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Abstract

Hypoxia research is in the focus, as three of its pioneers receive the Lasker Prize 2016 for their discovery of hypoxia-inducible transcription factors (HIFs) and prolyl-4-hydroxlase domain proteins (PHDs) as cellular oxygen sensors [1]. HIFs are heterodimers consisting of a labile α and a stable β unit. In the presence of molecular oxygen the α subunit is hydroxylated by PHDs leading to immediate proteasomal degradation.In cerebral ischemia, brain hypoperfusion results in tissue hypoxia, combined with nutrient depletion. Given that neuronal energy generation primarily relies on oxidative glucose metabolism, and their striking susceptibility to excitotoxicity, neurons exhibit the highest vulnerability to ischemic stress among all cells of the central nervous system. PHDs control endogenous mechanisms in nerve cells that promote adaptation to hypoxia/ischemia. As PHDs have many additional targets beside HIFα subunits, it remains to be established whether PHD-mediated effects are HIF-dependent or rather HIFindependent.Our major finding is that neuronal inactivation of PHD2 in mice improves recovery from cerebral ischemia [2,3]. One could hypothesize that this protective effect is either a direct one or alternatively occurs in an indirect manner, whereby PHD2 deficient neurons produce factors that act in a paracrine fashion on neighboring endothelial cells, astrocytes or microglia. The resulting activation/ modulation of these cells could then in turn support survival of neurons. We and others have demonstrated experimental evidence for both -direct and indirectprotective mechanisms.PHD2 inactivation in neurons resulted in HIF stabilization and subsequent transcriptional activation of erythropoietin and vascular endothelial growth factor (VEGF) [2,3]. Both mediators are well known to be potent anti-apoptotic factors, which directly support neuronal survival. Accordingly, application of the PHD inhibitor FG-4497 strongly increased cell survival in pure neuronal cultures exposed to ischemic conditions [4]. In addition, neuronal PHD2 deletion resulted in increased expression of HIF-dependent glucose transporters and glycolytic enzymes [2]. A switch from oxidative to glycolytic metabolism might improve ischemic tolerance of PHD2 deficient neuronal cells by enabling oxygen-independent energy generation, and reduction of mitochondrial reactive oxygen species (ROS) production.Recently, Quaegebeur et al. showed that genetic loss or inhibition of PHD1 in mice improves brain tissue damage and sensorimotor deficit upon focal cerebral ischemia by reprogramming neuronal glucose metabolism [5]. PHD1 deficient neurons maintained energy production via oxidative phosphorylation in mitochondria, but preferentially metabolized glutamine instead of glucose. PHD1 inactivation in neurons further redirected glucose away from glycolysis into the oxidative pentose phosphate pathway (oxPPP), which preserved the redox state of glutathione, and thus improved ROS scavenging capacity in neurons upon ischemia-reoxygenation. Enhanced oxPPP flux i...

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