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Oxidative Stress, Calcium Dysregulation, and Mitochondrial Dysfunction in Human Diseases

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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 (15 March 2022) | Viewed by 19811

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Special Issue Editors

Prof. Nuria Paricio

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Guest Editor

Department of Genetics and University Institute of Biotechnology and Biomedicine, University of Valencia, 46100 Burjassot, Spain
Interests: drosophila melanogaster; human cell models; Parkinson´s disease; neurodegenerative diseases; oxidative stress; mitochondria; drug discovery; therapeutic targets; biomarkers

Dr. Juan Antonio Navarro-Langa

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Guest Editor

Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain
Interests: drosophila melanogaster; neurodegenerative diseases; mitochondria; iron; oxidative stress; ferroptosis; lipid metabolism

Special Issue Information

The interplay between oxidative stress, mitochondrial dysfunction and elevated calcium (Ca²⁺) intracellular levels seems to be a central element in several pathological conditions, ranging from diabetes and cardiovascular diseases to neurological disorders and cancer. However, the contribution of each of these three pivotal events to the development and progression of diseases or as molecular triggers of cell death has not yet been fully elucidated.

Oxidative stress results from an imbalance between the production of reactive oxygen and nitrogen species (ROS and RNS, respectively) and the activity of antioxidant defenses and ROS-scavenging systems, thus leading to oxidative damage to cellular components. This damage may cause cell function impairment, whole organ failure and even cell death, consequently leading to human aging and disease. Mitochondrial alterations are known to promote oxidative stress, which in turn has been reported to exacerbate mitochondrial dysfunction. Both oxidative damage and mitochondrial dysfunction are cofactors in the pathogenesis of several diseases. In addition, although Ca²⁺ is well known for its role as a second messenger, mediating many cellular physiological functions, abnormal cytosolic and mitochondrial Ca²⁺levels (scarcity and overload) are currently gaining importance as detrimental factors for mitochondrial function. By sequestering and releasing Ca²⁺, mitochondria act as an important regulator of cellular Ca²⁺ levels, which are tightly regulated. It has been shown that mitochondrial Ca²⁺ overload leads to an increase in ROS production, and mitochondrial ROS are also able to modulate Ca²⁺ metabolism. In sum, emerging evidence highlights that oxidative stress, mitochondrial dysfunction and Ca²⁺ dysregulation are interrelated and play a crucial role in controlling several physiopathological events.

In this Special Issue, we aim to bring together manuscripts, in the form of either Original Research or Reviews, that highlight the relevance of disease models (human, cellular, murine and invertebrate) in our understanding of the reciprocal interactions between Ca²⁺ dysregulation, elevated ROS levels and mitochondrial dysfunction in the onset and progression of human disorders. Additionally, manuscripts that report emerging pharmacological approaches targeting such cellular alterations in human diseases will be also welcome. Our aim is for this collection to stimulate further research that will go beyond the state of the art in order to open new avenues for the design of novel therapies to treat these diseases.

Prof. Nuria Paricio
Dr. Juan Antonio Navarro-Langa
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

Oxidative stress
Calcium dyshomeostasis
Mitochondrial dysfunction
Parkinson’s disease
Friedreich’s ataxia
Alzheimer’s disease
Huntington’s disease
Other human diseases
Preclinical models
Therapeutics

Published Papers (5 papers)

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Research

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15 pages, 1876 KiB

Open AccessArticle

Ex Vivo Lung Perfusion with β-Nicotinamide Adenine Dinucleotide (NAD⁺) Improves Ischemic Lung Function

by Jonas Peter Ehrsam, Jin Chen, Hector Rodriguez Cetina Biefer, Isabelle Opitz, Stephan Arni and Ilhan Inci

Antioxidants 2022, 11(5), 843; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11050843 - 26 Apr 2022

Cited by 4 | Viewed by 1851

Abstract

Ischemia-reperfusion injury compromises short- and long-term outcomes after lung transplantation. The scarce existing data on NAD⁺ suggest effects on hypoxia-induced vasoconstriction, on reactive oxygen species and on tampering inflammation. We exposed rat lungs to 14 h of cold ischemic storage and perfused them in a rat ex vivo lung perfusion (EVLP) system for 4 h. A control group (n = 6) was compared to groups receiving 100 µM (n = 6) or 200 µM NAD⁺ (n = 6) in the preservation solution and groups receiving 200 µM (n = 4) or 2000 µM (n = 6) NAD⁺ every 30 min in the perfusate, starting at 1 h of EVLP. Compared to the control, significant effects were only achieved in the 2000 µM NAD⁺ group. During the 4 h of EVLP, we monitored higher vascular flow, lower mean pulmonary arterial pressure and increased oxygenation capacity. Tissue inflammation estimated with the myeloperoxidase assay was lower in the 2000 µM NAD⁺ group. We observed higher levels of anti-inflammatory IL-10, higher anti-inflammatory IL-6/IL-10 ratios and lower levels of pro-inflammatory IL-12 and IL-18 as well as a trend of more anti-inflammatory IFNy in the 2000 µM NAD⁺ perfusate. In the bronchoalveolar lavage, the pro-inflammatory levels of IL-1α and IL-1β were lower in the 2000 µM NAD⁺ group. NAD⁺ administered during EVLP is a promising agent with both anti-inflammatory properties and the ability to improve ischemic lung function. Full article

(This article belongs to the Special Issue Oxidative Stress, Calcium Dysregulation, and Mitochondrial Dysfunction in Human Diseases)

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22 pages, 3718 KiB

Open AccessArticle

The cAMP Inducers Modify N-Acetylaspartate Metabolism in Wistar Rat Brain

by Robert Kowalski, Piotr Pikul, Krzysztof Lewandowski, Monika Sakowicz-Burkiewicz, Tadeusz Pawełczyk and Marlena Zyśk

Antioxidants 2021, 10(9), 1404; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10091404 - 01 Sep 2021

Cited by 1 | Viewed by 2690

Abstract

Neuronal N-acetylaspartate production appears in the presence of aspartate N-acetyltransferase (NAT8L) and binds acetyl groups from acetyl-CoA with aspartic acid. Further N-acetylaspartate pathways are still being elucidated, although they seem to involve neuron-glia crosstalk. Together with N-acetylaspartate, NAT8L takes part in oligoglia and astroglia cell maturation, myelin production, and dopamine-dependent brain signaling. Therefore, understanding N-acetylaspartate metabolism is an emergent task in neurobiology. This project used in in vitro and in vivo approaches in order to establish the impact of maturation factors and glial cells on N-acetylaspartate metabolism. Embryonic rat neural stem cells and primary neurons were maturated with either nerve growth factor, trans-retinoic acid or activators of cAMP-dependent protein kinase A (dibutyryl-cAMP, forskolin, theophylline). For in vivo, adult male Wistar rats were injected with theophylline (20 mg/kg b.w.) daily for two or eight weeks. Our studies showed that the N-acetylaspartate metabolism differs between primary neurons and neural stem cell cultures. The presence of glia cells protected N-acetylaspartate metabolism from dramatic changes within the maturation processes, which was impossible in the case of pure primary neuron cultures. In the case of differentiation processes, our data points to dibutyryl-cAMP as the most prominent regulator of N-acetylaspartate metabolism. Full article

(This article belongs to the Special Issue Oxidative Stress, Calcium Dysregulation, and Mitochondrial Dysfunction in Human Diseases)

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Review

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17 pages, 2210 KiB

Open AccessReview

Antioxidant and Neuroprotective Effects of Carnosine: Therapeutic Implications in Neurodegenerative Diseases

by Cristina Solana-Manrique, Francisco José Sanz, Guillermo Martínez-Carrión and Nuria Paricio

Antioxidants 2022, 11(5), 848; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11050848 - 26 Apr 2022

Cited by 26 | Viewed by 3801

Abstract

Neurodegenerative diseases (NDs) constitute a global challenge to human health and an important social and economic burden worldwide, mainly due to their growing prevalence in an aging population and to their associated disabilities. Despite their differences at the clinical level, NDs share fundamental pathological mechanisms such as abnormal protein deposition, intracellular Ca²⁺ overload, mitochondrial dysfunction, redox homeostasis imbalance and neuroinflammation. Although important progress is being made in deciphering the mechanisms underlying NDs, the availability of effective therapies is still scarce. Carnosine is a natural endogenous molecule that has been extensively studied during the last years due to its promising beneficial effects for human health. It presents multimodal mechanisms of action, being able to exert antioxidant, anti-inflammatory and anti-aggregate activities, among others. Interestingly, most NDs exhibit oxidative and nitrosative stress, protein aggregation and inflammation as molecular hallmarks. In this review, we discuss the neuroprotective functions of carnosine and its implications as a therapeutic strategy in different NDs. We summarize the existing works that study alterations in carnosine metabolism in Alzheimer’s disease and Parkinson’s disease, the two most common NDs. In addition, we review the beneficial effect that carnosine supplementation presents in models of such diseases as well as in aging-related neurodegeneration. Full article

(This article belongs to the Special Issue Oxidative Stress, Calcium Dysregulation, and Mitochondrial Dysfunction in Human Diseases)

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25 pages, 2377 KiB

Open AccessReview

Mitochondrial Calcium: Effects of Its Imbalance in Disease

by Deyamira Matuz-Mares, Martin González-Andrade, Minerva Georgina Araiza-Villanueva, María Magdalena Vilchis-Landeros and Héctor Vázquez-Meza

Antioxidants 2022, 11(5), 801; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11050801 - 20 Apr 2022

Cited by 39 | Viewed by 6526

Abstract

Calcium is used in many cellular processes and is maintained within the cell as free calcium at low concentrations (approximately 100 nM), compared with extracellular (millimolar) concentrations, to avoid adverse effects such as phosphate precipitation. For this reason, cells have adapted buffering strategies by compartmentalizing calcium into mitochondria and the endoplasmic reticulum (ER). In mitochondria, the calcium concentration is in the millimolar range, as it is in the ER. Mitochondria actively contribute to buffering cellular calcium, but if matrix calcium increases beyond physiological demands, it can promote the opening of the mitochondrial permeability transition pore (mPTP) and, consequently, trigger apoptotic or necrotic cell death. The pathophysiological implications of mPTP opening in ischemia-reperfusion, liver, muscle, and lysosomal storage diseases, as well as those affecting the central nervous system, for example, Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) have been reported. In this review, we present an updated overview of the main cellular mechanisms of mitochondrial calcium regulation. We specially focus on neurodegenerative diseases related to imbalances in calcium homeostasis and summarize some proposed therapies studied to attenuate these diseases. Full article

(This article belongs to the Special Issue Oxidative Stress, Calcium Dysregulation, and Mitochondrial Dysfunction in Human Diseases)

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24 pages, 947 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

by Laura R. Rodríguez, Tamara Lapeña-Luzón, Noelia Benetó, Vicent Beltran-Beltran, Federico V. Pallardó, Pilar Gonzalez-Cabo and Juan Antonio Navarro

Antioxidants 2022, 11(1), 165; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11010165 - 15 Jan 2022

Cited by 18 | Viewed by 3710

Abstract

Calcium (Ca²⁺) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca²⁺ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca²⁺ exchange is mediated by appositions, termed endoplasmic reticulum–mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca²⁺ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich’s ataxia, and Charcot–Marie–Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca²⁺ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca²⁺ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca²⁺ uptake as an emergent approach for neurological diseases. Full article

(This article belongs to the Special Issue Oxidative Stress, Calcium Dysregulation, and Mitochondrial Dysfunction in Human Diseases)

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