Glucose negatively affects Nrf2/SKN-1-mediated innate immunity in C. elegans

Li, Le; Chen, Yi; Chenzhao, Changchi; Fu, Shuxiang; Xu, Qumiao; Zhao, Jinfeng

doi:10.18632/aging.101610

Cited by 21 publications

(14 citation statements)

References 46 publications

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“…The correlation observed between the decreased mRNA levels of skn-1 and two of their transcriptional targets in glucose-treated worms surely warrants a further in-depth study. A similar downregulation of gcs-1 and gst-4 mRNA has been reported in glucose-fed worms, which was shown to be a consequence of the inhibition of the SKN-1-mediated immune response to the infection with Salmonella typhimurium [69]. Along the same lines, the SKN-1-mediated increase of expression of gcs-1 and gst-4 in response to Paraquat was suppressed in the presence of glucose [70].…”

Section: Discussionsupporting

confidence: 57%

High-glucose diets induce mitochondrial dysfunction in Caenorhabditis elegans

et al. 2019

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Glucose is an important nutrient that dictates the development, fertility and lifespan of all organisms. In humans, a deficit in its homeostatic control might lead to hyperglucemia and the development of obesity and type 2 diabetes, which show a decreased ability to respond to and metabolize glucose. Previously, we have reported that high-glucose diets (HGD) induce alterations in triglyceride content, body size, progeny, and the mRNA accumulation of key regulators of carbohydrate and lipid metabolism, and longevity in Caenorhabditis elegans (PLoS ONE 13(7): e0199888). Herein, we show that increasing amounts of glucose in the diet induce the swelling of both mitochondria in germ and muscle cells. Additionally, HGD alter the enzymatic activities of the different respiratory complexes in an intricate pattern. Finally, we observed a downregulation of ceramide synthases (hyl-1 and hyl-2) and antioxidant genes (gcs-1 and gst-4), while mitophagy genes (pink-1 and dct-1) were upregulated, probably as part of a mitohormetic mechanism in response to glucose toxicity.

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Section: Discussionsupporting

confidence: 57%

High-glucose diets induce mitochondrial dysfunction in Caenorhabditis elegans

et al. 2019

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“…Gene expression levels were normalized to actin ( ACT1 ) and expressed as fold changes to that of the wild-type. Primers have been published before [14], which are also listed in Supplementary Information, Supplementary Table 2.…”

Section: Methodsmentioning

confidence: 99%

“…Similarly, high glucose can robustly increase the mortality rate and shorten lifespan [11–13]. High glucose uptake compromises the innate immune response to infection in C. elegans [14]. RNA sequencing in C. elegans demonstrates that in response to glucose, conserved genetic programs are induced to modulate several biological processes [15].…”

Section: Introductionmentioning

confidence: 99%

Conserved roles of glucose in suppressing reactive oxygen species-induced cell death and animal survival

Wang

Zhang

et al. 2019

Aging

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Carbohydrate overconsumption increases blood glucose levels, which contributes to the development of various diseases including obesity and diabetes. It is generally believed that high glucose metabolism increases cellular reactive oxygen species (ROS) levels, damages insulin-secreting cells and leads to age-associated diabetic phenotypes. Here we find that in contrast, high glucose suppresses ROS production induced by paraquat in both mammalian cells and the round worm C. elegans . The role of glucose in suppressing ROS is further supported by glucose’s ability to alleviate paraquat’s toxicity on C. elegans development . Consistently, we find that the ROS-regulated transcription factor SKN-1 is inactivated by glucose. As a result, the ROS/SKN-1-dependent lifespan extension observed in paraquat-treated animals, mitochondrial respiration mutant isp-1 and germline-less mutant glp-1 are all suppressed by glucose. Our study reveals an unprecedented interaction of glucose with ROS, which could have significant impact on our current understanding of glucose- and ROS-related diseases.

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“…If it is required for mitochondrial functioning, UPR mt is triggered to actively promote the repair and recovery of mitochondrial function and integrity. In Caenorhabditis elegans , the UPR mt is monitored primarily by the stress activated transcription factor ATFS-1 (of the basic-region leucine zipper family), as well by SKN-1 (skinhead-1, sharing an orthologous homology with Nrf1 and Nrf2) (55,56). The mammalian UPR mt is regulated by ATF5-mediated expression of several mitochondrial chaperone and protease genes to promote its OXPHOS and cell growth during mitochondrial dysfunction (57).…”

Section: Resultsmentioning

confidence: 99%

Nrf1 is an indispensable redox-determining factor for mitochondrial homeostasis by integrating multi-hierarchical regulatory networks

Feng

Wang

et al. 2022

Preprint

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To defend a vast variety of challenges in the oxygenated environments, all life forms have been evolutionally established a set of antioxidant, detoxification and cytoprotective systems during natural selection and adaptive survival, in order to maintain cell redox homeostasis and organ integrity in the healthy development and growth. Such antioxidant defense systems are predominantly regulated by two key transcription factors Nrf1 and Nrf2, but the underlying mechanism(s) for their coordinated redox control remains elusive. Here, we found that loss of full-length Nrf1 led to a dramatic increase in reactive oxygen species (ROS) and oxidative damages in Nrf1-/- cells, and this increase was not eliminated by drastic elevation of Nrf2, even though the antioxidant systems were also substantially enhanced by hyperactive Nrf2. Further studies revealed that the increased ROS production in Nrf1-/- resulted from a striking impairment in the mitochondrial oxidative respiratory chain and its gene expression regulated by nuclear respiratory factors, called aPalNRF1 and GABPNRF2. In addition to antioxidant capacity of cells, glycolysis was greatly augmented by aberrantly-elevated Nrf2, so to partially relieve the cellular energy demands, but aggravate its mitochondrial stress. The generation of ROS was also differentially regulated by Nrf1 and Nrf2 through miR-195 and/or mIR-497-mediated UCP2 pathway. Consequently, the epithelial-mesenchymal transformation (EMT) of Nrf1-/- cells was activated by putative ROS-stimulated signaling via MAPK, HIF1α, NF-kB, PI3K and AKT, all players involved in cancer development and progression. Taken together, it is inferable that Nrf1 acts as a potent integrator of redox regulation by multi-hierarchical networks.

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Glucose negatively affects Nrf2/SKN-1-mediated innate immunity in C. elegans

Cited by 21 publications

References 46 publications

High-glucose diets induce mitochondrial dysfunction in Caenorhabditis elegans

High-glucose diets induce mitochondrial dysfunction in Caenorhabditis elegans

Conserved roles of glucose in suppressing reactive oxygen species-induced cell death and animal survival

Nrf1 is an indispensable redox-determining factor for mitochondrial homeostasis by integrating multi-hierarchical regulatory networks

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