The Role of Free Radicals in Autophagy Regulation: Implications for Ageing

Reactive oxygen and nitrogen species (ROS and RNS, resp.) have been traditionally perceived solely as detrimental, leading to oxidative damage of biological macromolecules and organelles, cellular demise, and ageing. However, recent data suggest that ROS/RNS also plays an integral role in intracellular signalling and redox homeostasis (redoxtasis), which are necessary for the maintenance of cellular functions. There is a complex relationship between cellular ROS/RNS content and autophagy, which represents one of the major quality control systems in the cell. In this review, we focus on redox signalling and autophagy regulation with a special interest on ageing-associated changes. In the last section, we describe the role of autophagy and redox signalling in the context of Alzheimer’s disease as an example of a prevalent age-related disorder.

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Differential regulation of Ca2+ influx by ORAI channels mediates enamel mineralization

Science Signaling ◽

10.1126/scisignal.aav4663 ◽

2019 ◽

Vol 12 (578) ◽

pp. eaav4663 ◽

Cited By ~ 12

Author(s):

Miriam Eckstein ◽

Martin Vaeth ◽

Francisco J. Aulestia ◽

Veronica Costiniti ◽

Serena N. Kassam ◽

...

Keyword(s):

Consumption Rate ◽

Redox Homeostasis ◽

Direct Interaction ◽

Redox Status ◽

Cellular Functions ◽

Enamel Defects ◽

Targeted Deletion ◽

Anhidrotic Ectodermal Dysplasia ◽

Enamel Mineralization

Store-operated Ca2+ entry (SOCE) channels are highly selective Ca2+ channels activated by the endoplasmic reticulum (ER) sensors STIM1 and STIM2. Their direct interaction with the pore-forming plasma membrane ORAI proteins (ORAI1, ORAI2, and ORAI3) leads to sustained Ca2+ fluxes that are critical for many cellular functions. Mutations in the human ORAI1 gene result in immunodeficiency, anhidrotic ectodermal dysplasia, and enamel defects. In our investigation of the role of ORAI proteins in enamel, we identified enamel defects in a patient with an ORAI1 null mutation. Targeted deletion of the Orai1 gene in mice showed enamel defects and reduced SOCE in isolated enamel cells. However, Orai2−/− mice showed normal enamel despite having increased SOCE in the enamel cells. Knockdown experiments in the enamel cell line LS8 suggested that ORAI2 and ORAI3 modulated ORAI1 function, with ORAI1 and ORAI2 being the main contributors to SOCE. ORAI1-deficient LS8 cells showed altered mitochondrial respiration with increased oxygen consumption rate and ATP, which was associated with altered redox status and enhanced ER Ca2+ uptake, likely due to S-glutathionylation of SERCA pumps. Our findings demonstrate an important role of ORAI1 in Ca2+ influx in enamel cells and establish a link between SOCE, mitochondrial function, and redox homeostasis.

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The Redox System inC. elegans, a Phylogenetic Approach

Journal of Toxicology ◽

10.1155/2012/546915 ◽

2012 ◽

Vol 2012 ◽

pp. 1-20 ◽

Cited By ~ 12

Author(s):

Andrew D. Johnston ◽

Paul R. Ebert

Keyword(s):

Oxidative Stress ◽

Oxidative Damage ◽

Cellular Damage ◽

Future Research ◽

Homologous Proteins ◽

Redox Biology ◽

Redox Signalling ◽

C Elegans ◽

Age Related

Oxidative stress is a toxic state caused by an imbalance between the production and elimination of reactive oxygen species (ROS). ROS cause oxidative damage to cellular components such as proteins, lipids, and nucleic acids. While the role of ROS in cellular damage is frequently all that is noted, ROS are also important in redox signalling. The “Redox Hypothesis" has been proposed to emphasize a dual role of ROS. This hypothesis suggests that the primary effect of changes to the redox state is modified cellular signalling rather than simply oxidative damage. In extreme cases, alteration of redox signalling can contribute to the toxicity of ROS, as well as to ageing and age-related diseases. The nematode speciesCaenorhabditis elegansprovides an excellent model for the study of oxidative stress and redox signalling in animals. We use protein sequences from central redox systems inHomo sapiens,Drosophila melanogaster, andSaccharomyces cerevisiaeto query Genbank for homologous proteins inC. elegans. We then use maximum likelihood phylogenetic analysis to compare protein families betweenC. elegansand the other organisms to facilitate future research into the genetics of redox biology.

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Nitrosative Stress in Retinal Pathologies: Review

Antioxidants ◽

10.3390/antiox8110543 ◽

2019 ◽

Vol 8 (11) ◽

pp. 543 ◽

Cited By ~ 6

Author(s):

Antolin Cantó ◽

Teresa Olivar ◽

Francisco Javier Romero ◽

María Miranda

Keyword(s):

Lipid Membranes ◽

Nitrosative Stress ◽

Age Related Macular Degeneration ◽

Retinal Blood Flow ◽

Vascular Endothelial ◽

Nitrogen Species ◽

Cellular Functions ◽

Age Related ◽

Retinal Pathologies

Nitric oxide (NO) is a gas molecule with diverse physiological and cellular functions. In the eye, NO is used to maintain normal visual function as it is involved in photoreceptor light transduction. In addition, NO acts as a rapid vascular endothelial relaxant, is involved in the control of retinal blood flow under basal conditions and mediates the vasodilator responses of different substances such as acetylcholine, bradykinin, histamine, substance P or insulin. However, the retina is rich in polyunsaturated lipid membranes and is sensitive to the action of reactive oxygen and nitrogen species. Products generated from NO (i.e., dinitrogen trioxide (N2O3) and peroxynitrite) have great oxidative damaging effects. Oxygen and nitrogen species can react with biomolecules (lipids, proteins and DNA), potentially leading to cell death, and this is particularly important in the retina. This review focuses on the role of NO in several ocular diseases, including diabetic retinopathy, retinitis pigmentosa, glaucoma or age-related macular degeneration (AMD).

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Post-Translational S-Nitrosylation of Proteins in Regulating Cardiac Oxidative Stress

Antioxidants ◽

10.3390/antiox9111051 ◽

2020 ◽

Vol 9 (11) ◽

pp. 1051 ◽

Cited By ~ 1

Author(s):

Xiaomeng Shi ◽

Hongyu Qiu

Keyword(s):

Therapeutic Potential ◽

Heart Diseases ◽

Redox Homeostasis ◽

Redox Status ◽

Cardiac Protection ◽

Cellular Functions ◽

Post Translational Modifications ◽

Cellular Redox ◽

Novel Therapeutic Strategies

Like other post-translational modifications (PTMs) of proteins, S-nitrosylation has been considered a key regulatory mechanism of multiple cellular functions in many physiological and disease conditions. Emerging evidence has demonstrated that S-nitrosylation plays a crucial role in regulating redox homeostasis in the stressed heart, leading to discoveries in the mechanisms underlying the pathogenesis of heart diseases and cardiac protection. In this review, we summarize recent studies in understanding the molecular and biological basis of S-nitrosylation, including the formation, spatiotemporal specificity, homeostatic regulation, and association with cellular redox status. We also outline the currently available methods that have been applied to detect S-nitrosylation. Additionally, we synopsize the up-to-date studies of S-nitrosylation in various cardiac diseases in humans and animal models, and we discuss its therapeutic potential in cardiac protection. These pieces of information would bring new insights into understanding the role of S-nitrosylation in cardiac pathogenesis and provide novel avenues for developing novel therapeutic strategies for heart diseases.

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Aging reduces responsiveness to BSO- and heat stress-induced perturbations of glutathione and antioxidant enzymes

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00254.2005 ◽

2005 ◽

Vol 289 (4) ◽

pp. R1035-R1041 ◽

Cited By ~ 19

Author(s):

Joanna P. Morrison ◽

Mitchell C. Coleman ◽

Elizabeth S. Aunan ◽

Susan A. Walsh ◽

Douglas R. Spitz ◽

...

Keyword(s):

Antioxidant Enzymes ◽

Heat Stress ◽

Redox Homeostasis ◽

Buthionine Sulfoximine ◽

Sod Activity ◽

Glutamate Cysteine Ligase ◽

Age Related ◽

Rate Limiting ◽

And Oxidative Stress

Aging alters cellular responses to both heat and oxidative stress. Thiol-mediated metabolism of reactive oxygen species (ROS) is believed to be important in aging. To begin to determine the role of thiols in aging and heat stress, we depleted liver glutathione (GSH) by administering l-buthionine sulfoximine (BSO) in young (6 mo) and old (24 mo) Fisher 344 rats before heat stress. Animals were given BSO (4 mmol/kg ip) or saline (1 ml ip) 2 h before heat stress and subsequently heated to a core temperature of 41°C over a 90-min period. Liver tissue was collected before and 0, 30, and 60 min after heat stress. BSO inhibited glutamate cysteine ligase (GCL, the rate-limiting enzyme in GSH synthesis) catalytic activity and resulted in a decline in liver GSH and GSSG that was more pronounced in young compared with old animals. Catalase activity did not change between groups until 60 min after heat stress in young BSO-treated rats. Young animals experienced a substantial and persistent reduction in Cu,Zn-SOD activity with BSO treatment. Mn-SOD activity increased with BSO but declined after heat stress. The differences in thiol depletion observed between young and old animals with BSO treatment may be indicative of age-related differences in GSH compartmentalization that could have an impact on maintenance of redox homeostasis and antioxidant balance immediately after a physiologically relevant stress. The significant changes in antioxidant enzyme activity after GSH depletion suggest that thiol status can influence the regulation of other antioxidant enzymes.

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Mitochondrial Quality Control in COPD and IPF

Cells ◽

10.3390/cells7080086 ◽

2018 ◽

Vol 7 (8) ◽

pp. 86 ◽

Cited By ~ 18

Author(s):

Hiromichi Hara ◽

Kazuyoshi Kuwano ◽

Jun Araya

Keyword(s):

Quality Control ◽

Control Systems ◽

Cell Fate ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Atp Production ◽

Age Related ◽

Mitochondria Dynamics ◽

Response To Stress

Mitochondria play important roles in the maintenance of intracellular homeostasis; hence, the quality control of mitochondria is crucial for cell fate determination. Mitochondria dynamics and mitochondria-specific autophagy, known as mitophagy, are two main quality control systems in cells. Mitochondria fuse to increase energy production in response to stress, and damaged mitochondria are segregated by fission and degraded by mitophagy. Once these systems are disrupted, dysfunctional mitochondria with decreased adenosine triphosphate (ATP) production and increased reactive oxygen species (ROS) production accumulate, affecting cell fate. Recently, increasing evidence suggests that the dysregulation of mitochondria quality control is pathogenic in several age-related diseases. In this review, we outlined the role of mitochondria quality control systems in the pathogenesis of age-associated lung diseases, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF).

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Enhancing autophagy by redox regulation extends lifespan in Drosophila

10.1101/790378 ◽

2019 ◽

Author(s):

Helena M. Cochemé ◽

Ivana Bjedov ◽

Sebastian Grönke ◽

Katja E. Menger ◽

Andrew M. James ◽

...

Keyword(s):

Redox Regulation ◽

Redox Homeostasis ◽

Model Organism ◽

Fruit Fly ◽

Cysteine Residue ◽

Lifespan Extension ◽

Post Translational Modification ◽

Redox Signalling ◽

Age Related

Redox signalling is an important modulator of diverse biological pathways and processes, and operates through specific post-translational modification of redox-sensitive thiols on cysteine residues 1–4. Critically, redox signalling is distinct from irreversible oxidative damage and functions as a reversible ‘redox switch’ to regulate target proteins. H2O2 acts as the major effector of redox signalling, both directly and through intracellular thiol redox relays 5,6. Dysregulation of redox homeostasis has long been implicated in the pathophysiology of many age-related diseases, as well as in the ageing process itself, however the underlying mechanisms remain largely unclear 7,8. To study redox signalling by H2O2in vivo and explore its involvement in metabolic health and longevity, we used the fruit fly Drosophila as a model organism, with its tractable lifespan and strong evolutionary conservation with mammals 9. Here we report that inducing an endogenous redox-shift, by manipulating levels of the H2O2-degrading enzyme catalase, improves health and robustly extends lifespan in flies, independently of oxidative stress resistance and dietary restriction. We find that the catalase redox-shifted flies are acutely sensitive to starvation stress, which relies on autophagy as a vital survival mechanism. Importantly, we show that autophagy is essential for the lifespan extension of the catalase flies. Furthermore, using redox-inactive knock-in mutants of Atg4a, a major effector of autophagy, we show that the lifespan extension in response to catalase requires a key redox-regulatory cysteine residue, Cys102 in Atg4a. These findings demonstrate that redox regulation of autophagy can extend lifespan, confirming the importance of redox signalling in ageing and as a potential pro-longevity target.

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mTOR and Aging: An Old Fashioned Dress

International Journal of Molecular Sciences ◽

10.3390/ijms20112774 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2774 ◽

Cited By ~ 11

Author(s):

Giovanni Stallone ◽

Barbara Infante ◽

Concetta Prisciandaro ◽

Giuseppe Grandaliano

Keyword(s):

Mammalian Target Of Rapamycin ◽

Nutrient Sensing ◽

Protective Effects ◽

Cellular Functions ◽

Cellular Processes ◽

Age Related ◽

Signalling Network ◽

Evolutionarily Conserved ◽

Mtor Signalling

Aging is a physiologic/pathologic process characterized by a progressive impairment of cellular functions, supported by the alterations of several molecular pathways, leading to an increased cell susceptibility to injury. This deterioration is the primary risk factor for several major human pathologies. Numerous cellular processes, including genomic instability, telomere erosion, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, stem cell exhaustion, and altered intercellular signal transduction represent common denominators of aging in different organisms. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved nutrient sensing protein kinase that regulates growth and metabolism in all eukaryotic cells. Studies in flies, worms, yeast, and mice support the hypothesis that the mTOR signalling network plays a pivotal role in modulating aging. mTOR is emerging as the most robust mediator of the protective effects of various forms of dietary restriction, which has been shown to extend lifespan and slow the onset of age-related diseases across species. Herein we discuss the role of mTor signalling network in the development of classic age-related diseases, focused on cardiovascular system, immune response, and cancer.

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Bioactive Polyphenols and Neuromodulation: Molecular Mechanisms in Neurodegeneration

International Journal of Molecular Sciences ◽

10.3390/ijms21072564 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2564 ◽

Cited By ~ 5

Author(s):

Francesco Di Meo ◽

Anna Valentino ◽

Orsolina Petillo ◽

Gianfranco Peluso ◽

Stefania Filosa ◽

...

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Web Of Science ◽

Cellular Functions ◽

Active Metabolites ◽

Dietary Polyphenols ◽

Age Related ◽

Age Related Cognitive Decline ◽

Preventive Effects

The interest in dietary polyphenols in recent years has greatly increased due to their antioxidant bioactivity with preventive properties against chronic diseases. Polyphenols, by modulating different cellular functions, play an important role in neuroprotection and are able to neutralize the effects of oxidative stress, inflammation, and apoptosis. Interestingly, all these mechanisms are involved in neurodegeneration. Although polyphenols display differences in their effectiveness due to interindividual variability, recent studies indicated that bioactive polyphenols in food and beverages promote health and prevent age-related cognitive decline. Polyphenols have a poor bioavailability and their digestion by gut microbiota produces active metabolites. In fact, dietary bioactive polyphenols need to be modified by microbiota present in the intestine before being absorbed, and to exert health preventive effects by interacting with cellular signalling pathways. This literature review includes an evaluation of the literature in English up to December 2019 in PubMed and Web of Science databases. A total of 307 studies, consisting of research reports, review articles and articles were examined and 146 were included. The review highlights the role of bioactive polyphenols in neurodegeneration, with a particular emphasis on the cellular and molecular mechanisms that are modulated by polyphenols involved in protection from oxidative stress and apoptosis prevention.

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Age-Related Mitochondrial Impairment and Renal Injury Is Ameliorated by Sulforaphane via Activation of Transcription Factor NRF2

Antioxidants ◽

10.3390/antiox11010156 ◽

2022 ◽

Vol 11 (1) ◽

pp. 156

Author(s):

Razia Sultana Mohammad ◽

Mustafa F. Lokhandwala ◽

Anees A. Banday

Keyword(s):

Transcription Factor ◽

Mitochondrial Function ◽

Redox Homeostasis ◽

Fischer 344 Rats ◽

Kidney Dysfunction ◽

Fischer 344 ◽

Mitochondrial Impairment ◽

Age Related ◽

Nrf2 Expression

Age is one of the major risk factors for the development of chronic pathologies, including kidney diseases. Oxidative stress and mitochondrial dysfunction play a pathogenic role in aging kidney disease. Transcription factor NRF2, a master regulator of redox homeostasis, is altered during aging, but the exact implications of altered NRF2 signaling on age-related renal mitochondrial impairment are not yet clear. Herein, we investigated the role of sulforaphane, a well-known NRF2 activator, on age-related mitochondrial and kidney dysfunction. Young (2–4 month) and aged (20–24 month) male Fischer 344 rats were treated with sulforaphane (15 mg/kg body wt/day) in drinking water for four weeks. We observed significant impairment in renal cortical mitochondrial function along with perturbed redox homeostasis, decreased kidney function and marked impairment in NRF2 signaling in aged Fischer 344 rats. Sulforaphane significantly improved mitochondrial function and ameliorated kidney injury by increasing cortical NRF2 expression and activity and decreasing protein expression of KEAP1, an NRF2 repressor. Sulforaphane treatment did not affect the renal NRF2 expression or activity and mitochondrial function in young rats. Taken together, our results provide novel insights into the protective role of the NRF2 pathway in kidneys during aging and highlight the therapeutic potential of sulforaphane in mitigating kidney dysfunction in elders.

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