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Antioxidants
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Targeting Antioxidants to Mitochondria: A Novel Therapeutic Direction
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Targeting Antioxidants to Mitochondria: A Novel Therapeutic Direction

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 July 2023) | Viewed by 14293

Special Issue Editors

Prof. Dr. Mariano Stornaiuolo

E-Mail Website
Guest Editor
Department of Pharmacy, University of Naples Federico II, Via Montesano 49, 80149 Naples, Italy
Interests: mechanism of action of antioxidants; interaction food and genes; cell biology; nutraceuticals; food supplements; metabolic syndrome
Special Issues, Collections and Topics in MDPI journals
Dr. Giuseppe Annunziata

E-Mail Website
Guest Editor
Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
Interests: food science; nutraceutical; nutrition; metabolism; polyphenols; antioxidants; oxidative stress; inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The spectrum disorder of mitochondrial diseases (MDs) includes a large number of rare diseases that share an impairment of ATP production as their main feature. Clinically, MDs are reflected in multi-organ diseases, including cardiovascular, musculoskeletal and metabolic diseases (such as type 2 diabetes mellitus and dyslipidaemia).

Notably, a close relationship between MDs and oxidative stress (OxS) has been described. OxS is defined as an imbalance between the production and elimination of oxidants, mainly reactive oxygen species (ROS) (including •OH, O2•−, HO2•, and ROO•) and oxygen nitrogen species (RSN) (including NO• and •ONOO). In physiological conditions, ROS/RSN are involved as signalling molecules in various biological processes, including cell proliferation, programmed cell death and gene expression. On the contrary, when levels of ROS/RSN increase progressively and chronically, biomolecules are damaged, triggering pathophysiological alteration and finally culminating in the development of chronic and chronic-degenerative diseases. However, whether oxidants increase within certain limits, by switching on the biology resolution pathway, cells are able to counteract OxS via the activation of endogenous antioxidant systems, including enzymes (i.e., catalase, superoxide dismutase, lactoperoxidase and glutathione peroxidase) acting as free radical scavengers.

A huge amount of evidence suggests exogenous antioxidants can be used to contrast OxS and manage OxS-related diseases. In general, antioxidants act through two major levels: (i) directly, as ROS-scavenging agents and modulators of the endogenous antioxidant defences and (ii) indirectly, via the inhibition of both the metal-dependent production of free radicals and ROS-producing enzymes. In this sense, a great amount of interest was focused on the ability of antioxidants (in particular polyphenols) to enhance the activity of antioxidant enzymes. This is mainly due to the up-regulation of their gene expression via the activation of different signalling pathways, including the Keap1/Nrf2/ARE and Sirt1 pathways.

Based on this evidence, antioxidants are promising novel therapeutical approaches for the management of OxS related to MDs.

The present Special Issue welcomes the submission of papers either describing original research (in vitro, ex vivo and animal-based studies or clinical trials) or scientific literature reviews (including narrative reviews, systematic reviews, meta-analyses and opinion papers) covering novel insights on the effects of antioxidants in managing MDs. Papers describing novel mechanisms of action/targets will be profoundly appreciated.

Prof. Dr. Mariano Stornaiuolo
Dr. Giuseppe Annunziata
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
  • oxidative stress
  • ROS
  • RNS
  • antioxidants
  • chronic diseases

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Published Papers (5 papers)

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16 pages, 2160 KiB  
Article
Uncovering the Early Events Associated with Oligomeric Aβ-Induced Src Activation
by Sandra I. Mota, Lígia Fão, Patrícia Coelho and A. Cristina Rego
Antioxidants 2023, 12(9), 1770; https://doi.org/10.3390/antiox12091770 - 16 Sep 2023
Cited by 2 | Viewed by 1651
Abstract
Soluble Aβ1–42 oligomers (AβO) are formed in the early stages of Alzheimer’s disease (AD) and were previously shown to trigger enhanced Ca2+ levels and mitochondrial dysfunction via the activation of N-methyl-D-aspartate receptors (NMDAR). Src kinase is a ubiquitous redox-sensitive non-receptor [...] Read more.
Soluble Aβ1–42 oligomers (AβO) are formed in the early stages of Alzheimer’s disease (AD) and were previously shown to trigger enhanced Ca2+ levels and mitochondrial dysfunction via the activation of N-methyl-D-aspartate receptors (NMDAR). Src kinase is a ubiquitous redox-sensitive non-receptor tyrosine kinase involved in the regulation of several cellular processes, which was demonstrated to have a reciprocal interaction towards NMDAR activation. However, little is known about the early-stage mechanisms associated with AβO-induced neurodysfunction involving Src. Thus, in this work, we analysed the influence of brief exposure to oligomeric Aβ1–42 on Src activation and related mechanisms involving mitochondria and redox changes in mature primary rat hippocampal neurons. Data show that brief exposure to AβO induce H2O2-dependent Src activation involving different cellular events, including NMDAR activation and mediated intracellular Ca2+ rise, enhanced cytosolic and subsequent mitochondrial H2O2 levels, accompanied by mild mitochondrial fragmentation. Interestingly, these effects were prevented by Src inhibition, suggesting a feedforward modulation. The current study supports a relevant role for Src kinase activation in promoting the loss of postsynaptic glutamatergic synapse homeostasis involving cytosolic and mitochondrial ROS generation after brief exposure to AβO. Therefore, restoring Src activity can constitute a protective strategy for mitochondria and related hippocampal glutamatergic synapses. Full article
(This article belongs to the Special Issue Targeting Antioxidants to Mitochondria: A Novel Therapeutic Direction)
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15 pages, 5381 KiB  
Article
Ginsenoside Rc, an Active Component of Panax ginseng, Alleviates Oxidative Stress-Induced Muscle Atrophy via Improvement of Mitochondrial Biogenesis
by Aeyung Kim, Sang-Min Park, No Soo Kim and Haeseung Lee
Antioxidants 2023, 12(8), 1576; https://doi.org/10.3390/antiox12081576 - 7 Aug 2023
Cited by 7 | Viewed by 2467
Abstract
Loss of skeletal muscle mass and function has detrimental effects on quality of life, morbidity, and mortality, and is particularly relevant in aging societies. The enhancement of mitochondrial function has shown promise in promoting muscle differentiation and function. Ginsenoside Rc (gRc), a major [...] Read more.
Loss of skeletal muscle mass and function has detrimental effects on quality of life, morbidity, and mortality, and is particularly relevant in aging societies. The enhancement of mitochondrial function has shown promise in promoting muscle differentiation and function. Ginsenoside Rc (gRc), a major component of ginseng, has various pharmacological activities; however, its effect on muscle loss remains poorly explored. In this study, we examined the effects of gRc on the hydrogen peroxide (H2O2)-induced reduction of cell viability in C2C12 myoblasts and myotubes and H2O2-induced myotube degradation. In addition, we investigated the effects of gRc on the production of intracellular reactive oxygen species (ROS) and mitochondrial superoxide, ATP generation, and peroxisome proliferator-activated receptor-gamma co-activator 1α (PGC-1α) activity in myoblasts and myotubes under H2O2 treatment. Furthermore, to elucidate the mechanism of action of gRc, we conducted a transcriptome analysis of myotubes treated with or without gRc under H2O2 treatment. gRc effectively suppressed H2O2-induced cytotoxicity, intracellular ROS, and mitochondrial superoxide production, restored PGC-1α promoter activity, and increased ATP synthesis. Moreover, gRc significantly affected the expression levels of genes involved in maintaining mitochondrial mass and biogenesis, while downregulating genes associated with muscle degradation in C2C12 myotubes under oxidative stress. We provide compelling evidence supporting the potential of gRc as a promising treatment for muscle loss and weakness. Further investigations of the pharmacological effects of gRc under various pathological conditions of muscle loss will contribute to the clinical development of gRc as a therapeutic intervention. Full article
(This article belongs to the Special Issue Targeting Antioxidants to Mitochondria: A Novel Therapeutic Direction)
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12 pages, 3951 KiB  
Article
Trehalose Inhibits Inflammatory Responses through Mitochondrial Reprogramming in RAW 264.7 Macrophages
by Seungmin Yu, Hyejeong Park and Wooki Kim
Antioxidants 2023, 12(6), 1166; https://doi.org/10.3390/antiox12061166 - 28 May 2023
Cited by 5 | Viewed by 2615
Abstract
Studies reported the beneficial effects of trehalose on metabolic syndromes, hyperlipidemia, and autophagy, but its action mechanisms are still poorly understood. Even though trehalose is digested by disaccharidase and absorbed in the intestine, intact molecules encounter immune cells which form a solid balance [...] Read more.
Studies reported the beneficial effects of trehalose on metabolic syndromes, hyperlipidemia, and autophagy, but its action mechanisms are still poorly understood. Even though trehalose is digested by disaccharidase and absorbed in the intestine, intact molecules encounter immune cells which form a solid balance between the allowance of nutritive substances and the removal of harmful pathogens. In this regard, the polarization of intestinal macrophages into an anti-inflammatory phenotype through metabolic regulation is emerging as a therapeutic strategy for the prevention of gastrointestinal inflammation. The current study investigated the effects of trehalose on immunological phenotypes, energy metabolism, and LPS-induced macrophage mitochondrial functioning. Results indicate that trehalose reduces prostaglandin E2 and nitric oxide, which are inflammatory mediators of LPS-induced macrophages. In addition, trehalose further significantly suppressed inflammatory cytokines and mediators via energy metabolism reprogramming towards M2-like status in LPS-stimulated macrophages. Full article
(This article belongs to the Special Issue Targeting Antioxidants to Mitochondria: A Novel Therapeutic Direction)
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20 pages, 3358 KiB  
Article
GK-1 Induces Oxidative Stress, Mitochondrial Dysfunction, Decreased Membrane Potential, and Impaired Autophagy Flux in a Mouse Model of Breast Cancer
by Alfredo Cruz-Gregorio, Ana Karina Aranda-Rivera, Omar Emiliano Aparicio-Trejo, Omar Noel Medina-Campos, Edda Sciutto, Gladis Fragoso and José Pedraza-Chaverri
Antioxidants 2023, 12(1), 56; https://doi.org/10.3390/antiox12010056 - 27 Dec 2022
Cited by 2 | Viewed by 3059
Abstract
Breast cancer (BC) is the second most common cancer worldwide in women. During the last decades, the mortality due to breast cancer has progressively decreased due to early diagnosis and the emergence of more effective new treatments. However, human epidermal growth factor receptor [...] Read more.
Breast cancer (BC) is the second most common cancer worldwide in women. During the last decades, the mortality due to breast cancer has progressively decreased due to early diagnosis and the emergence of more effective new treatments. However, human epidermal growth factor receptor 2 (HER2) and triple-negative breast cancer (TNBC) remain with poor prognoses. In our research group, we are proposing the GK-1 immunomodulatory peptide as a new alternative for immunotherapy of these aggressive tumors. GK-1 reduced the growth rate of established tumors and effectively reduced lung metastasis in the 4T1 experimental murine model of breast cancer. Herein, the effect of GK-1 on the redox state, mitochondrial metabolism, and autophagy of triple-negative tumors that can be linked to cancer evolution was studied. GK-1 decreased catalase activity, reduced glutathione (GSH) content and GSH/oxidized glutathione (GSSG) ratio while increased hydrogen peroxide (H2O2) production, GSSG, and protein carbonyl content, inducing oxidative stress (OS) in tumoral tissues. This imbalance between reactive oxygen species (ROS) and antioxidants was related to mitochondrial dysfunction and uncoupling, characterized by reduced mitochondrial respiratory parameters and dissipation of mitochondrial membrane potential (ΔΨm), respectively. Furthermore, GK-1 likely affected autophagy flux, confirmed by elevated levels of p62, a marker of autophagy flux. Overall, the induction of OS, dysfunction, and uncoupling of the mitochondria and the reduction of autophagy could be molecular mechanisms that underlie the reduction of the 4T1 breast cancer induced by GK-1. Full article
(This article belongs to the Special Issue Targeting Antioxidants to Mitochondria: A Novel Therapeutic Direction)
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27 pages, 5558 KiB  
Article
Sulforaphane Protects against Unilateral Ureteral Obstruction-Induced Renal Damage in Rats by Alleviating Mitochondrial and Lipid Metabolism Impairment
by Ana Karina Aranda-Rivera, Alfredo Cruz-Gregorio, Omar Emiliano Aparicio-Trejo, Edilia Tapia, Laura Gabriela Sánchez-Lozada, Fernando Enrique García-Arroyo, Isabel Amador-Martínez, Marisol Orozco-Ibarra, Francisca Fernández-Valverde and José Pedraza-Chaverri
Antioxidants 2022, 11(10), 1854; https://doi.org/10.3390/antiox11101854 - 20 Sep 2022
Cited by 19 | Viewed by 3424
Abstract
Unilateral ureteral obstruction (UUO) is an animal rodent model that allows the study of obstructive nephropathy in an accelerated manner. During UUO, tubular damage is induced, and alterations such as oxidative stress, inflammation, lipid metabolism, and mitochondrial impairment favor fibrosis development, leading to [...] Read more.
Unilateral ureteral obstruction (UUO) is an animal rodent model that allows the study of obstructive nephropathy in an accelerated manner. During UUO, tubular damage is induced, and alterations such as oxidative stress, inflammation, lipid metabolism, and mitochondrial impairment favor fibrosis development, leading to chronic kidney disease progression. Sulforaphane (SFN), an isothiocyanate derived from green cruciferous vegetables, might improve mitochondrial functions and lipid metabolism; however, its role in UUO has been poorly explored. Therefore, we aimed to determine the protective effect of SFN related to mitochondria and lipid metabolism in UUO. Our results showed that in UUO SFN decreased renal damage, attributed to increased mitochondrial biogenesis. We showed that SFN augmented peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and nuclear respiratory factor 1 (NRF1). The increase in biogenesis augmented the mitochondrial mass marker voltage-dependent anion channel (VDAC) and improved mitochondrial structure, as well as complex III (CIII), aconitase 2 (ACO2) and citrate synthase activities in UUO. In addition, lipid metabolism was improved, observed by the downregulation of cluster of differentiation 36 (CD36), sterol regulatory-element binding protein 1 (SREBP1), fatty acid synthase (FASN), and diacylglycerol O-acyltransferase 1 (DGAT1), which reduces triglyceride (TG) accumulation. Finally, restoring the mitochondrial structure reduced excessive fission by decreasing the fission protein dynamin-related protein-1 (DRP1). Autophagy flux was further restored by reducing beclin and sequestosome (p62) and increasing B-cell lymphoma 2 (Bcl2) and the ratio of microtubule-associated proteins 1A/1B light chain 3 II and I (LC3II/LC3I). These results reveal that SFN confers protection against UUO-induced kidney injury by targeting mitochondrial biogenesis, which also improves lipid metabolism. Full article
(This article belongs to the Special Issue Targeting Antioxidants to Mitochondria: A Novel Therapeutic Direction)
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