Inhibition of HIF2 Prevents the Development of Neurodegenerative Disorder Induced by Deficiency of IRP2

Abstract Background: IRP2 (Iron regulatory protein 2) deficiency in mice and humans causes microcytic anemia and neurodegeneration due to functional cellular iron depletion. Our previous in vitro data have demonstrated that Irp2 depletion upregulates hypoxia-inducible factor subunits Hif1α and Hif2α expression and inhibition of Hif2α rescues Irp2 ablation-induced mitochondrial dysfunction and inhibition of Hif1α suppresses the overdose production of lactic acid derived from actively aerobic glycolysis. We wonder whether Hif1α and Hif2α are also elevated in vivo, and if they are elevated, are they related to the neurodegenerative disorder of Irp2-/- mice.Results: In this study, we confirmed the upregulated Hif2α, not Hif1α, in tissues, particularly, the central nervous system including the mainly affected cerebellum and spinal cord of Irp2-/- mice. Consistent with this observation, inhibition of Hif2α by PT-2385, not Hif1α by PX-478, prevented the neurodegenerative symptoms, which was proved by Purkinje cells arrangement from the shrunken and irregular to the full and regular array. PT-2385 treatment did not only modulate mitochondrial morphology and quality in vivo, but also suppressed the glycolysis. Consequently, the shift of energy metabolism from glycolysis to oxidative phosphorylation reversed. Conclusions: Our results indicate that Irp2 depletion-induced Hif2α is alone, in vivo, in charge of the switch between oxidative phosphorylation and glycolysis, suggesting that, for the first time to our knowledge, Hif2α is a clinically potential target in the treatment of IRP2 deficiency-induced neurodegenerative syndrome.