文章基本信息

标题：NADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum Homeostasis
本地全文：下载
作者：Erica R. Gansemer ; Kyle S. McCommis ; Michael Martino 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：5
页码：1-29
DOI：10.1016/j.isci.2020.101116
语种：English
出版社：Elsevier
摘要：SummaryMany 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.Graphical AbstractDisplay OmittedHighlights•Inhibiting nutrient catabolism alleviates ER stress in metabolically active cells•NADPH production and glutathione redox link TCA activity to ER homeostasis•ER client protein oxidation, maturation, and ERAD respond to metabolic activity•Cells lacking the Mitochondrial Pyruvate Carrier are resistant to ER stressbiological sciences; cell biology; functional aspects of cell biology