Journal article
NADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum Homeostasis
iScience, Vol.23(5), pp.101116-101116
05/22/2020
DOI: 10.1016/j.isci.2020.101116
PMID: 32417402
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.
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•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 stress
biological sciences; cell biology; functional aspects of cell biology
Details
- Title: Subtitle
- NADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum Homeostasis
- Creators
- Erica R Gansemer - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAKyle S McCommis - Center for Human Nutrition, Department of Medicine, Washington University School of Medicine in Saint Louis, St. Louis, MO 63110, USAMichael Martino - Center for Human Nutrition, Department of Medicine, Washington University School of Medicine in Saint Louis, St. Louis, MO 63110, USAAbdul Qaadir King-McAlpin - Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAMatthew J Potthoff - Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USABrian N Finck - Center for Human Nutrition, Department of Medicine, Washington University School of Medicine in Saint Louis, St. Louis, MO 63110, USAEric B Taylor - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAD. Thomas Rutkowski - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- iScience, Vol.23(5), pp.101116-101116
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.isci.2020.101116
- PMID
- 32417402
- ISSN
- 2589-0042
- eISSN
- 2589-0042
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: R01DK104735, R01DK104998, R01DK106104, T32GM067795
- Language
- English
- Date published
- 05/22/2020
- Academic Unit
- Molecular Physiology and Biophysics; Anatomy and Cell Biology; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984070298002771
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