Deletion or inhibition of the oxygen sensor PHD1 protects against ischemic stroke via reprogramming of neuronal metabolism

Annelies Quaegebeur, Inmaculada Segura, Roberta Schmieder, Dries Verdegem, Ilaria Decimo, Francesco Bifari, Tom Dresselaers, Guy Eelen, Debapriva Ghosh, Shawn M. Davidson, Sandra Schoors, Dorien Broekaert, Bert Cruys, Kristof Govaerts, Carla De Legher, Ann Bouché, Luc Schoonjans, Matt S. Ramer, Gene Hung, Goele BossaertDon W. Cleveland, Uwe Himmelreich, Thomas Voets, Robin Lemmens, C. Frank Bennett, Wim Robberecht, Katrien De Bock, Mieke Dewerchin, Bart Ghesquière, Sarah Maria Fendt, Peter Carmeliet*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

The oxygen-sensing prolyl hydroxylase domain proteins (PHDs) regulate cellular metabolism, but their role in neuronal metabolism during stroke is unknown. Here we report that PHD1 deficiency provides neuroprotection in a murine model of permanent brain ischemia. This was not due to an increased collateral vessel network. Instead, PHD1-/- neurons were protected against oxygen-nutrient deprivation by reprogramming glucose metabolism. Indeed, PHD1-/- neurons enhanced glucose flux through the oxidative pentose phosphate pathway by diverting glucose away from glycolysis. As a result, PHD1-/- neurons increased their redox buffering capacity to scavenge oxygen radicals in ischemia. Intracerebroventricular injection of PHD1-antisense oligonucleotides reduced the cerebral infarct size and neurological deficits following stroke. These data identify PHD1 as a regulator of neuronal metabolism and a potential therapeutic target in ischemic stroke.

Original languageEnglish (US)
Pages (from-to)280-291
Number of pages12
JournalCell Metabolism
Volume23
Issue number2
DOIs
StatePublished - Feb 9 2016

Funding

The authors thank Matthew Vander Heiden for providing training in in vivo 13 C-glucose infusions and Carlos Dotti for advice on the use of aged cultured neurons. Funding support: Research Foundation–Flanders (FWO) (A.Q., I.S., B.G., K.D.B., and S.-M.F.); FP7 Marie Curie Intra-European Fellowship (I.D. and F.B.); Pegasus Marie Curie-FWO (R.Q.); senior clinical investigator of FWO Flanders (R.L.); Agency for Innovation by Science and Technology in Flanders (IWT) (B.C. and S.S.). The work of P.C. is supported by a Belgian Science Policy grant (IUAP P7/03), long-term structural Methusalem funding by the Flemish Government, grants from the FWO (G.0671.12N, 1.5.244.11N) and Foundation Leducq Transatlantic Network (ARTEMIS), funding by “A cure for ALS” from ALS Liga Belgium, Motor Neuron Disease Association, ALS Association (ID#C44128), the European Research Council (ERC grant agreement n° 340429) and the European Union's Seventh Framework Programme (FP7/2007-2013; grant agreement n° 259867), and the Leuven University Fund - Opening the Future. W.R. is supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders & Geneeskundige Stichting Koningin Elisabeth (G.S.K.E.).

ASJC Scopus subject areas

  • Molecular Biology
  • Physiology
  • Cell Biology

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