NADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum Homeostasis

Gansemer, Erica R.; McCommis, Kyle S.; Martino, Michael R.; King-McAlpin, Abdul Qaadir; Potthoff, Matthew J.; Finck, Brian N.; Taylor, Eric B.; Rutkowski, D. Thomas

doi:10.1016/j.isci.2020.101116

Cited by 65 publications

(75 citation statements)

References 102 publications

(93 reference statements)

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“…54 Besides, TCA cycle activity and ER homeostasis have been shown to be metabolically related. 55 As in our study, TBT increased the TCA cycle intermediates cis-aconitic acid, FAD, and FADH ( Fig. 2E), which illustrated that TBT could enhance the energy supply for maintaining the function of ER and metabolic progress.…”

Section: Discussionsupporting

confidence: 83%

Gut microbiota-mediated tributyltin-induced metabolic disorder in rats

et al. 2020

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Section: Discussionsupporting

confidence: 83%

Gut microbiota-mediated tributyltin-induced metabolic disorder in rats

et al. 2020

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“…35,[37][38][39] The antioxidant glutathione plays a pivotal role in regulating the ER protein folding process. [40][41][42][43][44][45] Cells generate glutathione through a two-step process. First, cells combine glutamate and cysteine to create γ-glutamylcysteine.…”

Section: Introductionmentioning

confidence: 99%

Bifidobacterium dentium-derived y-glutamylcysteine suppresses ER-mediated goblet cell stress and reduces TNBS-driven colonic inflammation

et al. 2021

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Endoplasmic reticulum (ER) stress compromises the secretion of MUC2 from goblet cells and has been linked with inflammatory bowel disease (IBD). Although Bifidobacterium can beneficially modulate mucin production, little work has been done investigating the effects of Bifidobacterium on goblet cell ER stress. We hypothesized that secreted factors from Bifidobacterium dentium downregulate ER stress genes and modulates the unfolded protein response (UPR) to promote MUC2 secretion. We identified by mass spectrometry that B. dentium secretes the antioxidant γ-glutamylcysteine, which we speculate dampens ER stress-mediated ROS and minimizes ER stress phenotypes. B. dentium cell-free supernatant and γ-glutamylcysteine were taken up by human colonic T84 cells, increased glutathione levels, and reduced ROS generated by the ER-stressors thapsigargin and tunicamycin. Moreover, B. dentium supernatant and γ-glutamylcysteine were able to suppress NF-kB activation and IL-8 secretion. We found that B. dentium supernatant, γ-glutamylcysteine, and the positive control IL-10 attenuated the induction of UPR genes GRP78, CHOP, and sXBP1. To examine ER stress in vivo, we first examined mono-association of B. dentium in germ-free mice which increased MUC2 and IL-10 levels compared to germ-free controls. However, no changes were observed in ER stress-related genes, indicating that B. dentium can promote mucus secretion without inducing ER stress. In a TNBS-mediated ER stress model, we observed increased levels of UPR genes and pro-inflammatory cytokines in TNBS treated mice, which were reduced with addition of live B. dentium or γ-glutamylcysteine. We also observed increased colonic and serum levels of IL-10 in B. dentium-and γ-glutamylcysteine-treated mice compared to vehicle control. Immunostaining revealed retention of goblet cells and mucus secretion in both B. dentium-and γ-glutamylcysteine-treated animals. Collectively, these data demonstrate positive modulation of the UPR and MUC2 production by B. dentium-secreted compounds.

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“…The tricarboxylic acid cycle is the basic metabolic pathway shared by most organisms. The tricarboxylic acid cycle is the central hub of metabolism, participating in both catabolism and anabolism 15 . The tricarboxylic acid cycle also provides precursors for biosynthetic pathways 16 such as the synthesis of acetyl-CoA, which has been implicated in the synthesis of secondary metabolites including flavonoids (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the tricarboxylic acid cycle can also meet most requirements for cell energy via the complete oxidation of acetyl-CoA. The activity of citrate synthase is fundamental to combine acetyl-CoA with oxaloacetate to form citrate 15 . In this study, the expressions of genes and proteins involved in citrate synthase (TRINITY_DN6100_c0_g1 and TRINITY_DN26760_c1_g2_i5_m.177726) were both significantly higher in YFY samples than in control samples.…”

Section: Discussionmentioning

confidence: 99%

Combination of RNA-Seq transcriptomics and iTRAQ proteomics reveal the mechanism involved in fresh-cut yam yellowing

Guo

Wang²,

Ma³

et al. 2021

Sci Rep

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The aim of this study was to examine the regulation of transcriptomics and proteomics related to the yellowing of fresh-cut yams after storage. The comparison of yellow fresh-cut yam (YFY) vs. white fresh-cut yam (control) revealed 6894 upregulated and 6800 downregulated differentially expressed genes along with 1277 upregulated and 677 downregulated differentially expressed proteins. The results showed that the total carotenoids, flavonoids, and bisdemethoxycurcumin in YFY were higher than in the control due to the significant up-regulation of critical genes in the carotenoid biosynthesis pathway, flavonoid biosynthesis pathway, and stilbenoid, diarylheptanoid, and gingerol biosynthesis pathway. In addition, the tricarboxylic acid cycle and phenylpropanoid biosynthesis were both enhanced in YFY compared to the control, providing energy and precursors for the formation of yellow pigments. The results suggest that the synthesis of yellow pigments is regulated by critical genes, which might explain the yellowing of fresh-cut yam after storage.

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NADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum Homeostasis

Cited by 65 publications

References 102 publications

Gut microbiota-mediated tributyltin-induced metabolic disorder in rats

Gut microbiota-mediated tributyltin-induced metabolic disorder in rats

Bifidobacterium dentium-derived y-glutamylcysteine suppresses ER-mediated goblet cell stress and reduces TNBS-driven colonic inflammation

Combination of RNA-Seq transcriptomics and iTRAQ proteomics reveal the mechanism involved in fresh-cut yam yellowing

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