Modulation of Subcellular Redox Homeostasis with Trialkylphosphines

Jade Noémie Nam Nguyen
SWISS CHEMICAL SOC, 2022
Article

Redox homeostasis is essential for cell function and its disruption is associated with multiple pathologies. Redox balance is largely regulated by the relative concentrations of reduced (GSH) and oxidized (GSSG) glutathione. In eukaryotic cells, this ratio is different in each cell compartment. There is a lack of chemical probes able to modulate GSH/GSSG to study the impact of redox stress in an organelle specific manner. Here, we highlight the importance of trialkylphosphines to induce reductive stress and how it can be targeted to a specific organelle. Our probe is selectively activated by endogenous nitroreductases, and releases tributylphosphine to trigger redox stress in mitochondria. Mechanistic studies revealed that the induced stress activates a cellular response orchestrated by transcription factor ATF4, which upregulates genes involved in glutathione catabolism.

À propos de ce résultat

Cette page est générée automatiquement et peut contenir des informations qui ne sont pas correctes, complètes, à jour ou pertinentes par rapport à votre recherche. Il en va de même pour toutes les autres pages de ce site. Veillez à vérifier les informations auprès des sources officielles de l'EPFL.

Concepts associés

Chargement

Publications associées

Chargement

Jade Noémie Nam Nguyen
SWISS CHEMICAL SOC, 2022
Article

Résumé

Official source

https://infoscience.epfl.ch/record/295840?ln=fr

À propos de ce résultat

Concepts associés (11)

Concepts associés

Chargement

Publications associées (4)

Chargement

Afficher plus

Publications associées

Chargement

Glutathion

Le glutathion est un pseudo-tripeptide formé par la condensation d'acide glutamique, de cystéine et de glycine : . Le glutathion, qui existe sous forme oxydée et réduite, intervient dans le maintien

Homéostasie

En biologie et en systémique, l’homéostasie est un phénomène par lequel un facteur clé (par exemple, la température) est maintenu autour d'une valeur bénéfique pour le système considéré, grâce à un

Biologie cellulaire

thumb|Détection de filaments d'actine dans des cellules animales (immunofluorescence) La biologie cellulaire (anciennement appelée cytologie) est une discipline scientifique qui étudie les cellules,

Disruption of mitochondrial redox homeostasis by enzymatic activation of a trialkylphosphine probe

Jade Noémie Nam Nguyen, Pablo Rivera Fuentes

Redox homeostasis is essential for cell function and its disruption is associated with multiple pathologies. Redox balance is largely regulated by the relative concentrations of reduced and oxidized glutathione. In eukaryotic cells, this ratio is different in each cell compartment, and disruption of the mitochondrial redox balance has been specifically linked to metabolic diseases. Here, we report a probe that is selectively activated by endogenous nitroreductases, and releases tributylphosphine to trigger redox stress in mitochondria. Mechanistic studies revealed that, counterintuitively, release of a reducing agent in mitochondria rapidly induced oxidative stress through accumulation of superoxide. This response is mediated by glutathione, suggesting a link between reductive and oxidative stress. Furthermore, mitochondrial redox stress activates a cellular response orchestrated by transcription factor ATF4, which upregulates genes involved in glutathione catabolism.

ROYAL SOC CHEMISTRY2021

Chargement

Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability

Igor Allaman, Thierry Laroche, Hilal Lashuel, Pierre Magistretti, David Viertl

Amyloid-beta (Abeta) peptides play a key role in the pathogenesis of Alzheimer's disease and exert various toxic effects on neurons; however, relatively little is known about their influence on glial cells. Astrocytes play a pivotal role in brain homeostasis, contributing to the regulation of local energy metabolism and oxidative stress defense, two aspects of importance for neuronal viability and function. In the present study, we explored the effects of Abeta peptides on glucose metabolism in cultured astrocytes. Following Abeta(25-35) exposure, we observed an increase in glucose uptake and its various metabolic fates, i.e., glycolysis (coupled to lactate release), tricarboxylic acid cycle, pentose phosphate pathway, and incorporation into glycogen. Abeta increased hydrogen peroxide production as well as glutathione release into the extracellular space without affecting intracellular glutathione content. A causal link between the effects of Abeta on glucose metabolism and its aggregation and internalization into astrocytes through binding to members of the class A scavenger receptor family could be demonstrated. Using astrocyte-neuron cocultures, we observed that the overall modifications of astrocyte metabolism induced by Abeta impair neuronal viability. The effects of the Abeta(25-35) fragment were reproduced by Abeta(1-42) but not by Abeta(1-40). Finally, the phosphoinositide 3-kinase (PI3-kinase) pathway appears to be crucial in these events since both the changes in glucose utilization and the decrease in neuronal viability are prevented by LY294002, a PI3-kinase inhibitor. This set of observations indicates that Abeta aggregation and internalization into astrocytes profoundly alter their metabolic phenotype with deleterious consequences for neuronal viability.

2010

Chargement

Genetic Polymorphism Associated Prefrontal Glutathione and Its Coupling With Brain Glutamate and Peripheral Redox Status in Early Psychosis

Rolf Gruetter, Huanxiang Lu, Benoît Schaller, Lijing Xin

BACKGROUND: Oxidative stress and glutathione (GSH) metabolism dysregulation has been implicated in the pathophysiology of schizophrenia. GAG-trinucleotide repeat (TNR) polymorphisms in the glutamate-cysteine ligase catalytic gene (GCLC), the rate-limiting enzyme for GSH synthesis, are associated with schizophrenia. In addition, GSH may serve as a reserve pool for neuronal glutamate (Glu) through the gamma-glutamyl cycle. The aim of this study is to investigate brain [GSH] and its association with GCLC polymorphism, peripheral redox indices and brain Glu. METHODS: Magnetic resonance spectroscopy was used to measure [GSH] and [Glu] in the medial prefrontal cortex (mPFC) of 25 early-psychosis patients and 33 controls. GCLC polymorphism was genotyped, glutathione peroxidases (GPx) and glutathione reductase (GR) activities were determined in blood cells. RESULTS: Significantly lower [GSHmPFC] in GCLC high-risk genotype subjects were revealed as compared to low-risk genotype subjects independent of disease status. In male subjects, [GSHmPFC] and blood GPx activities correlate positively in controls (P = .021), but negatively in patients (P = .039). In GCLC low-risk genotypes, [GlumPFC] are lower in patients, while it is not the case for high-risk genotypes. CONCLUSIONS: GCLC high-risk genotypes are associated with low [GSHmPFC], highlighting that GCLC polymorphisms should be considered in pathology studies of cerebral GSH. Low brain GSH levels are related to low peripheral oxidation status in controls but with high oxidation status in patients, pointing to a dysregulated GSH homeostasis in early psychosis patients. GCLC polymorphisms and disease associated correlations between brain GSH and Glu levels may allow patients stratification.

Oxford University Press2016

Chargement

Afficher plus