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Antioxidants
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Mitochondrial Management of ROS in Physiological and Pathological Conditions
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Mitochondrial Management of ROS in Physiological and Pathological Conditions

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

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 20231

Special Issue Editors

Dr. Paola Venditti

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Guest Editor
Department of Biology, University of Naples Federico II, Monte Sant’Angelo Via Cinthia, 80126 Naples, Italy
Interests: ROS; oxidative stress; mitochondria; antioxidants; ischemia–reperfusion; functional and experimental hyperthyroidism; exercise; hyperthyroidism; diabetes
Special Issues, Collections and Topics in MDPI journals
Dr. Gaetana Napolitano

E-Mail Website
Guest Editor
Department of Sciences and Technology, University of Naples Parthenope, Via Acton 38, 80133 Naples, Italy
Interests: oxidative stress; fish physiology; endurance; ROS; environmental pollution; mitochondria
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mitochondria perform a wide spectrum of functions ranging from the regulation of calcium intracellular concentration to the oxidation of fatty acids, the metabolism of steroids and some amino acids, and the synthesis of urea and phospholipids. Their most important function is to provide most of the energy necessary for cellular endergonic reactions by synthesizing ATP via the oxidative phosphorylation process.

In fulfilling this function, mitochondria have the ability to undergo biochemical and morphological adaptations that allow them to meet cellular energy needs. Therefore, due to their incredible versatility, mitochondrial dysfunctions can be extremely damaging to the cell and even lead to cell death.

Mitochondria are also sources of cellular radicals and other reactive oxygen species (ROS), classically considered oxidizing agents capable of damaging biological macromolecules and, therefore, the cell. More recently, ROS have been shown to play a more complex role by being involved as secondary messenger agents in the signalling pathways necessary for adequate cell growth and proliferation. ROS also regulate mitochondrial dynamics, thereby stabilizing their function in mammalian cells.

To complicate the picture, several pieces of evidence indicate that mitochondria regulate cellular levels of ROS thanks to their efficient antioxidant defence system. Cellular levels of ROS are influenced by various factors and change in physiological and pathological conditions, the latter being associated with mitochondrial dysfunction. The goal of this Special Issue is to gather research focusing on recent advances in the production and management of mitochondrial ROS during health, disease, and ageing.

Potential topics include, but are not limited to, the effects on mitochondrial population of:

  • Aging;
  • Exercise;
  • Changes in dietary intake;
  • Altered thyroid status;
  • Environmental pollution;
  • Inflammation;
  • Cancer;
  • Autoimmune diseases.

Dr. Paola Venditti
Dr. Gaetana Napolitano
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.

Published Papers (8 papers)

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Research

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14 pages, 2836 KiB  
Article
Comparing Mitochondrial Activity, Oxidative Stress Tolerance, and Longevity of Thirteen Ascomycota Yeast Species
by Anna Gröger, Ilune Martínez-Albo, M. Mar Albà, José Ayté, Montserrat Vega and Elena Hidalgo
Antioxidants 2023, 12(10), 1810; https://doi.org/10.3390/antiox12101810 - 28 Sep 2023
Viewed by 1036
Abstract
Aging is characterized by a number of hallmarks including loss of mitochondrial homeostasis and decay in stress tolerance, among others. Unicellular eukaryotes have been widely used to study chronological aging. As a general trait, calorie restriction and activation of mitochondrial respiration has been [...] Read more.
Aging is characterized by a number of hallmarks including loss of mitochondrial homeostasis and decay in stress tolerance, among others. Unicellular eukaryotes have been widely used to study chronological aging. As a general trait, calorie restriction and activation of mitochondrial respiration has been proposed to contribute to an elongated lifespan. Most aging-related studies have been conducted with the Crabtree-positive yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, and with deletion collections deriving from these conventional yeast models. We have performed an unbiased characterization of longevity using thirteen fungi species, including S. cerevisiae and S. pombe, covering a wide range of the Ascomycota clade. We have determined their mitochondrial activity by oxygen consumption, complex IV activity, and mitochondrial redox potential, and the results derived from these three methodologies are highly overlapping. We have phenotypically compared the lifespans of the thirteen species and their capacity to tolerate oxidative stress. Longevity and elevated tolerance to hydrogen peroxide are correlated in some but not all yeasts. Mitochondrial activity per se cannot anticipate the length of the lifespan. We have classified the strains in four groups, with members of group 1 (Kluyveromyces lactis, Saccharomyces bayanus and Lodderomyces elongisporus) displaying high mitochondrial activity, elevated resistance to oxidative stress, and elongated lifespan. Full article
(This article belongs to the Special Issue Mitochondrial Management of ROS in Physiological and Pathological Conditions)
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22 pages, 6210 KiB  
Article
Tacrolimus Improves Therapeutic Efficacy of Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Diabetic Retinopathy by Suppressing DRP1-Mediated Mitochondrial Fission
by Hang Hyo Jo, Yeong Seok Goh, Hye Jih Kim, Dae Hyun Kim, Hyemin Kim, Jiyi Hwang, Ji Seung Jung, Nanyoung Kang, Sang Eun Park, Kyung Mee Park and Hyun Jik Lee
Antioxidants 2023, 12(9), 1727; https://doi.org/10.3390/antiox12091727 - 06 Sep 2023
Cited by 2 | Viewed by 1200
Abstract
Diabetic retinopathy (DR) is a leading cause of blindness in diabetic patients. Umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) are emerging as a promising new drug for degenerative disease associated with diabetes. Recent studies have shown that high glucose-increased excessive calcium levels are [...] Read more.
Diabetic retinopathy (DR) is a leading cause of blindness in diabetic patients. Umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) are emerging as a promising new drug for degenerative disease associated with diabetes. Recent studies have shown that high glucose-increased excessive calcium levels are a major risk factor for mitochondrial reactive oxygen species (mtROS) accumulation and apoptosis. This study aimed to investigate the role of high glucose-induced NFATC1 signaling in mitochondrial oxidative stress-stimulated apoptosis and the effect of tacrolimus on the therapeutic efficacy of subconjunctival transplantation of UCB-MSCs in a DR rat model. High glucose increased mtROS and cleaved caspase-9 expression in UCB-MSCs. High glucose conditions increased O-GlcNAcylated protein expression and nuclear translocation of NFATC1. Tacrolimus pretreatment recovered high glucose-induced mtROS levels and apoptosis. In the DR rat model, subconjunctival transplantation of tacrolimus-pretreated MSCs improved retinal vessel formation, retinal function, and uveitis. In high glucose conditions, tacrolimus pretreatment reduced protein and mRNA expression levels of DRP1 and inhibited mitochondrial fission. In conclusion, we demonstrated that high glucose-induced O-GlcNAcylation activates NFATC1 signaling, which is important for DRP1-mediated mitochondrial fission and mitochondrial apoptosis. Finally, we proposed NFATC1 suppression by tacrolimus as a promising therapeutic strategy to improve the therapeutic efficacy of UCB-MSC transplantation for DR treatment. Full article
(This article belongs to the Special Issue Mitochondrial Management of ROS in Physiological and Pathological Conditions)
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18 pages, 5859 KiB  
Article
Whey Improves In Vitro Endothelial Mitochondrial Function and Metabolic Redox Status in Diabetic State
by Elisa Martino, Amalia Luce, Anna Balestrieri, Luigi Mele, Camilla Anastasio, Nunzia D’Onofrio, Maria Luisa Balestrieri and Giuseppe Campanile
Antioxidants 2023, 12(6), 1311; https://doi.org/10.3390/antiox12061311 - 20 Jun 2023
Cited by 2 | Viewed by 1320
Abstract
Endothelial dysfunction plays a critical role in the progression of type 2 diabetes mellitus (T2DM), leading to cardiovascular complications. Current preventive antioxidant strategies to reduce oxidative stress and improve mitochondrial function in T2DM highlight dietary interventions as a promising approach, stimulating the deepening [...] Read more.
Endothelial dysfunction plays a critical role in the progression of type 2 diabetes mellitus (T2DM), leading to cardiovascular complications. Current preventive antioxidant strategies to reduce oxidative stress and improve mitochondrial function in T2DM highlight dietary interventions as a promising approach, stimulating the deepening of knowledge of food sources rich in bioactive components. Whey (WH), a dairy by-product with a considerable content of bioactive compounds (betaines and acylcarnitines), modulates cancer cell metabolism by acting on mitochondrial energy metabolism. Here, we aimed at covering the lack of knowledge on the possible effect of WH on the mitochondrial function in T2DM. The results showed that WH improved human endothelial cell (TeloHAEC) function during the in vitro diabetic condition mimicked by treating cells with palmitic acid (PA) (0.1 mM) and high glucose (HG) (30 mM). Of note, WH protected endothelial cells from PA+HG-induced cytotoxicity (p < 0.01) and prevented cell cycle arrest, apoptotic cell death, redox imbalance, and metabolic alteration (p < 0.01). Moreover, WH counteracted mitochondrial injury and restored SIRT3 levels (p < 0.01). The SiRNA-mediated suppression of SIRT3 abolished the protective effects exerted by WH on the mitochondrial and metabolic impairment caused by PA+HG. These in vitro results reveal the efficacy of whey as a redox and metabolic modulator in the diabetic state and pave the way for future studies to consider whey as the source of dietary bioactive molecules with health benefits in preventive strategies against chronic diseases. Full article
(This article belongs to the Special Issue Mitochondrial Management of ROS in Physiological and Pathological Conditions)
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22 pages, 4691 KiB  
Article
Traumatic Brain Injury Alters Cerebral Concentrations and Redox States of Coenzymes Q9 and Q10 in the Rat
by Giacomo Lazzarino, Renata Mangione, Miriam Wissam Saab, Barbara Tavazzi, Alessandra Pittalà, Stefano Signoretti, Valentina Di Pietro, Giuseppe Lazzarino and Angela Maria Amorini
Antioxidants 2023, 12(5), 985; https://doi.org/10.3390/antiox12050985 - 23 Apr 2023
Cited by 4 | Viewed by 1288
Abstract
To date, there is no information on the effect of TBI on the changes in brain CoQ levels and possible variations in its redox state. In this study, we induced graded TBIs (mild TBI, mTBI and severe TBI, sTBI) in male rats, using [...] Read more.
To date, there is no information on the effect of TBI on the changes in brain CoQ levels and possible variations in its redox state. In this study, we induced graded TBIs (mild TBI, mTBI and severe TBI, sTBI) in male rats, using the weight-drop closed-head impact acceleration model of trauma. At 7 days post-injury, CoQ9, CoQ10 and α-tocopherol were measured by HPLC in brain extracts of the injured rats, as well as in those of a group of control sham-operated rats. In the controls, about the 69% of total CoQ was in the form of CoQ9 and the oxidized/reduced ratios of CoQ9 and CoQ10 were, respectively, 1.05 ± 0.07 and 1.42 ± 0.17. No significant changes in these values were observed in rats experiencing mTBI. Conversely, in the brains of sTBI-injured animals, an increase in reduced and a decrease in oxidized CoQ9 produced an oxidized/reduced ratio of 0.81 ± 0.1 (p < 0.001 compared with both controls and mTBI). A concomitant decrease in both reduced and oxidized CoQ10 generated a corresponding oxidized/reduced ratio of 1.38 ± 0.23 (p < 0.001 compared with both controls and mTBI). An overall decrease in the concentration of the total CoQ pool was also found in sTBI-injured rats (p < 0.001 compared with both controls and mTBI). Concerning α-tocopherol, whilst no differences compared with the controls were found in mTBI animals, a significant decrease was observed in rats experiencing sTBI (p < 0.01 compared with both controls and mTBI). Besides suggesting potentially different functions and intracellular distributions of CoQ9 and CoQ10 in rat brain mitochondria, these results demonstrate, for the first time to the best of knowledge, that sTBI alters the levels and redox states of CoQ9 and CoQ10, thus adding a new explanation to the mitochondrial impairment affecting ETC, OXPHOS, energy supply and antioxidant defenses following sTBI. Full article
(This article belongs to the Special Issue Mitochondrial Management of ROS in Physiological and Pathological Conditions)
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12 pages, 3118 KiB  
Article
Shikonin Induces ROS-Dependent Apoptosis Via Mitochondria Depolarization and ER Stress in Adult T Cell Leukemia/Lymphoma
by Piyanard Boonnate, Ryusho Kariya and Seiji Okada
Antioxidants 2023, 12(4), 864; https://doi.org/10.3390/antiox12040864 - 02 Apr 2023
Cited by 5 | Viewed by 1719
Abstract
Adult T cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy that develops in some elderly human T-cell leukemia virus (HTVL-1) carriers. ATLL has a poor prognosis despite conventional and targeted therapies, and a new safe and efficient therapy is required. Here, we examined [...] Read more.
Adult T cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy that develops in some elderly human T-cell leukemia virus (HTVL-1) carriers. ATLL has a poor prognosis despite conventional and targeted therapies, and a new safe and efficient therapy is required. Here, we examined the anti-ATLL effect of Shikonin (SHK), a naphthoquinone derivative that has shown several anti-cancer activities. SHK induced apoptosis of ATLL cells accompanied by generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential, and induction of endoplasmic reticulum (ER) stress. Treatment with a ROS scavenger, N-acetylcysteine (NAC), blocked both loss of mitochondrial membrane potential and ER stress, and prevented apoptosis of ATLL cells, indicating that ROS is an upstream trigger of SHK-induced apoptosis of ATLL cells through disruption of the mitochondrial membrane potential and ER stress. In an ATLL xenografted mouse model, SHK treatment suppressed tumor growth without significant adverse effects. These results suggest that SHK could be a potent anti-reagent against ATLL. Full article
(This article belongs to the Special Issue Mitochondrial Management of ROS in Physiological and Pathological Conditions)
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20 pages, 2712 KiB  
Article
Progranulin Deficiency Induces Mitochondrial Dysfunction in Frontotemporal Lobar Degeneration with TDP-43 Inclusions
by Guiomar Rodríguez-Periñán, Ana de la Encarnación, Fermín Moreno, Adolfo López de Munain, Ana Martínez, Ángeles Martín-Requero, Carolina Alquézar and Fernando Bartolomé
Antioxidants 2023, 12(3), 581; https://doi.org/10.3390/antiox12030581 - 25 Feb 2023
Cited by 3 | Viewed by 2158
Abstract
Loss-of-function (LOF) mutations in GRN gene, which encodes progranulin (PGRN), cause frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). FTLD-TDP is one of the most common forms of early onset dementia, but its pathogenesis is not fully understood. Mitochondrial dysfunction has been associated with [...] Read more.
Loss-of-function (LOF) mutations in GRN gene, which encodes progranulin (PGRN), cause frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). FTLD-TDP is one of the most common forms of early onset dementia, but its pathogenesis is not fully understood. Mitochondrial dysfunction has been associated with several neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). Here, we have investigated whether mitochondrial alterations could also contribute to the pathogenesis of PGRN deficiency-associated FTLD-TDP. Our results showed that PGRN deficiency induced mitochondrial depolarization, increased ROS production and lowered ATP levels in GRN KD SH-SY5Y neuroblastoma cells. Interestingly, lymphoblasts from FTLD-TDP patients carrying a LOF mutation in the GRN gene (c.709-1G > A) also demonstrated mitochondrial depolarization and lower ATP levels. Such mitochondrial damage increased mitochondrial fission to remove dysfunctional mitochondria by mitophagy. Interestingly, PGRN-deficient cells showed elevated mitochondrial mass together with autophagy dysfunction, implying that PGRN deficiency induced the accumulation of damaged mitochondria by blocking its degradation in the lysosomes. Importantly, the treatment with two brain-penetrant CK-1δ inhibitors (IGS-2.7 and IGS-3.27), known for preventing the phosphorylation and cytosolic accumulation of TDP-43, rescued mitochondrial function in PGRN-deficient cells. Taken together, these results suggest that mitochondrial function is impaired in FTLD-TDP associated with LOF GRN mutations and that the TDP-43 pathology linked to PGRN deficiency might be a key mechanism contributing to such mitochondrial dysfunction. Furthermore, our results point to the use of drugs targeting TDP-43 pathology as a promising therapeutic strategy for restoring mitochondrial function in FTLD-TDP and other TDP-43-related diseases. Full article
(This article belongs to the Special Issue Mitochondrial Management of ROS in Physiological and Pathological Conditions)
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Review

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22 pages, 2792 KiB  
Review
Pitfalls of Mitochondrial Redox Signaling Research
by Petr Ježek
Antioxidants 2023, 12(9), 1696; https://doi.org/10.3390/antiox12091696 - 31 Aug 2023
Viewed by 984
Abstract
Redox signaling from mitochondria (mt) to the cytosol and plasma membrane (PM) has been scarcely reported, such as in the case of hypoxic cell adaptation or (2-oxo-) 2-keto-isocaproate (KIC) β-like-oxidation stimulating insulin secretion in pancreatic β-cells. Mutual redox state influence between mitochondrial major [...] Read more.
Redox signaling from mitochondria (mt) to the cytosol and plasma membrane (PM) has been scarcely reported, such as in the case of hypoxic cell adaptation or (2-oxo-) 2-keto-isocaproate (KIC) β-like-oxidation stimulating insulin secretion in pancreatic β-cells. Mutual redox state influence between mitochondrial major compartments, the matrix and the intracristal space, and the cytosol is therefore derived theoretically in this article to predict possible conditions, when mt-to-cytosol and mt-to-PM signals may occur, as well as conditions in which the cytosolic redox signaling is not overwhelmed by the mitochondrial antioxidant capacity. Possible peroxiredoxin 3 participation in mt-to-cytosol redox signaling is discussed, as well as another specific case, whereby mitochondrial superoxide release is diminished, whereas the matrix MnSOD is activated. As a result, the enhanced conversion to H2O2 allows H2O2 diffusion into the cytosol, where it could be a predominant component of the H2O2 release. In both of these ways, mt-to-cytosol and mt-to-PM signals may be realized. Finally, the use of redox-sensitive probes is discussed, which disturb redox equilibria, and hence add a surplus redox-buffering to the compartment, where they are localized. Specifically, when attempts to quantify net H2O2 fluxes are to be made, this should be taken into account. Full article
(This article belongs to the Special Issue Mitochondrial Management of ROS in Physiological and Pathological Conditions)
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37 pages, 2124 KiB  
Review
Aging Hallmarks and the Role of Oxidative Stress
by Edio Maldonado, Sebastián Morales-Pison, Fabiola Urbina and Aldo Solari
Antioxidants 2023, 12(3), 651; https://doi.org/10.3390/antiox12030651 - 06 Mar 2023
Cited by 42 | Viewed by 9938
Abstract
Aging is a complex biological process accompanied by a progressive decline in the physical function of the organism and an increased risk of age-related chronic diseases such as cardiovascular diseases, cancer, and neurodegenerative diseases. Studies have established that there exist nine hallmarks of [...] Read more.
Aging is a complex biological process accompanied by a progressive decline in the physical function of the organism and an increased risk of age-related chronic diseases such as cardiovascular diseases, cancer, and neurodegenerative diseases. Studies have established that there exist nine hallmarks of the aging process, including (i) telomere shortening, (ii) genomic instability, (iii) epigenetic modifications, (iv) mitochondrial dysfunction, (v) loss of proteostasis, (vi) dysregulated nutrient sensing, (vii) stem cell exhaustion, (viii) cellular senescence, and (ix) altered cellular communication. All these alterations have been linked to sustained systemic inflammation, and these mechanisms contribute to the aging process in timing not clearly determined yet. Nevertheless, mitochondrial dysfunction is one of the most important mechanisms contributing to the aging process. Mitochondria is the primary endogenous source of reactive oxygen species (ROS). During the aging process, there is a decline in ATP production and elevated ROS production together with a decline in the antioxidant defense. Elevated ROS levels can cause oxidative stress and severe damage to the cell, organelle membranes, DNA, lipids, and proteins. This damage contributes to the aging phenotype. In this review, we summarize recent advances in the mechanisms of aging with an emphasis on mitochondrial dysfunction and ROS production. Full article
(This article belongs to the Special Issue Mitochondrial Management of ROS in Physiological and Pathological Conditions)
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