scholarly journals Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation

2018 ◽  
Author(s):  
David Guerrero-Gómez ◽  
José Antonio Mora-Lorca ◽  
Beatriz Sáenz-Narciso ◽  
Francisco José Naranjo-Galindo ◽  
Fernando Muñoz-Lobato ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Glutathione Reductase ◽  
Mammalian Cells ◽  
Nuclear Translocation ◽  
Redox Homeostasis ◽  
Redox Status ◽  
C Elegans ◽  
Physiological Importance ◽  
Dramatic Shift ◽  
Glutathione Redox

ABSTRACTIn the presence of aggregation-prone proteins, the cytosol and endoplasmic reticulum (ER) undergo a dramatic shift in their respective redox status, with the cytosol becoming more oxidized and the ER more reducing. However, whether and how changes in the cellular redox status may affect protein aggregation is unknown. Here, we show that C. elegans mutants lacking glutathione reductase gsr-1 gene enhance the deleterious phenotypes of heterologous human as well as endogenous worm aggregation-prone proteins. These effects are phenocopied by the GSH depleting agent diethyl maleate. Additionally, gsr-1 mutants abolish the nuclear translocation of HLH-30/TFEB transcription factor, a key inducer of autophagy, and strongly impair the degradation of the autophagy substrate p62/SQST-1::GFP, revealing glutathione reductase may have a role in the clearance of protein aggregates by autophagy. Blocking autophagy in gsr-1 worms expressing aggregation-prone proteins results in strong synthetic developmental phenotypes and lethality, supporting the physiological importance of glutathione reductase in the regulation of misfolded protein clearance. Furthermore, impairing redox homeostasis in both yeast and mammalian cells induces toxicity phenotypes associated with protein aggregation. Together, our data reveal that glutathione redox homeostasis may be central to proteostasis maintenance through autophagy regulation.

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.

Compartmentalization and metabolic regulation of glycolysis

2021 ◽  
Vol 134 (20) ◽  
Author(s):  
Gregory G. Fuller ◽  
John K. Kim
Keyword(s):  
Protein Interactions ◽  
Mammalian Cells ◽  
Energy Production ◽  
Metabolic Regulation ◽  
Tca Cycle ◽  
Synaptic Function ◽  
Protein Protein Interactions ◽  
C Elegans ◽  
Physiological Importance ◽  
Condensate Formation

ABSTRACT Hypoxia inhibits the tricarboxylic acid (TCA) cycle and leaves glycolysis as the primary metabolic pathway responsible for converting glucose into usable energy. However, the mechanisms that compensate for this loss in energy production due to TCA cycle inactivation remain poorly understood. Glycolysis enzymes are typically diffuse and soluble in the cytoplasm under normoxic conditions. In contrast, recent studies have revealed dynamic compartmentalization of glycolysis enzymes in response to hypoxic stress in yeast, C. elegans and mammalian cells. These messenger ribonucleoprotein (mRNP) structures, termed glycolytic (G) bodies in yeast, lack membrane enclosure and display properties of phase-separated biomolecular condensates. Disruption of condensate formation correlates with defects such as impaired synaptic function in C. elegans neurons and decreased glucose flux in yeast. Concentrating glycolysis enzymes into condensates may lead to their functioning as ‘metabolons’ that enhance rates of glucose utilization for increased energy production. Besides condensates, glycolysis enzymes functionally associate in other organisms and specific tissues through protein–protein interactions and membrane association. However, as discussed in this Review, the functional consequences of coalescing glycolytic machinery are only just beginning to be revealed. Through ongoing studies, we anticipate the physiological importance of metabolic regulation mediated by the compartmentalization of glycolysis enzymes will continue to emerge.

scholarly journals CAMKII and Calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Li Tao ◽  
Qi Xie ◽  
Yue-He Ding ◽  
Shang-Tong Li ◽  
Shengyi Peng ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Nuclear Localization ◽  
Insulin Signaling ◽  
Mammalian Cells ◽  
Nuclear Translocation ◽  
Type Ii ◽  
Wild Type ◽  
C Elegans ◽  
Foxo Transcription Factors ◽  
Lifespan Regulation

The insulin-like signaling pathway maintains a relatively short wild-type lifespan in Caenorhabditis elegans by phosphorylating and inactivating DAF-16, the ortholog of the FOXO transcription factors of mammalian cells. DAF-16 is phosphorylated by the AKT kinases, preventing its nuclear translocation. Calcineurin (PP2B phosphatase) also limits the lifespan of C. elegans, but the mechanism through which it does so is unknown. Herein, we show that TAX-6•CNB-1 and UNC-43, the C. elegans Calcineurin and Ca2+/calmodulin-dependent kinase type II (CAMKII) orthologs, respectively, also regulate lifespan through DAF-16. Moreover, UNC-43 regulates DAF-16 in response to various stress conditions, including starvation, heat or oxidative stress, and cooperatively contributes to lifespan regulation by insulin signaling. However, unlike insulin signaling, UNC-43 phosphorylates and activates DAF-16, thus promoting its nuclear localization. The phosphorylation of DAF-16 at S286 by UNC-43 is removed by TAX-6•CNB-1, leading to DAF-16 inactivation. Mammalian FOXO3 is also regulated by CAMKIIA and Calcineurin.

scholarly journals GLUTATHIONE REDOX STATUS ALTERS THE DIMERIC-MONOMERIC EQUILIBRIUM OF HUMAN GLUTATHIONE REDUCTASE. + 1228

1996 ◽  
Vol 39 ◽  
pp. 207-207
Author(s):  
Jonathan F Elliston ◽  
Hiram F Gilbert ◽  
Charles V Smith ◽  
Thomas N Hansen
Keyword(s):  
Glutathione Reductase ◽  
Redox Status ◽  
Glutathione Redox

scholarly journals P. Edulis Extract Protects Against Amyloid-β Toxicity in Alzheimer’s Disease Models Through Maintenance of Mitochondrial Homeostasis via the FOXO3/DAF-16 Pathway

2021 ◽  
Author(s):  
Shu-qin Cao ◽  
Yahyah Aman ◽  
Evandro Fei Fang ◽  
Tewin Tencomnao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mammalian Cells ◽  
Nuclear Translocation ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
C Elegans ◽  
Drug Candidates ◽  
Mitochondrial Homeostasis ◽  
Amyloid Aβ

Abstract Alzheimer’s disease (AD) is a common and devastating disease characterized by pathological aggregations of beta-amyloid (Aβ) plaques extracellularly, and Tau tangles intracellularly. While our understandings of the aetiologies of AD have greatly expanded over the decades, there is no drug available to stop disease progression. Here, we demonstrate the potential of P. edulis pericarp extract in protecting against Aβ-mediated neurotoxicity in mammalian cells and Caenorhabditis elegans models of AD. We show P. edulis pericarp protects against memory deficit, neuronal loss, and promotes longevity in the Aβ model of AD via stimulation of mitophagy, a selective cellular clearance of damaged and dysfunctional mitochondria. P. edulis pericarp also restores memory and increases neuronal resilience in a C. elegans Tau model of AD. While defective mitophagy-induced accumulation of damaged mitochondria contributes to AD progression, P. edulis pericarp improves mitochondrial homeostasis through NIX/DCT1-dependent mitophagy and SOD3-dependent mitochondrial resilience, both via increased nuclear translocation of the upstream transcriptional regulator FOXO3/DAF-16. Further studies to identify active molecules in P. edulis pericarp that could maintain neuronal mitochondrial homeostasis may enable the development of potential drug candidates for AD.

Antifungal Activity Directed Toward the Cell Wall by 2-Cyclohexylidenhydrazo- 4-Phenyl-Thiazole Against Candida albicans

2019 ◽  
Vol 19 (4) ◽  
pp. 428-438 ◽  
Author(s):  
Nívea P. de Sá ◽  
Ana P. Pôssa ◽  
Pilar Perez ◽  
Jaqueline M.S. Ferreira ◽  
Nayara C. Fonseca ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Mammalian Cells ◽  
C Elegans ◽  
Buccal Epithelial Cells ◽  
Mutant Strains ◽  
Low Toxicity ◽  
High Concentrations ◽  
Mic Value

<p>Background: The increasing incidence of invasive forms of candidiasis and resistance to antifungal therapy leads us to seek new and more effective antifungal compounds. </P><P> Objective: To investigate the antifungal activity and toxicity as well as to evaluate the potential targets of 2- cyclohexylidenhydrazo-4-phenyl-thiazole (CPT) in Candida albicans. </P><P> Methods: The antifungal activity of CPT against the survival of C. albicans was investigated in Caenorhabditis elegans. Additionally, we determined the effect of CPT on the inhibition of C. albicans adhesion capacity to buccal epithelial cells (BECs), the toxicity of CPT in mammalian cells, and the potential targets of CPT in C. albicans. </P><P> Results: CPT exhibited a minimum inhibitory concentration (MIC) value of 0.4-1.9 µg/mL. Furthermore, CPT at high concentrations (>60 x MIC) showed no or low toxicity in HepG2 cells and <1% haemolysis in human erythrocytes. In addition, CPT decreased the adhesion capacity of yeasts to the BECs and prolonged the survival of C. elegans infected with C. albicans. Analysis of CPT-treated cells showed that their cell wall was thinner than that of untreated cells, especially the glucan layer. We found that there was a significantly lower quantity of 1,3-β-D-glucan present in CPT-treated cells than that in untreated cells. Assays performed on several mutant strains showed that the MIC value of CPT was high for its antifungal activity on yeasts with defective 1,3-β-glucan synthase. </P><P> Conclusion: In conclusion, CPT appears to target the cell wall of C. albicans, exhibits low toxicity in mammalian cells, and prolongs the survival of C. elegans infected with C. albicans.</p>

scholarly journals Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mercedes M. Pérez-Jiménez ◽  
José M. Monje-Moreno ◽  
Ana María Brokate-Llanos ◽  
Mónica Venegas-Calerón ◽  
Alicia Sánchez-García ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Caenorhabditis Elegans ◽  
Protein Aggregation ◽  
Steroid Hormones ◽  
Sensory Neurons ◽  
Environmental Cues ◽  
Steroid Sulfatase ◽  
Loss Of Function ◽  
C Elegans ◽  
Age Related

AbstractAging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer’s disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.

scholarly journals Alterations in glutathione redox homeostasis among adolescents with obesity and anemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dalal Alkazemi ◽  
Abdur Rahman ◽  
Banan Habra
Keyword(s):  
Defense Mechanism ◽  
Dynamic Balance ◽  
Redox Homeostasis ◽  
Redox Status ◽  
Cross Sectional Study ◽  
Normal Weight ◽  
Overweight And Obesity ◽  
Metabolic Disturbances ◽  
Cross Sectional ◽  
Gpx Activity

AbstractThe reduced (GSH)-to-oxidized (GSSG) glutathione ratio represents a dynamic balance between oxidants and antioxidants. However, redox status in adolescents with obesity and anemia has not been investigated. This study investigated the association of erythrocyte GSH redox status (GSH, GSH:GSSG ratio, and glutathione peroxidase [GPx] activity) with anemia and adiposity in adolescents. This case–control study nested in a cross-sectional study enrolled 524 adolescents (268 boys; 256 girls). The prevalence of anemia in overweight and obesity (OWOB) was 5.2% in boys and 11.7% in girls. The GSH:GSSG ratio and GPx activity were significantly higher in girls than in boys (p < 0.001), in anemic than in non-anemic subjects (p < 0.001), and in OWOB than in normal-weight subjects (p < 0.001). Similarly, significantly higher GSH: GSSG level (p < 0.001) and GPx activity (p < 0.001) were found in subjects with 90th percentile waist circumference than in those with < 90th percentile. GPx and GSH:GSSG were positively associated with anemia after adjusting for age, sex, and body mass index (adjusted odds ratio, adjOR [95% confidence interval, CI] 2.18 [1.44–3.29]) or tertiles (adjOR [95% CI], T3 = 2.49 [1.03–6.01]). A similar association was noted for GSH and GPx. A compensatory increased redox defense mechanism exists in anemia and obesity among adolescents without metabolic disturbances.

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