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

Andreas Kuehne, Hila Emmert, Joern Soehle, Marc Winnefeld, Frank Fischer, Horst Wenck, Stefan Gallinat, Lara Terstegen, Ralph Lucius, Janosch Hildebrand, Nicola Zamboni

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)359-71
Number of pages13
JournalMolecular Cell
Volume59
Issue number3
DOIs
Publication statusPublished - 6 Aug 2015

Keywords

  • Carrier Proteins
  • Cells, Cultured
  • Fibroblasts
  • Gene Expression Regulation
  • Humans
  • Hydrogen Peroxide
  • Infant, Newborn
  • Keratinocytes
  • Membrane Proteins
  • Metabolomics
  • NADP
  • Oxidative Stress
  • Pentose Phosphate Pathway
  • Reactive Oxygen Species
  • Thyroid Hormones

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