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 Carr

SUBMITTER: Gansemer ER 

PROVIDER: S-EPMC7254477 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature