt signalling pathways. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Antioxidants)

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16 pages, 2129 KiB

Open AccessArticle

Interaction of Potent Mitochondrial Uncouplers with Thiol-Containing Antioxidants

by Ljudmila S. Khailova, Alexander M. Firsov, Elena A. Kotova and Yuri N. Antonenko

Antioxidants 2019, 8(6), 194; https://doi.org/10.3390/antiox8060194 - 23 Jun 2019

Cited by 10 | Viewed by 3825

Abstract

It is generally considered that reactive oxygen species (ROS) are involved in the development of numerous pathologies. The level of ROS can be altered via the uncoupling of oxidative phosphorylation by using protonophores causing mitochondrial membrane depolarization. Here, we report that the uncoupling activity of potent protonophores, such as carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), carbonyl cyanide 3-chlorophenylhydrazone (CCCP), and fluazinam, can be abrogated by the addition of thiol-containing antioxidants to isolated mitochondria. In particular, N-acetylcysteine, glutathione, cysteine, and dithiothreitol removed both a decrease in the mitochondrial membrane potential and an increase in the respiration rate that is caused by FCCP. The thiols also reduced the electrical current that is induced by FCCP and CCCP across planar bilayer lipid membranes. Thus, when speculating on the mechanistic roles of ROS level modulation by mitochondrial uncoupling based on the antioxidant reversing certain FCCP and CCCP effects on cellular processes, one should take into account the ability of these protonophoric uncouplers to directly interact with the thiol-containing antioxidants. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Antioxidants)

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13 pages, 2326 KiB

Open AccessArticle

Suppression of AMD-Like Pathology by Mitochondria-Targeted Antioxidant SkQ1 Is Associated with a Decrease in the Accumulation of Amyloid β and in mTOR Activity

by Natalia A. Muraleva, Oyuna S. Kozhevnikova, Anzhela Z. Fursova and Nataliya G. Kolosova

Antioxidants 2019, 8(6), 177; https://doi.org/10.3390/antiox8060177 - 14 Jun 2019

Cited by 21 | Viewed by 4191

Abstract

Age-related macular degeneration (AMD) is a major cause of irreversible visual impairment and blindness in developed countries, and the molecular pathogenesis of AMD is poorly understood. Recent studies strongly indicate that amyloid β (Aβ) accumulation —found in the brain and a defining feature of Alzheimer’s disease—also forms in the retina in both Alzheimer’s disease and AMD. The reason why highly neurotoxic proteins of consistently aggregate in the aging retina, and to what extent they contribute to AMD, remains to be fully addressed. Nonetheless, the hypothesis that Aβ is a therapeutic target in AMD is debated. Here, we showed that long-term treatment with SkQ1 (250 nmol/[kg body weight] daily from the age of 1.5 to 22 months) suppressed the development of AMD-like pathology in senescence-accelerated OXYS rats by reducing the level of Aβ and suppressing the activity of mTOR in the retina. Inhibition of mTOR signaling activity, which plays key roles in aging and age-related diseases, can be considered a new mechanism of the prophylactic effect of SkQ1. It seems probable that dietary supplementation with mitochondria-targeted antioxidant SkQ1 can be a good prevention strategy to maintain eye health and possibly a treatment of AMD. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Antioxidants)

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13 pages, 10109 KiB

Open AccessArticle

Mitochondrial Damage and Mitochondria-Targeted Antioxidant Protection in LPS-Induced Acute Kidney Injury

by Egor Y. Plotnikov, Irina B. Pevzner, Ljubava D. Zorova, Valery P. Chernikov, Andrey N. Prusov, Igor I. Kireev, Denis N. Silachev, Vladimir P. Skulachev and Dmitry B. Zorov

Antioxidants 2019, 8(6), 176; https://doi.org/10.3390/antiox8060176 - 14 Jun 2019

Cited by 56 | Viewed by 7002

Abstract

Induced and frequently unwanted alterations in the mitochondrial structure and functions are a key component of the pathological cascade in many kidney pathologies, including those associated with acute damage. One of the principal pathogenic elements causing mitochondrial dysfunction in Acute Kidney Injury (AKI) is oxidative stress. After ischemia and nephrotoxic action of drugs, sepsis and systemic inflammation are the most frequent causes of AKI. As the kidney suffers from oxidative stress during sepsis, one of the most promising approaches to alleviate such damaging consequences is the use of antioxidants. Considering administration of lipopolysaccharide (LPS) as a model of sepsis, we demonstrate that the mitochondria of neonatal renal tissue are severely affected by LPS-induced AKI, with pathological ultrastructural changes observed in both the mitochondria of the renal tubular epithelium and the vascular endothelium. Upon mitochondrial damage, we evaluated the effect of the mitochondria-targeted antioxidant plastoquinol decylrhodamine 19 (SkQR1) on the development of acute renal failure in newborn rats associated with systemic inflammation induced by the administration of LPS. We found that SkQR1 administration 3 h before LPS led to decreased urinal expression of the AKI marker neutrophil gelatinase-associated lipocalin 2 (NGAL), in addition to a decrease in urea and creatinine levels in the blood. Additionally, an observed impairment of proliferative activity in the neonatal kidney caused by LPS treatment was also prevented by the treatment of rat pups with SkQR1. Thus, one of the key events for renal tissue damage in neonatal sepsis is an alteration in the structure and function of the mitochondria and the mitochondria-targeted antioxidant SkQR1 is an effective nephroprotective agent, which protects the neonatal kidney from sepsis-induced AKI. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Antioxidants)

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17 pages, 4785 KiB

Open AccessArticle

Protective Effect of Glutathione against Oxidative Stress-induced Cytotoxicity in RAW 264.7 Macrophages through Activating the Nuclear Factor Erythroid 2-Related Factor-2/Heme Oxygenase-1 Pathway

by Da Hye Kwon, Hee-Jae Cha, Hyesook Lee, Su-Hyun Hong, Cheol Park, Shin-Hyung Park, Gi-Young Kim, Suhkmann Kim, Heui-Soo Kim, Hye-Jin Hwang and Yung Hyun Choi

Antioxidants 2019, 8(4), 82; https://doi.org/10.3390/antiox8040082 - 01 Apr 2019

Cited by 78 | Viewed by 7119

Abstract

Reactive oxygen species (ROS), products of oxidative stress, contribute to the initiation and progression of the pathogenesis of various diseases. Glutathione is a major antioxidant that can help prevent the process through the removal of ROS. The aim of this study was to evaluate the protective effect of glutathione on ROS-mediated DNA damage and apoptosis caused by hydrogen peroxide, H₂O₂, in RAW 264.7 macrophages and to investigate the role of the nuclear factor erythroid 2-related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. The results showed that the decrease in the survival rate of RAW 264.7 cells treated with H₂O₂ was due to the induction of DNA damage and apoptosis accompanied by the increased production of ROS. However, H₂O₂-induced cytotoxicity and ROS generation were significantly reversed by glutathione. In addition, the H₂O₂-induced loss of mitochondrial membrane potential was related to a decrease in adenosine triphosphate (ATP) levels, and these changes were also significantly attenuated in the presence of glutathione. These protective actions were accompanied by a increase in the expression rate of B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X protein (Bax) and poly(ADP-ribose) polymerase cleavage by the inactivation of caspase-3. Moreover, glutathione-mediated cytoprotective properties were associated with an increased activation of Nrf2 and expression of HO-1; however, the inhibition of the HO-1 function using an HO-1 specific inhibitor, zinc protoporphyrin IX, significantly weakened the cytoprotective effects of glutathione. Collectively, the results demonstrate that the exogenous administration of glutathione is able to protect RAW 264.7 cells against oxidative stress-induced mitochondria-mediated apoptosis along with the activity of the Nrf2/HO-1 signaling pathway. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Antioxidants)

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17 pages, 2412 KiB

Open AccessArticle

Suppression of Light-Induced Oxidative Stress in the Retina by Mitochondria-Targeted Antioxidant

by Viktoriia E. Baksheeva, Veronika V. Tiulina, Natalia K. Tikhomirova, Olga S. Gancharova, Sergey V. Komarov, Pavel P. Philippov, Andrey A. Zamyatnin, Jr., Ivan I. Senin and Evgeni Yu. Zernii

Antioxidants 2019, 8(1), 3; https://doi.org/10.3390/antiox8010003 - 21 Dec 2018

Cited by 32 | Viewed by 4555

Abstract

Light-induced oxidation of lipids and proteins provokes retinal injuries and results in progression of degenerative retinal diseases, such as, for instance, iatrogenic photic maculopathies. Having accumulated over years retinal injuries contribute to development of age-related macular degeneration (AMD). Antioxidant treatment is regarded as a promising approach to protecting the retina from light damage and AMD. Here, we examine oxidative processes induced in rabbit retina by excessive light illumination with or without premedication using mitochondria-targeted antioxidant SkQ1 (10-(6’-plastoquinonyl)decyltriphenyl-phosphonium). The retinal extracts obtained from animals euthanized within 1–7 days post exposure were analyzed for H₂O₂, malondialdehyde (MDA), total antioxidant activity (AOA), and activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD) using colorimetric and luminescence assays. Oxidation of visual arrestin was monitored by immunoblotting. The light exposure induced lipid peroxidation and H₂O₂ accumulation in the retinal cells. Unexpectedly, it prominently upregulated AOA in retinal extracts although SOD and GPx activities were compromised. These alterations were accompanied by accumulation of disulfide dimers of arrestin revealing oxidative stress in the photoreceptors. Premedication of the eyes with SkQ1 accelerated normalization of H₂O₂ levels and redox-status of lipids and proteins, contemporarily enhancing AOA and, likely, sustaining normal activity of GPx. Thus, SkQ1 protects the retina from light-induced oxidative stress and could be employed to suppress oxidative damage of proteins and lipids contributing to AMD. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Antioxidants)

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Review

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14 pages, 1160 KiB

Open AccessReview

Physiologic Implications of Reactive Oxygen Species Production by Mitochondrial Complex I Reverse Electron Transport

by John O. Onukwufor, Brandon J. Berry and Andrew P. Wojtovich

Antioxidants 2019, 8(8), 285; https://doi.org/10.3390/antiox8080285 - 06 Aug 2019

Cited by 62 | Viewed by 9549

Abstract

Mitochondrial reactive oxygen species (ROS) can be either detrimental or beneficial depending on the amount, duration, and location of their production. Mitochondrial complex I is a component of the electron transport chain and transfers electrons from NADH to ubiquinone. Complex I is also a source of ROS production. Under certain thermodynamic conditions, electron transfer can reverse direction and reduce oxygen at complex I to generate ROS. Conditions that favor this reverse electron transport (RET) include highly reduced ubiquinone pools, high mitochondrial membrane potential, and accumulated metabolic substrates. Historically, complex I RET was associated with pathological conditions, causing oxidative stress. However, recent evidence suggests that ROS generation by complex I RET contributes to signaling events in cells and organisms. Collectively, these studies demonstrate that the impact of complex I RET, either beneficial or detrimental, can be determined by the timing and quantity of ROS production. In this article we review the role of site-specific ROS production at complex I in the contexts of pathology and physiologic signaling. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Antioxidants)

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19 pages, 1005 KiB

Open AccessReview

Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: A Systematic Review

by Chisato Fujimoto and Tatsuya Yamasoba

Antioxidants 2019, 8(4), 109; https://doi.org/10.3390/antiox8040109 - 24 Apr 2019

Cited by 68 | Viewed by 6577

Abstract

Mitochondrial dysfunction is associated with the etiologies of sensorineural hearing loss, such as age-related hearing loss, noise- and ototoxic drug-induced hearing loss, as well as hearing loss due to mitochondrial gene mutation. Mitochondria are the main sources of reactive oxygen species (ROS) and ROS-induced oxidative stress is involved in cochlear damage. Moreover, the release of ROS causes further damage to mitochondrial components. Antioxidants are thought to counteract the deleterious effects of ROS and thus, may be effective for the treatment of oxidative stress-related diseases. The administration of mitochondria-targeted antioxidants is one of the drug delivery systems targeted to mitochondria. Mitochondria-targeted antioxidants are expected to help in the prevention and/or treatment of diseases associated with mitochondrial dysfunction. Of the various mitochondria-targeted antioxidants, the protective effects of MitoQ and SkQR1 against ototoxicity have been previously evaluated in animal models and/or mouse auditory cell lines. MitoQ protects against both gentamicin- and cisplatin-induced ototoxicity. SkQR1 also provides auditory protective effects against gentamicin-induced ototoxicity. On the other hand, decreasing effect of MitoQ on gentamicin-induced cell apoptosis in auditory cell lines has been controversial. No clinical studies have been reported for otoprotection using mitochondrial-targeted antioxidants. High-quality clinical trials are required to reveal the therapeutic effect of mitochondria-targeted antioxidants in terms of otoprotection in patients. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Antioxidants)

Other

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7 pages, 802 KiB

Open AccessPerspective

Mitochondria-Targeted Antioxidants as Potential Therapy for the Treatment of Traumatic Brain Injury

by Elena V. Stelmashook, Nickolay K. Isaev, Elisaveta E. Genrikhs and Svetlana V. Novikova

Antioxidants 2019, 8(5), 124; https://doi.org/10.3390/antiox8050124 - 08 May 2019

Cited by 18 | Viewed by 6650

Abstract

The aim of this article is to review the publications describing the use of mitochondria-targeted antioxidant therapy after traumatic brain injury (TBI). Recent works demonstrated that mitochondria-targeted antioxidants are very effective in reducing the negative effects associated with the development of secondary damage caused by TBI. Using various animal models of TBI, mitochondria-targeted antioxidants were shown to prevent cardiolipin oxidation in the brain and neuronal death, as well as to markedly reduce behavioral deficits and cortical lesion volume, brain water content, and DNA damage. In the future, not only a more detailed study of the mechanisms of action of various types of such antioxidants needs to be conducted, but also their therapeutic values and toxicological properties are to be determined. Moreover, the optimal therapeutic effect needs to be achieved in the shortest time possible from the onset of damage to the nervous tissue, since secondary brain damage in humans can develop for a long time, days and even months, depending on the severity of the damage. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Antioxidants)

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