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

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ID: 269380
2016
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Abstract
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.
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culmsee2016cellinhibition Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors S Neitemeier,Amalia Dolga,Birgit Honrath,S S Karuppagounder,I Alim,R R Ratan,C Culmsee;S Neitemeier;Amalia Dolga;Birgit Honrath;S S Karuppagounder;I Alim;R R Ratan;C Culmsee;
Journal Cell death & disease
Year 2016
DOI
10.1038/cddis.2016.107
URL
https://sciprofiles.com/publication/view/79fb529ba96f13db25f094bec6b45167
Keywords
toxicity Cancer apoptosis autophagy transcription immunity stem cell neurodegeneration cell death cell growth signaling wallerian degeneration cornification keratinization

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