ER stress modulates cellular metabolism.
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.
Molecular Targets Program, James Graham Brown Cancer Center, 529 S. Jackson Street, Louisville, KY 40202, USA.
Xiaoli
X
Wang
Colins O
CO
Eno
Brian J
BJ
Altman
Yanglong
Y
Zhu
Guoping
G
Zhao
Kristen E
KE
Olberding
Jeffrey C
JC
Rathmell
Chi
C
Li
D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D016193:G1 Phase / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D055442:Metabolome / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological; D014415:Tunicamycin / Q000633:toxicity; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D051272:Glucose Transporter Type 1; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D014415:Tunicamycin; D051057:Proto-Oncogene Proteins c-akt
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