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Mitochondria-Mediated Oxidative Stress in Diseases: Cell Death and Treatment
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Mitochondria-Mediated Oxidative Stress in Diseases: Cell Death and Treatment

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 March 2025 | Viewed by 8133

Special Issue Editor

Prof. Dr. Renata A. Zvyagilskaya

E-Mail Website
Guest Editor
Bach Institute of Biochemistry, Fundamentals of Biotechnology Federal Research Center, Russian Academy of Sciences, Moscow 119071, Russia
Interests: yeast; mitochondria; bioenergetics; mitochondrial dynamics; mitophagy; apoptosis; oxidative stress; yeast models for neurodegenerative pathologies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mitochondria are essential organelles with versatile functions in cellular metabolism. Apart from their best-known function as main producers of energy, they are fully integrated into the cellular metabolism, being crucial for proliferation, cell signal transmission and adaptation to external stressors, in addition to maintaining calcium and redox homeostasis and regulating apoptosis. Mitochondria are the principal organelles responsible for reactive oxygen species (ROS) generation in the cell, with the respiratory chain being a major ROS producer. ROS play a dual role in biological systems. They serve as essential mediators in cell signaling, modifying ion channels and transporters, kinases and the proteasome system and regulating division, development, differentiation, systemic responses, adaptation to stress, interactions with other organisms and cell death. Mild redox stresses can protect an organism from subsequent, more severe stresses and improve metabolism and the immune system, thus prolonging an individual’s lifespan. To highlight positive effects of ROS on cells, the term “oxidative eustress” was introduced as an extension of the initial definition of “oxidative stress”, in contrast to “oxidative distress”, referring to excessive production of ROS, which is largely derived from mitochondrial dysfunction or an imbalance between ROS generation and clearance. Mitochondria-mediated oxidative distress often causes multifarious impairment to cells, thereby leading to the aggravation of many diseases and apoptosis induction. Muscle atrophy and frailty, cardiac disorders, age-related chronic wounds, obesity-related type 2 diabetes, the aging of mtDNA mutator mice, neurodegenerative disorders (Alzheimer’s, Parkinson’s and Huntington’s diseases) and atrophy of thymus epithelial cells are the most likely impacts of mitochondrial ROS (mROS). In cancer cells, mROS production contributes to evolution toward more aggressive phenotypes. Moreover, findings have emerged implicating a fundamental role of mROS in even highly glycolytic cells with relatively low energy requirements and mitochondrial content such as stem cells, epithelia and neutrophils. Fortunately, the most effective mitochondria-targeted (mitochondria-addressed) cationic lipophilic antioxidants are able to ameliorate or even prevent pathologies, contributing to a novel field of study, named “mitotherapy”.

Topics of interest for this Special Issue include the following:

  1. The role of mitochondrial oxidative stress in the pathogenesis of various diseases, including neurodegenerative diseases, cardiovascular diseases, cancer and aging-related diseases.
  2. Therapeutic approaches targeting mitochondrial oxidative stress for the treatment of these diseases, such as mitochondria-targeted antioxidants, mitophagy inducers and mitochondrial biogenesis enhancers.
  3. The role of mitochondrial dynamics and mitochondrial DNA damage in the development and progression of diseases associated with mitochondrial oxidative stress.
  4. The interplay between mitochondrial oxidative stress and other cellular pathways, such as inflammation, autophagy and immune response in the pathogenesis of various diseases.
  5. The identification and validation of novel biomarkers of mitochondrial oxidative stress in the diagnosis, prognosis and therapeutic monitoring of diseases.

This Special Issue, entitled “Mitochondria-Mediated Oxidative Stress in Diseases: Cell Death and Treatment”, aims to highlight and promote the latest scientific achievements in this exciting field, presenting original and update-to-date contributions.

Prof. Dr. Renata A. Zvyagilskaya
Guest Editor

Manuscript Submission Information

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 dysfunction
  • reactive oxygen species
  • oxidative stress
  • mitochondrial biogenesis
  • mitotherapy
  • neurodegenerative diseases
  • cardiovascular diseases
  • cancer
  • biomarkers
  • mitochondrial dynamics

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Published Papers (5 papers)

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Research

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19 pages, 7244 KiB  
Article
Reduction of Mitochondrial Calcium Overload via MKT077-Induced Inhibition of Glucose-Regulated Protein 75 Alleviates Skeletal Muscle Pathology in Dystrophin-Deficient mdx Mice
by Mikhail V. Dubinin, Anastasia E. Stepanova, Irina B. Mikheeva, Anastasia D. Igoshkina, Alena A. Cherepanova, Eugeny Yu. Talanov, Ekaterina I. Khoroshavina and Konstantin N. Belosludtsev
Int. J. Mol. Sci. 2024, 25(18), 9892; https://doi.org/10.3390/ijms25189892 - 13 Sep 2024
Viewed by 1054
Abstract
Duchenne muscular dystrophy is secondarily accompanied by Ca2+ excess in muscle fibers. Part of the Ca2+ accumulates in the mitochondria, contributing to the development of mitochondrial dysfunction and degeneration of muscles. In this work, we assessed the effect of intraperitoneal administration [...] Read more.
Duchenne muscular dystrophy is secondarily accompanied by Ca2+ excess in muscle fibers. Part of the Ca2+ accumulates in the mitochondria, contributing to the development of mitochondrial dysfunction and degeneration of muscles. In this work, we assessed the effect of intraperitoneal administration of rhodacyanine MKT077 (5 mg/kg/day), which is able to suppress glucose-regulated protein 75 (GRP75)-mediated Ca2+ transfer from the sarcoplasmic reticulum (SR) to mitochondria, on the Ca2+ overload of skeletal muscle mitochondria in dystrophin-deficient mdx mice and the concomitant mitochondrial dysfunction contributing to muscle pathology. MKT077 prevented Ca2+ overload of quadriceps mitochondria in mdx mice, reduced the intensity of oxidative stress, and improved mitochondrial ultrastructure, but had no effect on impaired oxidative phosphorylation. MKT077 eliminated quadriceps calcification and reduced the intensity of muscle fiber degeneration, fibrosis level, and normalized grip strength in mdx mice. However, we noted a negative effect of MKT077 on wild-type mice, expressed as a decrease in the efficiency of mitochondrial oxidative phosphorylation, SR stress development, ultrastructural disturbances in the quadriceps, and a reduction in animal endurance in the wire-hanging test. This paper discusses the impact of MKT077 modulation of mitochondrial dysfunction on the development of skeletal muscle pathology in mdx mice. Full article
(This article belongs to the Special Issue Mitochondria-Mediated Oxidative Stress in Diseases: Cell Death and Treatment)
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16 pages, 6393 KiB  
Article
SkQ3 Exhibits the Most Pronounced Antioxidant Effect on Isolated Rat Liver Mitochondria and Yeast Cells
by Anton G. Rogov, Tatyana N. Goleva, Dinara A. Aliverdieva and Renata A. Zvyagilskaya
Int. J. Mol. Sci. 2024, 25(2), 1107; https://doi.org/10.3390/ijms25021107 - 16 Jan 2024
Viewed by 1216
Abstract
Oxidative stress is involved in a wide range of age-related diseases. A critical role has been proposed for mitochondrial oxidative stress in initiating or promoting these pathologies and the potential for mitochondria-targeted antioxidants to fight them, making their search and testing a very [...] Read more.
Oxidative stress is involved in a wide range of age-related diseases. A critical role has been proposed for mitochondrial oxidative stress in initiating or promoting these pathologies and the potential for mitochondria-targeted antioxidants to fight them, making their search and testing a very urgent task. In this study, the mitochondria-targeted antioxidants SkQ1, SkQ3 and MitoQ were examined as they affected isolated rat liver mitochondria and yeast cells, comparing SkQ3 with clinically tested SkQ1 and MitoQ. At low concentrations, all three substances stimulated the oxidation of respiratory substrates in state 4 respiration (no ADP addition); at higher concentrations, they inhibited the ADP-triggered state 3 respiration and the uncoupled state, depolarized the inner mitochondrial membrane, contributed to the opening of the mPTP (mitochondrial permeability transition pore), did not specifically affect ATP synthase, and had a pronounced antioxidant effect. SkQ3 was the most active antioxidant, not possessing, unlike SkQ1 or MitoQ, prooxidant activity with increasing concentrations. In yeast cells, all three substances reduced prooxidant-induced intracellular oxidative stress and cell death and prevented and reversed mitochondrial fragmentation, with SkQ3 being the most efficient. These data allow us to consider SkQ3 as a promising potential therapeutic agent to mitigate pathologies associated with oxidative stress. Full article
(This article belongs to the Special Issue Mitochondria-Mediated Oxidative Stress in Diseases: Cell Death and Treatment)
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17 pages, 2241 KiB  
Article
Dose-Dependent Effect of Mitochondrial Superoxide Dismutase Gene Overexpression on Radioresistance of HEK293T Cells
by Marina M. Tavleeva, Elena E. Rasova, Anna V. Rybak, Elena S. Belykh, Elizaveta A. Fefilova, Elizaveta M. Pnachina and Ilya O. Velegzhaninov
Int. J. Mol. Sci. 2023, 24(24), 17315; https://doi.org/10.3390/ijms242417315 - 10 Dec 2023
Viewed by 1570
Abstract
Over the last two decades, a multitude of gain-of-function studies have been conducted on genes that encode antioxidative enzymes, including one of the key enzymes, manganese superoxide dismutase (SOD2). The results of such studies are often contradictory, as they strongly depend [...] Read more.
Over the last two decades, a multitude of gain-of-function studies have been conducted on genes that encode antioxidative enzymes, including one of the key enzymes, manganese superoxide dismutase (SOD2). The results of such studies are often contradictory, as they strongly depend on many factors, such as the gene overexpression level. In this study, the effect of altering the ectopic expression level of major transcript variants of the SOD2 gene on the radioresistance of HEK293T cells was investigated using CRISPRa technology. A significant increase in cell viability in comparison with the transfection control was detected in cells with moderate SOD2 overexpression after irradiation at 2 Gy, but not at 3 or 5 Gy. A further increase in the level of SOD2 ectopic expression up to 22.5-fold resulted in increased cell viability detectable only after irradiation at 5 Gy. Furthermore, a 15–20-fold increase in SOD2 expression raised the clonogenic survival of cells after irradiation at 5 Gy. Simultaneous overexpression of genes encoding SOD2 and Catalase (CAT) enhanced clonogenic cell survival after irradiation more effectively than separate overexpression of both. In conjunction with the literature data on the suppression of the procarcinogenic effects of superoxide dismutase overexpression by ectopic expression of CAT, the data presented here suggest the potential efficacy of simultaneous overexpression of SOD2 and CAT to reduce oxidative stress occurring in various pathological processes. Moreover, these results illustrate the importance of selecting the degree of SOD2 overexpression to obtain a protective effect. Full article
(This article belongs to the Special Issue Mitochondria-Mediated Oxidative Stress in Diseases: Cell Death and Treatment)
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15 pages, 2974 KiB  
Article
Parkin-Mediated Mitophagy by TGF-β Is Connected with Hepatic Stellate Cell Activation
by Ji Hyun Lee, Kyu Min Kim, Eun Hee Jung, Hye Rim Lee, Ji Hye Yang, Sam Seok Cho and Sung Hwan Ki
Int. J. Mol. Sci. 2023, 24(19), 14826; https://doi.org/10.3390/ijms241914826 - 2 Oct 2023
Cited by 5 | Viewed by 1796
Abstract
Hepatic stellate cells (HSCs) are the main contributors to the development and progression of liver fibrosis. Parkin is an E3 ligase involved in mitophagy mediated by lysosomes that maintains mitochondrial homeostasis. Unfortunately, there is little information regarding the regulation of parkin by transforming [...] Read more.
Hepatic stellate cells (HSCs) are the main contributors to the development and progression of liver fibrosis. Parkin is an E3 ligase involved in mitophagy mediated by lysosomes that maintains mitochondrial homeostasis. Unfortunately, there is little information regarding the regulation of parkin by transforming growth factor-β (TGF-β) and its association with HSC trans-differentiation. This study showed that parkin is upregulated in fibrotic conditions and elucidated the underlying mechanism. Parkin was observed in the cirrhotic region of the patient liver tissues and visualized using immunostaining and immunoblotting of mouse fibrotic liver samples and primary HSCs. The role of parkin-mediated mitophagy in hepatic fibrogenesis was examined using TGF-β-treated LX-2 cells with mitophagy inhibitor, mitochondrial division inhibitor 1. Parkin overexpression and its colocalization with desmin in human tissues were found. Increased parkin in fibrotic liver homogenates of mice was observed. Parkin was expressed more abundantly in HSCs than in hepatocytes and was upregulated under TGF-β. TGF-β-induced parkin was due to Smad3. TGF-β facilitated mitochondrial translocation, leading to mitophagy activation, reversed by mitophagy inhibitor. However, TGF-β did not change mitochondrial function. Mitophagy inhibitor suppressed profibrotic genes and HSC migration mediated by TGF-β. Collectively, parkin-involved mitophagy by TGF-β facilitates HSC activation, suggesting mitophagy may utilize targets for liver fibrosis. Full article
(This article belongs to the Special Issue Mitochondria-Mediated Oxidative Stress in Diseases: Cell Death and Treatment)
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Review

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13 pages, 967 KiB  
Review
Subcellular Effectors of Cocaine Cardiotoxicity: All Roads Lead to Mitochondria—A Systematic Review of the Literature
by Michela Peruch, Emiliana Giacomello, Davide Radaelli, Monica Concato, Riccardo Addobbati, Alessandra Lucia Fluca, Aneta Aleksova and Stefano D’Errico
Int. J. Mol. Sci. 2023, 24(19), 14517; https://doi.org/10.3390/ijms241914517 - 25 Sep 2023
Viewed by 1625
Abstract
Cocaine abuse is a serious public health problem as this drug exerts a plethora of functional and histopathological changes that potentially lead to death. Cocaine causes complex multiorgan toxicity, including in the heart where the blockade of the sodium channels causes increased catecholamine [...] Read more.
Cocaine abuse is a serious public health problem as this drug exerts a plethora of functional and histopathological changes that potentially lead to death. Cocaine causes complex multiorgan toxicity, including in the heart where the blockade of the sodium channels causes increased catecholamine levels and alteration in calcium homeostasis, thus inducing an increased oxygen demand. Moreover, there is evidence to suggest that mitochondria alterations play a crucial role in the development of cocaine cardiotoxicity. We performed a systematic review according to the Preferred Reporting Items for Systemic Reviews and Meta-Analysis (PRISMA) scheme to evaluate the mitochondrial mechanisms determining cocaine cardiotoxicity. Among the initial 106 articles from the Pubmed database and the 17 articles identified through citation searching, 14 final relevant studies were extensively reviewed. Thirteen articles included animal models and reported the alteration of specific mitochondria-dependent mechanisms such as reduced energy production, imbalance of membrane potential, increased oxidative stress, and promotion of apoptosis. However, only one study evaluated human cocaine overdose samples and observed the role of cocaine in oxidative stress and the induction of apoptosis though mitochondria. Understanding the complex processes mediated by mitochondria through forensic analysis and experimental models is crucial for identifying potential therapeutic targets to mitigate or reverse cocaine cardiotoxicity in humans. Full article
(This article belongs to the Special Issue Mitochondria-Mediated Oxidative Stress in Diseases: Cell Death and Treatment)
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