scholarly journals Enhancing autophagy by redox regulation extends lifespan in Drosophila

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.

scholarly journals Redox signalling and ageing: insights from Drosophila

2020 ◽  
Vol 48 (2) ◽  
pp. 367-377 ◽  
Author(s):  
Claudia Lennicke ◽  
Helena M. Cochemé
Keyword(s):  
Biological Effects ◽  
Fruit Fly ◽  
Model Organisms ◽  
Redox Signalling ◽  
Age Related ◽  
The Social ◽  
Low Levels ◽  
Specific Species

Ageing and age-related diseases are major challenges for the social, economic and healthcare systems of our society. Amongst many theories, reactive oxygen species (ROS) have been implicated as a driver of the ageing process. As by-products of aerobic metabolism, ROS are able to randomly oxidise macromolecules, causing intracellular damage that accumulates over time and ultimately leads to dysfunction and cell death. However, the genetic overexpression of enzymes involved in the detoxification of ROS or treatment with antioxidants did not generally extend lifespan, prompting a re-evaluation of the causal role for ROS in ageing. More recently, ROS have emerged as key players in normal cellular signalling by oxidising redox-sensitive cysteine residues within proteins. Therefore, while high levels of ROS may be harmful and induce oxidative stress, low levels of ROS may actually be beneficial as mediators of redox signalling. In this context, enhancing ROS production in model organisms can extend lifespan, with biological effects dependent on the site, levels, and specific species of ROS. In this review, we examine the role of ROS in ageing, with a particular focus on the importance of the fruit fly Drosophila as a powerful model system to study redox processes in vivo.

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

2018 ◽  
Vol 2018 ◽  
pp. 1-19 ◽  
Author(s):  
M. Pajares ◽  
A. Cuadrado ◽  
N. Engedal ◽  
Z. Jirsova ◽  
M. Cahova
Keyword(s):  
Control Systems ◽  
Redox Homeostasis ◽  
Biological Macromolecules ◽  
Complex Relationship ◽  
Cellular Functions ◽  
Related Disorder ◽  
Redox Signalling ◽  
Age Related ◽  
Integral Role

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.

scholarly journals SUMF1 enhances sulfatase activities in vivo in five sulfatase deficiencies

2007 ◽  
Vol 403 (2) ◽  
pp. 305-312 ◽  
Author(s):  
Alessandro Fraldi ◽  
Alessandra Biffi ◽  
Alessia Lombardi ◽  
Ilaria Visigalli ◽  
Stefano Pepe ◽  
...  
Keyword(s):  
Cysteine Residue ◽  
Chondrodysplasia Punctata ◽  
Post Translational Modification ◽  
Adeno Associated Virus ◽  
Diverse Range ◽  
Enhancing Effect ◽  
Multiple Sulfatase Deficiency ◽  
Sulfatase Activity ◽  
Lentivirus Vectors

Sulfatases are enzymes that hydrolyse a diverse range of sulfate esters. Deficiency of lysosomal sulfatases leads to human diseases characterized by the accumulation of either GAGs (glycosaminoglycans) or sulfolipids. The catalytic activity of sulfatases resides in a unique formylglycine residue in their active site generated by the post-translational modification of a highly conserved cysteine residue. This modification is performed by SUMF1 (sulfatase-modifying factor 1), which is an essential factor for sulfatase activities. Mutations in the SUMF1 gene cause MSD (multiple sulfatase deficiency), an autosomal recessive disease in which the activities of all sulfatases are profoundly reduced. In previous studies, we have shown that SUMF1 has an enhancing effect on sulfatase activity when co-expressed with sulfatase genes in COS-7 cells. In the present study, we demonstrate that SUMF1 displays an enhancing effect on sulfatases activity when co-delivered with a sulfatase cDNA via AAV (adeno-associated virus) and LV (lentivirus) vectors in cells from individuals affected by five different diseases owing to sulfatase deficiencies or from murine models of the same diseases [i.e. MLD (metachromatic leukodystrophy), CDPX (X-linked dominant chondrodysplasia punctata) and MPS (mucopolysaccharidosis) II, IIIA and VI]. The SUMF1-enhancing effect on sulfatase activity resulted in an improved clearance of the intracellular GAG or sulfolipid accumulation. Moreover, we demonstrate that the SUMF1-enhancing effect is also present in vivo after AAV-mediated delivery of the sulfamidase gene to the muscle of MPSIIIA mice, resulting in a more efficient rescue of the phenotype. These results indicate that co-delivery of SUMF1 may enhance the efficacy of gene therapy in several sulfatase deficiencies.

scholarly journals Arabidopsis glutathione reductase 2 is indispensable in plastids, while mitochondrial glutathione is safeguarded by additional reduction and transport systems

2019 ◽  
Author(s):  
Laurent Marty ◽  
Daniela Bausewein ◽  
Christopher Müller ◽  
Sajid Ali Khan Bangash ◽  
Anna Moseler ◽  
...  
Keyword(s):  
Glutathione Reductase ◽  
Redox Regulation ◽  
Redox Homeostasis ◽  
Immunogold Labelling ◽  
Transport Systems ◽  
List Type ◽  
Iron Sulfur Cluster ◽  
Thioredoxin System ◽  
Glutathione Redox

SummaryA highly negative glutathione redox potential (EGSH) is maintained in the cytosol, plastids and mitochondria of plant cells to support fundamental processes, including antioxidant defence, redox regulation and iron-sulfur cluster biogenesis. Out of two glutathione reductase (GR) proteins in Arabidopsis, GR2 is predicted to be dual-targeted to plastids and mitochondria, but its differential roles in these organelles remain unclear.We dissected the role of GR2 in organelle glutathione redox homeostasis and plant development using a combination of genetic complementation and stacked mutants, biochemical activity studies, immunogold labelling and in vivo biosensing.Our data demonstrate that GR2 is dual-targeted to plastids and mitochondria, but embryo lethality of gr2 null mutants is caused specifically in plastids. Whereas lack of mitochondrial GR2 leads to a partially oxidised glutathione pool in the matrix, the ABC transporter ATM3 and the mitochondrial thioredoxin system provide functional backup and maintain plant viability.We identify GR2 as essential in the plastid stroma, where it counters GSSG accumulation and developmental arrest. By contrast a functional triad of GR2, ATM3 and the thioredoxin system in the mitochondria provides resilience to excessive glutathione oxidation.

Fly-on-a-Chip: Microfluidics for Drosophila melanogaster Studies

2019 ◽  
Vol 11 (12) ◽  
pp. 425-443 ◽  
Author(s):  
Alireza Zabihihesari ◽  
Arthur J Hilliker ◽  
Pouya Rezai
Keyword(s):  
Drosophila Melanogaster ◽  
Developmental Stages ◽  
Model Organism ◽  
Fruit Fly ◽  
In Vitro Assays ◽  
Behavioral Studies ◽  
And Behavior ◽  
Manual Manipulation

Abstract The fruit fly or Drosophila melanogaster has been used as a promising model organism in genetics, developmental and behavioral studies as well as in the fields of neuroscience, pharmacology, and toxicology. Not only all the developmental stages of Drosophila, including embryonic, larval, and adulthood stages, have been used in experimental in vivo biology, but also the organs, tissues, and cells extracted from this model have found applications in in vitro assays. However, the manual manipulation, cellular investigation and behavioral phenotyping techniques utilized in conventional Drosophila-based in vivo and in vitro assays are mostly time-consuming, labor-intensive, and low in throughput. Moreover, stimulation of the organism with external biological, chemical, or physical signals requires precision in signal delivery, while quantification of neural and behavioral phenotypes necessitates optical and physical accessibility to Drosophila. Recently, microfluidic and lab-on-a-chip devices have emerged as powerful tools to overcome these challenges. This review paper demonstrates the role of microfluidic technology in Drosophila studies with a focus on both in vivo and in vitro investigations. The reviewed microfluidic devices are categorized based on their applications to various stages of Drosophila development. We have emphasized technologies that were utilized for tissue- and behavior-based investigations. Furthermore, the challenges and future directions in Drosophila-on-a-chip research, and its integration with other advanced technologies, will be discussed.

scholarly journals The RxxRxRxxC motif conserved in all Rel/kappa B proteins is essential for the DNA-binding activity and redox regulation of the v-Rel oncoprotein.

1992 ◽  
Vol 12 (7) ◽  
pp. 3094-3106 ◽  
Author(s):  
S Kumar ◽  
A B Rabson ◽  
C Gélinas
Keyword(s):  
Dna Binding ◽  
Transcriptional Activation ◽  
Redox Regulation ◽  
Biological Activities ◽  
Cysteine Residue ◽  
Binding Activity ◽  
Lymphoid Cells ◽  
Redox Control ◽  
Dna Binding Activity

The v- and c-Rel oncoproteins bind to oligonucleotides containing kappa B motifs, form heterodimers with other members of the Rel family, and modulate expression of genes linked to kappa B motifs. Here, we report that the RxxRxRxxC motif conserved in all Rel/kappa B family proteins is absolutely required for v-Rel protein-DNA contact and its resulting transforming activity. We also demonstrate that serine substitution of the cysteine residue conserved within this motif enables v-Rel to escape redox control, thereby promoting overall DNA binding. These mutant proteins retained the ability to competitively inhibit kappa B-mediated transcriptional activation of the human immunodeficiency virus long terminal repeat but failed to efficiently transform chicken lymphoid cells both in vitro and in vivo. Our data indicate that reduction of the conserved cysteine residue in the RxxRxRxxC motif may be required for optimal DNA-protein interactions. These results provide direct biochemical evidence that the DNA-binding activity of v-Rel is subject to redox control and that the conserved cysteine residue in the RxxRxRxxC motif is critical for this regulation. These studies suggest that the DNA-binding, transcriptional, and biological activities of Rel family proteins may also be subject to redox control in vivo.

scholarly journals Global profiling of distinct cysteine redox forms reveals wide-ranging redox regulation in C. elegans

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jin Meng ◽  
Ling Fu ◽  
Keke Liu ◽  
Caiping Tian ◽  
Ziyun Wu ◽  
...  
Keyword(s):  
Redox Regulation ◽  
Mapk Pathway ◽  
Model Organism ◽  
Redox Signaling ◽  
P38 Map Kinase ◽  
Redox Biology ◽  
C Elegans ◽  
Protein Functions ◽  
Redox Forms

AbstractPost-translational changes in the redox state of cysteine residues can rapidly and reversibly alter protein functions, thereby modulating biological processes. The nematode C. elegans is an ideal model organism for studying cysteine-mediated redox signaling at a network level. Here we present a comprehensive, quantitative, and site-specific profile of the intrinsic reactivity of the cysteinome in wild-type C. elegans. We also describe a global characterization of the C. elegans redoxome in which we measured changes in three major cysteine redox forms after H2O2 treatment. Our data revealed redox-sensitive events in translation, growth signaling, and stress response pathways, and identified redox-regulated cysteines that are important for signaling through the p38 MAP kinase (MAPK) pathway. Our in-depth proteomic dataset provides a molecular basis for understanding redox signaling in vivo, and will serve as a valuable and rich resource for the field of redox biology.

scholarly journals Nrf2 activation induces mitophagy and reverses Parkin/Pink1 knock down-mediated neuronal and muscle degeneration phenotypes

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Sentiljana Gumeni ◽  
Eleni-Dimitra Papanagnou ◽  
Maria S. Manola ◽  
Ioannis P. Trougakos
Keyword(s):  
Critical Role ◽  
Model Organism ◽  
Dependent Manner ◽  
Degenerative Diseases ◽  
Knock Down ◽  
Age Related ◽  
Degenerative Disorders ◽  
Pathway Activation

AbstractThe balanced functionality of cellular proteostatic modules is central to both proteome stability and mitochondrial physiology; thus, the age-related decline of proteostasis also triggers mitochondrial dysfunction, which marks multiple degenerative disorders. Non-functional mitochondria are removed by mitophagy, including Parkin/Pink1-mediated mitophagy. A common feature of neuronal or muscle degenerative diseases, is the accumulation of damaged mitochondria due to disrupted mitophagy rates. Here, we exploit Drosophila as a model organism to investigate the functional role of Parkin/Pink1 in regulating mitophagy and proteostatic responses, as well as in suppressing degenerative phenotypes at the whole organism level. We found that Parkin or Pink1 knock down in young flies modulated proteostatic components in a tissue-dependent manner, increased cell oxidative load, and suppressed mitophagy in neuronal and muscle tissues, causing mitochondrial aggregation and neuromuscular degeneration. Concomitant to Parkin or Pink1 knock down cncC/Nrf2 overexpression, induced the proteostasis network, suppressed oxidative stress, restored mitochondrial function, and elevated mitophagy rates in flies’ tissues; it also, largely rescued Parkin or Pink1 knock down-mediated neuromuscular degenerative phenotypes. Our in vivo findings highlight the critical role of the Parkin/Pink1 pathway in mitophagy, and support the therapeutic potency of Nrf2 (a druggable pathway) activation in age-related degenerative diseases.

scholarly journals Anti-Apoptosis and Autophagy Effects of Melatonin Protect Rat Chondrocytes against Oxidative Stress via Regulation of AMPK/Foxo3 Pathways

Cartilage ◽  
2021 ◽  
pp. 194760352110387
Author(s):  
Zhaoxun Chen ◽  
Chen Zhao ◽  
Pengcheng Liu ◽  
Haohan Huang ◽  
Shuhong Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Western Blotting ◽  
Redox Homeostasis ◽  
Cartilage Degeneration ◽  
Cell Counting ◽  
Autophagic Flux ◽  
Sprague Dawley ◽  
Melatonin Treatment ◽  
Age Related

Objective Emerging evidence has indicated that excessive reactive oxygen species (ROS) have detrimental effects on osteoarthritis (OA). This study aimed to elucidate the effects of melatonin (MT), an antioxidant indolamine secreted from the pineal gland, on chondrocyte senescence and cartilage degeneration, thereby clarifying the underlying mechanisms of ROS-induced OA pathogenesis. Design Hydrogen peroxide (H2O2) was used to induce oxidative stress in rat chondrocytes. ROS levels were evaluated using cytometry and immunofluorescence. Cell viability was detected using the Cell Counting Kit-8 (CCK-8) assay. Western blotting and qPCR (Quantiative Real-Time Polymerase Chain Reaction) were used to examine apoptosis and autophagy. For in vivo experiments, male Sprague-Dawley rats were randomly divided into a sham-operated group, DMM (destabilization of the medial meniscus) surgery group, and surgery groups that received melatonin. Knee joints were collected and stained for histological analysis. Results The data demonstrated that melatonin treatment significantly suppressed H2O2-induced matrix degradation and apoptosis, and maintained mitochondrial redox homeostasis. In addition, an enhancement of autophagic flux was observed through western blotting. These findings corresponded with activation of the AMPK/Foxo3 signaling pathways upon melatonin treatment. Histological staining and transmission electron microscopy (TEM) micrographs also demonstrated that melatonin alleviated cartilage ossification and chondrocyte hypertrophy in vivo. Conclusions Our results indicated that melatonin protected chondrocytes via mitochondrial redox homeostasis and autophagy. The effects of melatonin on senescence may apply to other age-related diseases. Thus, melatonin may have multiple potential therapeutic applications.

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