NADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum Homeostasis
Summary: 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...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-05-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004220303011 |
| _version_ | 1811222593198358528 |
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| author | Erica R. Gansemer Kyle S. McCommis Michael Martino Abdul Qaadir King-McAlpin Matthew J. Potthoff Brian N. Finck Eric B. Taylor D. Thomas Rutkowski |
| author_facet | Erica R. Gansemer Kyle S. McCommis Michael Martino Abdul Qaadir King-McAlpin Matthew J. Potthoff Brian N. Finck Eric B. Taylor D. Thomas Rutkowski |
| author_sort | Erica R. Gansemer |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-04-12T08:18:32Z |
| format | Article |
| id | doaj.art-25bef5b0b1f54b1a9a1b238346997cb8 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-12T08:18:32Z |
| publishDate | 2020-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-25bef5b0b1f54b1a9a1b238346997cb82022-12-22T03:40:39ZengElsevieriScience2589-00422020-05-01235NADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum HomeostasisErica R. Gansemer0Kyle S. McCommis1Michael Martino2Abdul Qaadir King-McAlpin3Matthew J. Potthoff4Brian N. Finck5Eric B. Taylor6D. Thomas Rutkowski7Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USACenter for Human Nutrition, Department of Medicine, Washington University School of Medicine in Saint Louis, St. Louis, MO 63110, USACenter for Human Nutrition, Department of Medicine, Washington University School of Medicine in Saint Louis, St. Louis, MO 63110, USADepartment of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADepartment of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Obesity Research Initiative, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USACenter for Human Nutrition, Department of Medicine, Washington University School of Medicine in Saint Louis, St. Louis, MO 63110, USADepartment of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Obesity Research Initiative, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004220303011biological sciencescell biologyfunctional aspects of cell biology |
| spellingShingle | Erica R. Gansemer Kyle S. McCommis Michael Martino Abdul Qaadir King-McAlpin Matthew J. Potthoff Brian N. Finck Eric B. Taylor D. Thomas Rutkowski NADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum Homeostasis iScience biological sciences cell biology functional aspects of cell biology |
| title | NADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum Homeostasis |
| title_full | NADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum Homeostasis |
| title_fullStr | NADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum Homeostasis |
| title_full_unstemmed | NADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum Homeostasis |
| title_short | NADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum Homeostasis |
| title_sort | nadph and glutathione redox link tca cycle activity to endoplasmic reticulum homeostasis |
| topic | biological sciences cell biology functional aspects of cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004220303011 |
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