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

ABSTRACT: Many metabolic diseases disrupt endoplasmic reticulum (ER) homeostasis, but little is known about how metabolic activity is communicated to the ER. Here, we show in hepatocytes and other metabolically active cells that decreasing the availability of substrate for the tricarboxylic acid (TCA) cycle diminished NADPH production, elevated glutathione oxidation, led to altered oxidative maturation of ER client proteins, and attenuated ER stress. This attenuation was prevented when glutathione oxidation was disfavored. ER stress was also alleviated by inhibiting either TCA-dependent NADPH production or Glutathione Reductase. Conversely, stimulating TCA activity increased NADPH production, glutathione reduction, and ER stress. Validating these findings, deletion of the Mitochondrial Pyruvate Carrier-which is known to decrease TCA cycle activity and protect the liver from steatohepatitis-also diminished NADPH, elevated glutathione oxidation, and alleviated ER stress. Together, our results demonstrate a novel pathway by which mitochondrial metabolic activity is communicated to the ER through the relay of redox metabolites.

SUBMITTER: Gansemer ER

PROVIDER: S-EPMC7254477 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Lipase maturation factor 1 affects redox homeostasis in the endoplasmic reticulum.

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Project description:Endothelial dysfunction induced by hyperhomocysteinemia (HHcy) plays a critical role in vascular pathology. However, little is known about the role of endoplasmic reticulum (ER) redox homeostasis in HHcy-induced endothelial dysfunction. Here, we show that Hcy induces ER oxidoreductin-1? (Ero1?) expression with ER stress and inflammation in human umbilical vein endothelial cells and in the arteries of HHcy mice. Hcy upregulates Ero1? expression by promoting binding of hypoxia-inducible factor 1? to the ERO1A promoter. Notably, Hcy rather than other thiol agents markedly increases the GSH/GSSG ratio in the ER, therefore allosterically activating Ero1? to produce H2O2 and trigger ER oxidative stress. By contrast, the antioxidant pathway mediated by ER glutathione peroxidase 7 (GPx7) is downregulated in HHcy mice. Ero1? knockdown and GPx7 overexpression protect the endothelium from HHcy-induced ER oxidative stress and inflammation. Our work suggests that targeting ER redox homeostasis could be used as an intervention for HHcy-related vascular diseases.

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Lipase Maturation Factor 1 Affects Redox Homeostasis in the Endoplasmic Reticulum

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Project description: Not available

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| S-EPMC8324082 | biostudies-literature

Depletion of cyclophilins B and C leads to dysregulation of endoplasmic reticulum redox homeostasis.

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| S-EPMC4279222 | biostudies-literature

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