Nrf2 regulates glucose uptake and metabolism in neurons and astrocytes

Esteras, Noemí; Blacker, Thomas S.; Zherebtsov, Evgeny; Stelmashchuk, Olga; Zhang, Ying; Wigley, W. Christian; Duchen, Michael R.; Dinkova‐Kostova, Albena T.; Abramov, Andrey Y.

doi:10.1016/j.redox.2023.102672

Cited by 20 publications

(11 citation statements)

References 38 publications

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“…Several NADP-related terms were highly enriched in C1 followed by C2 at the level of MF in the GO analysis ( Supplementary Figure 2A ). Active NRF2 is associated with increased glucose uptake, which is preferentially metabolized through PPP resulting in increased reducing equivalent capacity, via the production of NADPH ( 24 ). NADPH is required for and consumed during fatty acid synthesis and the scavenging of ROS.…”

Section: Resultsmentioning

confidence: 99%

Antioxidant network-based signatures cluster glioblastoma into distinct redox-resistant phenotypes

Yang,

More,

De Smet

et al. 2024

Front. Immunol.

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IntroductionAberrant reactive oxygen species (ROS) production is one of the hallmarks of cancer. During their growth and dissemination, cancer cells control redox signaling to support protumorigenic pathways. As a consequence, cancer cells become reliant on major antioxidant systems to maintain a balanced redox tone, while avoiding excessive oxidative stress and cell death. This concept appears especially relevant in the context of glioblastoma multiforme (GBM), the most aggressive form of brain tumor characterized by significant heterogeneity, which contributes to treatment resistance and tumor recurrence. From this viewpoint, this study aims to investigate whether gene regulatory networks can effectively capture the diverse redox states associated with the primary phenotypes of GBM.MethodsIn this study, we utilized publicly available GBM datasets along with proprietary bulk sequencing data. Employing computational analysis and bioinformatics tools, we stratified GBM based on their antioxidant capacities and evaluated the distinctive functionalities and prognostic values of distinct transcriptional networks in silico.ResultsWe established three distinct transcriptional co-expression networks and signatures (termed clusters C1, C2, and C3) with distinct antioxidant potential in GBM cancer cells. Functional analysis of each cluster revealed that C1 exhibits strong antioxidant properties, C2 is marked with a discrepant inflammatory trait and C3 was identified as the cluster with the weakest antioxidant capacity. Intriguingly, C2 exhibited a strong correlation with the highly aggressive mesenchymal subtype of GBM. Furthermore, this cluster holds substantial prognostic importance: patients with higher gene set variation analysis (GSVA) scores of the C2 signature exhibited adverse outcomes in overall and progression-free survival.ConclusionIn summary, we provide a set of transcriptional signatures that unveil the antioxidant potential of GBM, offering a promising prognostic application and a guide for therapeutic strategies in GBM therapy.

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Section: Resultsmentioning

confidence: 99%

Antioxidant network-based signatures cluster glioblastoma into distinct redox-resistant phenotypes

Yang,

More,

De Smet

et al. 2024

Front. Immunol.

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“…Despite extensive research in the field, there are few studies that have reported on the specific role of mitochondria in relation to premature rupture of membranes. Studies have demonstrated that the absence of NRF2 in the mitochondria of neurons and mouse embryonic fibroblasts results in impaired mitochondrial respiration, decreased ATP levels, and reduced mitochondrial membrane potential [32]. In addition, it has been established that NRF2 directly regulates the expression of mitochondrial respiratory complexes, including ATP synthase subunit α , NDUFA4, and cytochrome C oxidase subunits COX2 and COX4B, in various experimental systems [33, 34].…”

Section: Discussionmentioning

confidence: 99%

Nuclear erythroid 2-related factor 2 protects against reactive oxygen species -induced preterm premature rupture of membranes through regulation of mitochondria

Zhang

Wei

et al. 2023

Biology of Reproduction

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Preterm premature rupture of membranes (pPROM) is a major cause of preterm birth and neonatal mortality. Reactive oxygen species (ROS) have been identified as a critical factor in the development of pPROM. Mitochondria are known to be the primary source of ROS and play a vital role in maintaining cellular function. The Nuclear erythroid 2-related factor 2 (NRF2) has been demonstrated to play a crucial role in regulating mitochondrial function. However, research exploring the impact of NRF2-regulated mitochondria on pPROM is limited. Therefore, we collected fetal membrane tissues from pPROM and spontaneous preterm labor (sPTL) puerpera, measured the expression level of NRF2, and evaluated the degree of mitochondrial damage in both groups. Additionally, we isolated human amniotic epithelial cells (hAECs) from the fetal membranes and employed siRNA to suppress NRF2 expression, enabling us to evaluate the impact of NRF2 on mitochondrial damage and ROS production. Our findings indicated that the expression level of NRF2 in pPROM fetal membranes was significantly lower than in sPTL fetal membranes, accompanied by increased mitochondrial damage. Furthermore, following the inhibition of NRF2 in hAECs, the degree of mitochondrial damage was significantly exacerbated, along with a marked increase in both cellular and mitochondrial ROS levels. The regulation of the mitochondrial metabolic process via NRF2 in fetal membranes has the potential to influence ROS production.

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“…However, kidneys must adapt quickly in response to additional challenge, suggesting that the functional-metabolic coupling that supports basal renal activity might be further re-wired to match physiological activity. Nrf2, a well-known regulator of the antioxidant stress response, is increasingly being implicated in the reprogramming of metabolism 87 . We previously demonstrated that Nrf2 antioxidant activity is modulated within Drosophila renal tubules according to renal physiological activity 28 , suggesting that Nrf2 could be well-placed to further fine-tune PC metabolism.…”

Section: Discussionmentioning

confidence: 99%

Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing

Holcombe,

Weavers

2023

Nat Commun

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Precise coupling between cellular physiology and metabolism is emerging as a vital relationship underpinning tissue health and longevity. Nevertheless, functional-metabolic coupling within heterogenous microenvironments in vivo remains poorly understood due to tissue complexity and metabolic plasticity. Here, we establish the Drosophila renal system as a paradigm for linking mechanistic analysis of metabolism, at single-cell resolution, to organ-wide physiology. Kidneys are amongst the most energetically-demanding organs, yet exactly how individual cell types fine-tune metabolism to meet their diverse, unique physiologies over the life-course remains unclear. Integrating live-imaging of metabolite and organelle dynamics with spatio-temporal genetic perturbation within intact functional tissue, we uncover distinct cellular metabolic signatures essential to support renal physiology and healthy ageing. Cell type-specific programming of glucose handling, PPP-mediated glutathione regeneration and FA β-oxidation via dynamic lipid-peroxisomal networks, downstream of differential ERR receptor activity, precisely match cellular energetic demands whilst limiting damage and premature senescence; however, their dramatic dysregulation may underlie age-related renal dysfunction.

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Nrf2 regulates glucose uptake and metabolism in neurons and astrocytes

Cited by 20 publications

References 38 publications

Antioxidant network-based signatures cluster glioblastoma into distinct redox-resistant phenotypes

Antioxidant network-based signatures cluster glioblastoma into distinct redox-resistant phenotypes

Nuclear erythroid 2-related factor 2 protects against reactive oxygen species -induced preterm premature rupture of membranes through regulation of mitochondria

Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing

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