Inhibition of HIF-prolyl-4-hydroxylases prevents mitochondrial impairment and cell death in a model of neuronal oxytosis.

TitleInhibition of HIF-prolyl-4-hydroxylases prevents mitochondrial impairment and cell death in a model of neuronal oxytosis.
Publication TypeJournal Article
Year of Publication2016
AuthorsNeitemeier S, Dolga AM, Honrath B, Karuppagounder SS, Alim I, Ratan RR, Culmsee C
JournalCell Death Dis
Date Published2016 May 05
KeywordsActivating Transcription Factor 4, Adenosine Triphosphate, Animals, Apoptosis, Cell Line, CRISPR-Cas Systems, Gene Expression Regulation, Glutamic Acid, Hippocampus, Hydroxyquinolines, Hypoxia-Inducible Factor-Proline Dioxygenases, Lipid Peroxidation, Membrane Potential, Mitochondrial, Mice, Neurons, Oxidative Phosphorylation, Oxidative Stress, Procollagen-Proline Dioxygenase, Prolyl-Hydroxylase Inhibitors, Reactive Oxygen Species, Signal Transduction

Mitochondrial impairment induced by oxidative stress is a main characteristic of intrinsic cell death pathways in neurons underlying the pathology of neurodegenerative diseases. Therefore, protection of mitochondrial integrity and function is emerging as a promising strategy to prevent neuronal damage. Here, we show that pharmacological inhibition of hypoxia-inducible factor prolyl-4-hydroxylases (HIF-PHDs) by adaptaquin inhibits lipid peroxidation and fully maintains mitochondrial function as indicated by restored mitochondrial membrane potential and ATP production, reduced formation of mitochondrial reactive oxygen species (ROS) and preserved mitochondrial respiration, thereby protecting neuronal HT-22 cells in a model of glutamate-induced oxytosis. Selective reduction of PHD1 protein using CRISPR/Cas9 technology also reduced both lipid peroxidation and mitochondrial impairment, and attenuated glutamate toxicity in the HT-22 cells. Regulation of activating transcription factor 4 (ATF4) expression levels and related target genes may mediate these beneficial effects. Overall, these results expose HIF-PHDs as promising targets to protect mitochondria and, thereby, neurons from oxidative cell death.

Alternate JournalCell Death Dis
PubMed ID27148687
PubMed Central IDPMC4917646