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Mol Cell. 2015 Aug 6;59(3):359-71. doi: 10.1016/j.molcel.2015.06.017. Epub 2015 Jul 16.

Acute Activation of Oxidative Pentose Phosphate Pathway as First-Line Response to Oxidative Stress in Human Skin Cells.

Author information

1
Institute of Molecular Systems Biology, ETH Zurich, Auguste-Piccard-Hof 1, 8093 Zurich, Switzerland; PhD Program Systems Biology, Life Science Zurich Graduate School, 8093 Zurich, Switzerland.
2
Beiersdorf AG, R&D, Skin Research Center, Unnastrasse 48, Hamburg, 20253 Germany.
3
Christian Albrecht University Kiel, Department of Anatomy, Otto-Hahn-Platz 8, 24118 Kiel, Germany.
4
Beiersdorf AG, R&D, Skin Research Center, Unnastrasse 48, Hamburg, 20253 Germany. Electronic address: Janosch.Hildebrand@Beiersdorf.com.
5
Institute of Molecular Systems Biology, ETH Zurich, Auguste-Piccard-Hof 1, 8093 Zurich, Switzerland. Electronic address: zamboni@imsb.biol.ethz.ch.

Abstract

Integrity of human skin is endangered by exposure to UV irradiation and chemical stressors, which can provoke a toxic production of reactive oxygen species (ROS) and oxidative damage. Since oxidation of proteins and metabolites occurs virtually instantaneously, immediate cellular countermeasures are pivotal to mitigate the negative implications of acute oxidative stress. We investigated the short-term metabolic response in human skin fibroblasts and keratinocytes to H2O2 and UV exposure. In time-resolved metabolomics experiments, we observed that within seconds after stress induction, glucose catabolism is routed to the oxidative pentose phosphate pathway (PPP) and nucleotide synthesis independent of previously postulated blocks in glycolysis (i.e., of GAPDH or PKM2). Through ultra-short (13)C labeling experiments, we provide evidence for multiple cycling of carbon backbones in the oxidative PPP, potentially maximizing NADPH reduction. The identified metabolic rerouting in oxidative and non-oxidative PPP has important physiological roles in stabilization of the redox balance and ROS clearance.

PMID:
26190262
DOI:
10.1016/j.molcel.2015.06.017
[Indexed for MEDLINE]
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