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Oxidative Stress, Endoplasmic Reticulum and Mitochondrial Stress and Senescence

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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 December 2021) | Viewed by 19859

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Special Issue Editors

Prof. Dr. Han Moshage

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Guest Editor

Department of Gastroenterology and Hepatology, University of Groningen, Groningen, The Netherlands
Interests: non-alcoholic liver disease; lipotoxicity; oxidative stress; unfolded protein response; cell death; liver fibrosis; inflammation; liver cells

Prof. Dr. Amalia Dolga

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Guest Editor

Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands
Interests: neurodegeneration; mitochondrial function; inflammation; potassium channels

Special Issue Information

Dear Colleagues,

Oxidative stress compromises cellular homeostasis. Oxidative stress arises when the generation or exposure to pro-oxidants exceeds the cellular capacity to detoxify these pro-oxidants. Cells can be exposed to pro-oxidants from both external as well as internal sources. Normal cellular metabolism also generates pro-oxidants that are detoxified by intracellular antioxidants.

Mitochondria and the endoplasmic reticulum (ER) are important sources of pro-oxidants. In normal conditions, these pro-oxidants are detoxified by antioxidants. Metabolic disturbances can increase the generation of pro-oxidants through organelles such as mitochondria and the ER. In conditions of metabolic stress, or when organellar function is compromised, or when antioxidants are depleted, oxidative stress occurs. The ER is the key organelle in protein homeostasis. Defects in protein folding by protein disulfide isomerases and chaperones can lead to excess generation of pro-oxidants. Disturbed lipid metabolism, e.g., in non-alcoholic fatty liver disease, can also affect ER function and lead to excess generation of pro-oxidants. ER stress elicits the unfolded protein response which is aimed at alleviating ER stress. However, chronic ER stress leads to the initiation of cell death. Likewise, disturbed mitochondrial function, e.g., as a consequence of disturbed lipid metabolism in non-alcoholic fatty liver disease or during aging, may lead to oxidative stress and the initiation of cell death.

Aging leads to increased exposure to oxidative stress; however, increased exposure to oxidative stress also accelerates aging. Aging mitochondria and ER are more susceptible to oxidative stress but also generate more pro-oxidants. Oxidative DNA damage may induce senescence. Taken together, oxidative stress and senescence are intricately connected. Oxidative stress induces aging/senescence, and aging induces oxidative stress. Since mitochondria and ER are both important sources and targets of intracellular oxidative stress, the key to understanding the interaction between oxidative stress and aging/senescence is in understanding the role of ER and mitochondria in aging/senescence.

In this Special Issue of Antioxidants, we invite you to present your latest research or a review on this topic. We welcome submissions on any topic at the intersection of oxidative stress, aging/senescence, and ER/mitochondrial stress. In addition, we also welcome contributions addressing the prevention of and intervention in the detrimental effects of oxidative stress and aging/senescence on organellar function.

We look forward to your contribution and are open to discussing your suggestions.

Prof. Dr. Han Moshage
Prof. Dr. Amalia Dolga
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
Mitochondria
Endoplasmic reticulum
Unfolded protein response
Senescence
Reactive oxygen species
Aging
Calcium

Published Papers (7 papers)

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Research

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16 pages, 3137 KiB

Open AccessArticle

Lysophosphatidic Acid Receptor 3 Promotes Mitochondrial Homeostasis against Oxidative Stress: Potential Therapeutic Approaches for Hutchinson–Gilford Progeria Syndrome

by Jui-Chung Chiang, Wei-Min Chen, Ciara Newman, Benjamin P. C. Chen and Hsinyu Lee

Antioxidants 2022, 11(2), 351; https://doi.org/10.3390/antiox11020351 - 10 Feb 2022

Cited by 4 | Viewed by 2235

Abstract

Lysophosphatidic acid (LPA) is a growth factor-like lipid mediator that regulates various physiological functions via activation of multiple LPA G protein-coupled receptors. We previously reported that LPA suppresses oxidative stress in premature aging Hutchinson-Gilford progeria syndrome (HGPS) patient fibroblasts via its type 3 receptor (LPA₃). Mitochondria have been suggested to be the primary origin of oxidative stress via the overproduction of reactive oxygen species (ROS). Mitochondria are responsible for producing ATP through oxidative phosphorylation (OXPHOS) and have a calcium buffering capacity for the cell. Defects in mitochondria will lead to declined antioxidant capacity and cell apoptosis. Therefore, we aim to demonstrate the regulatory role of LPA₃ in mitochondrial homeostasis. siRNA-mediated depletion of LPA₃ leads to the depolarization of mitochondrial potential (ΔΨm) and cellular ROS accumulation. In addition, the depletion of LPA₃ enhances cisplatin-induced cytochrome C releasing. This indicates that LPA₃ is essential to suppress the mitochondrial apoptosis pathway. LPA₃ is also shown to improve mitochondrial ADP-ATP exchange by enhancing the protein level of ANT2. On the other hand, LPA₃ regulates calcium uptake from the ER to mitochondria via the IP3R1-VDAC1 channel. Moreover, activation of LPA₃ by selective agonist OMPT rescues mitochondrial homeostasis of H₂O₂-induced oxidative stress cells and HGPS patient fibroblasts by improving mitochondrial ΔΨm and OXPHOS. In summary, our findings imply that LPA₃ acts as the gatekeeper for mitochondrial healthiness to maintain cell youth. Furthermore, LPA₃ can be a promising therapeutic target to prevent mitochondrial oxidative stress in aging and HGPS. Full article

(This article belongs to the Special Issue Oxidative Stress, Endoplasmic Reticulum and Mitochondrial Stress and Senescence)

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20 pages, 4372 KiB

Open AccessArticle

Pharmacological Inhibition of Epac1 Averts Ferroptosis Cell Death by Preserving Mitochondrial Integrity

by Nshunge Musheshe, Asmaa Oun, Angélica María Sabogal-Guáqueta, Marina Trombetta-Lima, Sarah C. Mitchel, Ahmed Adzemovic, Oliver Speek, Francesca Morra, Christina H. J. T. van der Veen, Frank Lezoualc’h, Xiaodong Cheng, Martina Schmidt and Amalia M. Dolga

Antioxidants 2022, 11(2), 314; https://doi.org/10.3390/antiox11020314 - 4 Feb 2022

Cited by 18 | Viewed by 3047

Abstract

Exchange proteins directly activated by cAMP (Epac) proteins are implicated in a wide range of cellular functions including oxidative stress and cell survival. Mitochondrial-dependent oxidative stress has been associated with progressive neuronal death underlying the pathology of many neurodegenerative diseases. The role of Epac modulation in neuronal cells in relation to cell survival and death, as well as its potential effect on mitochondrial function, is not well established. In immortalized hippocampal (HT-22) neuronal cells, we examined mitochondria function in the presence of various Epac pharmacological modulators in response to oxidative stress due to ferroptosis. Our study revealed that selective pharmacological modulation of Epac1 or Epac2 isoforms, exerted differential effects in erastin-induced ferroptosis conditions in HT-22 cells. Epac1 inhibition prevented cell death and loss of mitochondrial integrity induced by ferroptosis, while Epac2 inhibition had limited effects. Our data suggest Epac1 as a plausible therapeutic target for preventing ferroptosis cell death associated with neurodegenerative diseases. Full article

(This article belongs to the Special Issue Oxidative Stress, Endoplasmic Reticulum and Mitochondrial Stress and Senescence)

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8 pages, 1228 KiB

Open AccessArticle

Protective Effects of Transient Glucose Exposure in Adult C. elegans

by Katharina Murillo, Azat Samigullin, Per M. Humpert, Thomas Fleming, Kübra Özer, Andrea Schlotterer, Hans-Peter Hammes and Michael Morcos

Antioxidants 2022, 11(1), 160; https://doi.org/10.3390/antiox11010160 - 14 Jan 2022

Cited by 3 | Viewed by 2423

Abstract

C. elegans are used to study molecular pathways, linking high glucose levels (HG) to diabetic complications. Persistent exposure of C. elegans to a HG environment induces the mitochondrial formation of reactive oxygen species (ROS) and advanced glycation endproducts (AGEs), leading to neuronal damage and decreased lifespan. Studies suggest that transient high glucose exposure (TGE) exerts different effects than persistent exposure. Thus, the effects of TGE on ROS, AGE-formation and life span were studied in C. elegans. Four-day TGE (400 mM) as compared to controls (0mM) showed a persistent increase of ROS (4-days 286 ± 40 RLUs vs. control 187 ± 23 RLUs) without increased formation of AGEs. TGE increased body motility (1-day 0.14 ± 0.02; 4-days 0.15 ± 0.01; 6-days 0.16 ± 0.02 vs. control 0.10 ± 0.02 in mm/s), and bending angle (1-day 17.7 ± 1.55; 3-days 18.7 ± 1.39; 6-days 20.3 ± 0.61 vs. control 15.3 ± 1.63 in degree/s) as signs of neuronal damage. Lifespan was increased by 27% (21 ± 2.4 days) after one-day TGE, 34% (22 ± 1.2 days) after four-days TGE, and 26% (21 ± 1.4 days) after six-days TGE vs. control (16 ± 1.3 days). These experiments suggest that TGE in C. elegans has positive effects on life span and neuronal function, associated with mildly increased ROS-formation. From the perspective of metabolic memory, hormetic effects outweighed the detrimental effects of a HG environment. Full article

(This article belongs to the Special Issue Oxidative Stress, Endoplasmic Reticulum and Mitochondrial Stress and Senescence)

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13 pages, 2211 KiB

Open AccessArticle

Metabolic and Transcriptional Adaptations Improve Physical Performance of Zebrafish

by Franziska J. Heinkele, Bowen Lou, Vanessa Erben, Katrin Bennewitz, Gernot Poschet, Carsten Sticht and Jens Kroll

Antioxidants 2021, 10(10), 1581; https://doi.org/10.3390/antiox10101581 - 7 Oct 2021

Cited by 3 | Viewed by 2643

Abstract

Obesity is a worldwide public health problem with increasing prevalence and affects 80% of diabetes mellitus type 2 cases. Zebrafish (Danio rerio) is an established model organism for studying obesity and diabetes including diabetic microvascular complications. We aimed to determine whether physical activity is an appropriate tool to examine training effects in zebrafish and to analyse metabolic and transcriptional processes in trained zebrafish. A 2- and 8-week experimental training phase protocol with adult zebrafish in a swim tunnel system was established. We examined zebrafish basic characteristics before and after training such as body weight, body length and maximum speed and considered overfeeding as an additional parameter in the 8-weeks training protocol. Ultimately, the effects of training and overfeeding on blood glucose, muscle core metabolism and liver gene expression using RNA-Seq were investigated. Zebrafish maximum speed was correlated with body length and was significantly increased after 2 weeks of training. Maximum swim speed further increased after 8 weeks of training in both the normal-fed and the overfed groups, but training was found not to be sufficient in preventing weight gain in overfed fish. Metabolome and transcriptome profiling in trained fish exhibited increased blood glucose levels in the short-term and upregulated energy supply pathways as well as response to oxidative stress in the long-term. In conclusion, swim training is a valuable tool to study the effects of physical activity in zebrafish, which is accompanied by metabolic and transcriptional adaptations. Full article

(This article belongs to the Special Issue Oxidative Stress, Endoplasmic Reticulum and Mitochondrial Stress and Senescence)

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11 pages, 991 KiB

Open AccessArticle

Plasma Nitrate Levels Are Related to Metabolic Syndrome and Are Not Altered by Treatment with DPP-4 Inhibitor Linagliptin: A Randomised, Placebo-Controlled Trial in Patients with Early Type 2 Diabetes Mellitus

by Melanie Reijrink, Stefanie A. De Boer, Anniek M. Van Roon, Riemer H. J. A. Slart, Bernadette O. Fernandez, Martin Feelisch, Hiddo J. L. Heerspink, Harry Van Goor, Jan-Luuk Hillebrands and Douwe J. Mulder

Antioxidants 2021, 10(10), 1548; https://doi.org/10.3390/antiox10101548 - 29 Sep 2021

Cited by 2 | Viewed by 2029

Abstract

The depletion of nitrate and nitrite, stable nitric oxide (NO) end-products, promotes adipose tissue dysfunction and insulin resistance (IR). Dipeptidyl peptidase-4 (DPP-4) inhibitors have the potentially beneficial side effect of increasing NO availability. In this study, nitrate and nitrite levels and the effects of DPP-4 inhibitor linagliptin were investigated in relation to metabolic syndrome (MetS) markers. Treatment-naive patients with early type 2 diabetes mellitus (T2DM) (n = 40, median age 63 IQR (55–67) years, 63% male, mean HbA1c 45 ± 4.4 mmol/mol) were randomized (1:1) to linagliptin (5 mg/day) or placebo. MetS-related markers (body mass index (BMI), triglycerides, HOMA-IR, gamma-glutamyltransferase (GGT), C-reactive protein (CRP), and adiponectin), plasma levels of nitrate, nitrite, total free thiols (TFT) and vegetable intake were estimated at baseline and after 4 and 26 weeks of treatment. Plasma nitrate, but not nitrite, correlated positively with vegetable intake (r = 0.38, p = 0.018) and was inversely associated with HOMA-IR (r = −0.44, p = 0.006), BMI (r = −0.35, p = 0.028), GGT (r = −0.37, p = 0.019) and CRP (r = −0.34, p = 0.034). The relationship between nitrate and HOMA-IR remained significant after adjusting for BMI, CRP, vegetable intake and GGT. With stable vegetable intake, nitrate and nitrite, TFT, adipokines and CRP did not change after 26 weeks of linagliptin treatment. While plasma nitrate is inversely associated with MetS, linagliptin treatment does not significantly influence nitrate and nitrite concentrations, oxidative stress, adipose tissue function and systemic inflammation. Full article

(This article belongs to the Special Issue Oxidative Stress, Endoplasmic Reticulum and Mitochondrial Stress and Senescence)

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19 pages, 16810 KiB

Open AccessArticle

Exacerbated Age-Related Hippocampal Alterations of Microglia Morphology, β-Amyloid and Lipofuscin Deposition and Presenilin Overexpression in Per1^−/−-Mice

by Jan Hendrik Börner, Oliver Rawashdeh and Abdelhaq Rami

Antioxidants 2021, 10(9), 1330; https://doi.org/10.3390/antiox10091330 - 24 Aug 2021

Cited by 5 | Viewed by 2626

Abstract

In humans, alterations of circadian rhythms and autophagy are linked to metabolic, cardiovascular and neurological dysfunction. Autophagy constitutes a specific form of cell recycling in many eukaryotic cells. Aging is the principal risk factor for the development of neurodegenerative diseases. Thus, we assume that both the circadian clock and autophagy are indispensable to counteract aging. We have previously shown that the hippocampus of Per1^−/−-mice exhibits a reduced autophagy and higher neuronal susceptibility to ischemic insults compared to wild type (WT). Therefore, we chose to study the link between aging and loss of clock gene Per1^−/−-mice. Young and aged C3H- and Per1^−/−-mice were used as models to analyze the hippocampal distribution of Aβ42, lipofuscin, presenilin, microglia, synaptophysin and doublecortin. We detected several changes in the hippocampus of aged Per1^−/−-mice compared to their wild type littermates. Our results show significant alterations of microglia morphology, an increase in Aβ42 deposition, overexpression of presenilin, decrease in synaptophysin levels and massive accumulation of lipofuscin in the hippocampus of 24-month-old Per1^−/−-mice, without alteration of adult neurogenesis. We suggest that the marked lipofuscin accumulation, Aβ42 deposition, and overexpression of presenilin-2 observed in our experiments may be some of the consequences of the slowed autophagy in the hippocampus of aged Per1^−/−-mice. This may lead during aging to excessive accumulation of misfolded proteins which may, consequently, result in higher neuronal vulnerability. Full article

(This article belongs to the Special Issue Oxidative Stress, Endoplasmic Reticulum and Mitochondrial Stress and Senescence)

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Review

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30 pages, 1314 KiB

Open AccessReview

Modulation of Oxidative Stress-Induced Senescence during Non-Alcoholic Fatty Liver Disease

by Johanna Pedroza-Diaz, Johanna C. Arroyave-Ospina, Sandra Serna Salas and Han Moshage

Antioxidants 2022, 11(5), 975; https://doi.org/10.3390/antiox11050975 - 16 May 2022

Cited by 5 | Viewed by 3761

Abstract

Non-alcoholic fatty liver disease is characterized by disturbed lipid metabolism and increased oxidative stress. These conditions lead to the activation of different cellular response mechanisms, including senescence. Cellular senescence constitutes an important response to injury in the liver. Recent findings show that chronic oxidative stress can induce senescence, and this might be a driving mechanism for NAFLD progression, aggravating the disturbance of lipid metabolism, organelle dysfunction, pro-inflammatory response and hepatocellular damage. In this context, the modulation of cellular senescence can be beneficial to ameliorate oxidative stress-related damage during NAFLD progression. This review focuses on the role of oxidative stress and senescence in the mechanisms leading to NAFLD and discusses the possibilities to modulate senescence as a therapeutic strategy in the treatment of NAFLD. Full article

(This article belongs to the Special Issue Oxidative Stress, Endoplasmic Reticulum and Mitochondrial Stress and Senescence)

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