Changes in metabolic processes play a critical role in the survival or death of cells subjected to various stresses. In the present study, we have investigated the effects of ER (endoplasmic reticulum) stress on cellular metabolism. A major difficulty in studying metabolic responses to ER stress is that ER stress normally leads to apoptosis and metabolic changes observed in dying cells may be misleading. Therefore we have used IL-3 (interleukin 3)-dependent Bak−/−Bax−/− haemopoietic cells which do not die in the presence of the ER-stress-inducing drug tunicamycin. Tunicamycin-treated Bak−/−Bax−/− cells remain viable, but cease growth, arresting in G1-phase and undergoing autophagy in the absence of apoptosis. In these cells, we used NMR-based SIRM (stable isotope-resolved metabolomics) to determine the metabolic effects of tunicamycin. Glucose was found to be the major carbon source for energy production and anabolic metabolism. Following tunicamycin exposure, glucose uptake and lactate production are greatly reduced. Decreased 13C labelling in several cellular metabolites suggests that mitochondrial function in cells undergoing ER stress is compromised. Consistent with this, mitochondrial membrane potential, oxygen consumption and cellular ATP levels are much lower compared with untreated cells. Importantly, the effects of tunicamycin on cellular metabolic processes may be related to a reduction in cell-surface GLUT1 (glucose transporter 1) levels which, in turn, may reflect decreased Akt signalling. These results suggest that ER stress exerts profound effects on several central metabolic processes which may help to explain cell death arising from ER stress in normal cells.
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Research Article|
March 15 2011
ER stress modulates cellular metabolism
Xiaoli Wang;
Xiaoli Wang
*Molecular Targets Program, James Graham Brown Cancer Center, 529 S. Jackson Street, Louisville, KY 40202, U.S.A.
†Department of Medicine, University of Louisville, Louisville, KY 40202, U.S.A.
‡Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, U.S.A.
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Colins O. Eno;
Colins O. Eno
*Molecular Targets Program, James Graham Brown Cancer Center, 529 S. Jackson Street, Louisville, KY 40202, U.S.A.
†Department of Medicine, University of Louisville, Louisville, KY 40202, U.S.A.
‡Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, U.S.A.
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Brian J. Altman;
Brian J. Altman
§Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, U.S.A.
∥Department of Immunology, Duke University, Durham, NC 27710, U.S.A.
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Yanglong Zhu;
Yanglong Zhu
*Molecular Targets Program, James Graham Brown Cancer Center, 529 S. Jackson Street, Louisville, KY 40202, U.S.A.
†Department of Medicine, University of Louisville, Louisville, KY 40202, U.S.A.
‡Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, U.S.A.
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Guoping Zhao;
Guoping Zhao
*Molecular Targets Program, James Graham Brown Cancer Center, 529 S. Jackson Street, Louisville, KY 40202, U.S.A.
†Department of Medicine, University of Louisville, Louisville, KY 40202, U.S.A.
‡Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, U.S.A.
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Kristen E. Olberding;
Kristen E. Olberding
*Molecular Targets Program, James Graham Brown Cancer Center, 529 S. Jackson Street, Louisville, KY 40202, U.S.A.
†Department of Medicine, University of Louisville, Louisville, KY 40202, U.S.A.
‡Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, U.S.A.
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Jeffrey C. Rathmell;
Jeffrey C. Rathmell
§Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, U.S.A.
∥Department of Immunology, Duke University, Durham, NC 27710, U.S.A.
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Chi Li
Chi Li
1
*Molecular Targets Program, James Graham Brown Cancer Center, 529 S. Jackson Street, Louisville, KY 40202, U.S.A.
†Department of Medicine, University of Louisville, Louisville, KY 40202, U.S.A.
‡Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, U.S.A.
1To whom correspondence should be addressed (email chi.li@louisville.edu).
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Publisher: Portland Press Ltd
Received:
November 19 2010
Revision Received:
January 13 2011
Accepted:
January 17 2011
Accepted Manuscript online:
January 17 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 435 (1): 285–296.
Article history
Received:
November 19 2010
Revision Received:
January 13 2011
Accepted:
January 17 2011
Accepted Manuscript online:
January 17 2011
Citation
Xiaoli Wang, Colins O. Eno, Brian J. Altman, Yanglong Zhu, Guoping Zhao, Kristen E. Olberding, Jeffrey C. Rathmell, Chi Li; ER stress modulates cellular metabolism. Biochem J 1 April 2011; 435 (1): 285–296. doi: https://doi.org/10.1042/BJ20101864
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