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Phosphorylation of the PDH complex precedes HIF-1-mediated effects and PDK1 upregulation during the first hours of hypoxic treatment in HCC cells

Authors Zimmer AD, Walbrecq G, Kozar I, Behrmann I, Haan C

Received 24 October 2015

Accepted for publication 22 February 2016

Published 16 August 2016 Volume 2016:4 Pages 135—145

DOI https://doi.org/10.2147/HP.S99044

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Prof. Dr. Max Gassmann

Peer reviewer comments 4

Editor who approved publication: Prof. Dr. Dörthe Katschinski


Andreas David Zimmer, Geoffroy Walbrecq, Ines Kozar, Iris Behrmann, Claude Haan

Life Sciences Research Unit, University of Luxembourg, Belvaux, Luxembourg


Abstract: The pyruvate dehydrogenase complex (PDC) is an important gatekeeper enzyme connecting glycolysis to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Thereby, it has a strong impact on the glycolytic flux as well as the metabolic phenotype of a cell. PDC activity is regulated via reversible phosphorylation of three serine residues on the pyruvate dehydrogenase (PDH) E1α subunit. Phosphorylation of any of these residues by the PDH kinases (PDKs) leads to a strong decrease in PDC activity. Under hypoxia, the inactivation of the PDC has been described to be dependent on the hypoxia-inducible factor 1 (HIF-1)-induced PDK1 protein upregulation. In this study, we show in two hepatocellular carcinoma cell lines (HepG2 and JHH-4) that, during the adaptation to hypoxia, PDH is already phosphorylated at time points preceding HIF-1-mediated transcriptional events and PDK1 protein upregulation. Using siRNAs and small molecule inhibitor approaches, we show that this inactivation of PDC is independent of HIF-1α expression but that the PDKs need to be expressed and active. Furthermore, we show that reactive oxygen species might be important for the induction of this PDH phosphorylation since it correlates with the appearance of an altered redox state in the mitochondria and is also inducible by H2O2 treatment under normoxic conditions. Overall, these results show that neither HIF-1 expression nor PDK1 upregulation is necessary for the phosphorylation of PDH during the first hours of the adaptation to hypoxia.

Keywords: pyruvate dehydrogenase complex, pyruvate dehydrogenase kinase, hypoxia metabolism, glycolytic switch, radical oxygen species

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