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

• Published in: Cell death & disease Vol. 7; no. 5; p. e2214
• Main Authors: Neitemeier, S, Dolga, A M, Honrath, B, Karuppagounder, S S, Alim, I, Ratan, R R, Culmsee, C
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 05.05.2016; Nature Publishing Group
• Subjects: Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Adenosine Triphosphate - agonists; Adenosine Triphosphate - biosynthesis; Animals; Apoptosis; Apoptosis - drug effects; Cell death; Cell Line; CRISPR-Cas Systems; Gene Expression Regulation; Glutamic Acid - toxicity; Hippocampus - cytology; Hippocampus - drug effects; Hippocampus - metabolism; Hydroxyquinolines - pharmacology; Hypoxia-Inducible Factor-Proline Dioxygenases - antagonists & inhibitors; Hypoxia-Inducible Factor-Proline Dioxygenases - genetics; Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism; Lipid Peroxidation - drug effects; Membrane Potential, Mitochondrial - drug effects; Membrane Potential, Mitochondrial - genetics; Mice; Mitochondria; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Original; Oxidative Phosphorylation - drug effects; Oxidative Stress; Pathology; Procollagen-Proline Dioxygenase - deficiency; Procollagen-Proline Dioxygenase - genetics; Procollagen-Proline Dioxygenase - metabolism; Prolyl-Hydroxylase Inhibitors - pharmacology; Proteins; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Signal Transduction
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2016.107

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.