TY - JOUR
T1 - NADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum Homeostasis
AU - Gansemer, Erica R.
AU - McCommis, Kyle S.
AU - Martino, Michael
AU - King-McAlpin, Abdul Qaadir
AU - Potthoff, Matthew J.
AU - Finck, Brian N.
AU - Taylor, Eric B.
AU - Rutkowski, D. Thomas
N1 - Funding Information:
The authors would like to thank the University of Iowa Viral Vector Core and Central Microscopy Research Facility—especially Jian Shao—for technical assistance. Funding sources were as follows: D.T.R.: R01GM115424 (National Institutes of Health, U.S.A. (NIH)); E.R.G.: T32GM067795 (NIH); M.J.P.: R01DK106104 (NIH); B.N.F.: R01DK104735 (NIH); E.B.T.: R01DK104998 (NIH); and Central Microscopy Research Facility: S10RR018998 (NIH) (for JEOL JEM-1230 Transmission Electron Microscope). Conceptualization: E.R.G. and D.T.R.; Investigation: E.R.G. K.S.M. M.M. A.Q.K.-M. and D.T.R.; Writing – Original Draft: E.R.G. and D.T.R.; Writing – Review and Editing: all authors; Supervision: M.J.P. B.N.F. E.B.T. and D.T.R.; Funding Acquisition: E.R.G. M.J.P. B.N.F. E.B.T. and D.T.R. B.N.F. is a shareholder and member of the Scientific Advisory Board for Cirius Therapeutics. K.S.M. received research support from Cirius Therapeutics between 2017 and 2019. E.B.T. receives research grant funding for MPC-related research administered through the University of Iowa from Cirius Therapeutics and Poxel SA.
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/5/22
Y1 - 2020/5/22
N2 - 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.
AB - 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.
KW - biological sciences
KW - cell biology
KW - functional aspects of cell biology
UR - http://www.scopus.com/inward/record.url?scp=85084515207&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2020.101116
DO - 10.1016/j.isci.2020.101116
M3 - Article
C2 - 32417402
AN - SCOPUS:85084515207
SN - 2589-0042
VL - 23
JO - iScience
JF - iScience
IS - 5
M1 - 101116
ER -