Abstract
Because of insufficient understanding of the molecular effects of low levels of radiation exposure, there is a great uncertainty regarding its health risks. We report here that treatment of normal human cells with low-dose radiation induces a metabolic shift from oxidative phosphorylation to aerobic glycolysis resulting in increased radiation resistance. This metabolic change is highlighted by upregulation of genes encoding glucose transporters and enzymes of glycolysis and the oxidative pentose phosphate pathway, concomitant with downregulation of mitochondrial genes, with corresponding changes in metabolic flux through these pathways. Mechanistically, the metabolic reprogramming depends on HIF1α, which is induced specifically by low-dose irradiation linking the metabolic pathway with cellular radiation dose response. Increased glucose flux and radiation resistance from low-dose irradiation are also observed systemically in mice. This highly sensitive metabolic response to low-dose radiation has important implications in understanding and assessing the health risks of radiation exposure.
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Abbreviations
- CT:
-
computed tomography
- ECAR:
-
elevated extracellular acidification rate
- 2-DG:
-
2-deoxyglucose
- G6PD:
-
glucose-6-phosphate dehydrogenase
- GLUT:
-
glucose transporter
- HIF-1:
-
hypoxia induced factor
- IR:
-
ionizing radiation
- LDH:
-
lactate dehydrogenase
- LNT:
-
linear no-threshold
- LD50:
-
lethal dose of 50%
- MCT:
-
monocarboxylate transporter
- PPP:
-
pentose phosphate pathway
- ROS:
-
reactive oxygen species
- SOD:
-
superoxide dismutase
- TCA:
-
tricarboxylic acid cycle
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Acknowledgements
We would like to thank the UTHSCSA Small Animal Image Core, Suresh Prajapati for animal imaging studies, Min Yuan for help with mass spectrometry analyses and Drs. Hotamisligil & Fu at HSPH for the XF Analyzer analysis. These studies were supported by the Morningside Foundation, the Department of Energy (DOE 110976 and 65089), NIH/NCI (2 R01CA085679, RO1CA167814, RO1CA125144, and P01CA120964).
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ZY designed the experiments. RL, TX, HS, SX and MS contributed to cell-based studies. MY performed gene expression experiments. SG and CSH did in vivo work. JMA, IB-S, BDM and JBL planed and conducted metabolic analyses. Z-MY wrote and BDM and JBL edited the manuscript.
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Lall, R., Ganapathy, S., Yang, M. et al. Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response. Cell Death Differ 21, 836–844 (2014). https://doi.org/10.1038/cdd.2014.24
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DOI: https://doi.org/10.1038/cdd.2014.24
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