title: Inhibition of HIF-prolyl-4-hydroxylases prevents mitochondrial impairment and cell death in a model of neuronal oxytosis.
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.
authors.affiliation: Institut für Pharmakologie und Klinische Pharmazie, Biochemisch-Pharmakologisches Centrum Marburg, Fachbereich Pharmazie, Philipps-Universität Marburg, Karl-von-Frisch-Straße 1, Marburg 35032, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Neitemeier
authors.affiliation: Institut für Pharmakologie und Klinische Pharmazie, Biochemisch-Pharmakologisches Centrum Marburg, Fachbereich Pharmazie, Philipps-Universität Marburg, Karl-von-Frisch-Straße 1, Marburg 35032, Germany.
authors.forename: A M
authors.initials: AM
authors.lastname: Dolga
authors.affiliation: Institut für Pharmakologie und Klinische Pharmazie, Biochemisch-Pharmakologisches Centrum Marburg, Fachbereich Pharmazie, Philipps-Universität Marburg, Karl-von-Frisch-Straße 1, Marburg 35032, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Honrath
authors.affiliation: Burke-Cornell Medical Research Institute, White Plains, NY, USA.|Feil Family Brain and Mind Research Institute, Department of Neurology and Neuroscience, Weill Medical College, Cornell University, New York, NY, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Karuppagounder
authors.affiliation: Burke-Cornell Medical Research Institute, White Plains, NY, USA.|Feil Family Brain and Mind Research Institute, Department of Neurology and Neuroscience, Weill Medical College, Cornell University, New York, NY, USA.
authors.forename: I
authors.initials: I
authors.lastname: Alim
authors.affiliation: Burke-Cornell Medical Research Institute, White Plains, NY, USA.|Feil Family Brain and Mind Research Institute, Department of Neurology and Neuroscience, Weill Medical College, Cornell University, New York, NY, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Ratan
authors.affiliation: Institut für Pharmakologie und Klinische Pharmazie, Biochemisch-Pharmakologisches Centrum Marburg, Fachbereich Pharmazie, Philipps-Universität Marburg, Karl-von-Frisch-Straße 1, Marburg 35032, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Culmsee
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000819:agonists / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064113:CRISPR-Cas Systems; D002460:Cell Line; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006912:Hydroxyquinolines / Q000494:pharmacology*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress; D011393:Procollagen-Proline Dioxygenase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D064800:Prolyl-Hydroxylase Inhibitors / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C081452:Atf4 protein, mouse; D006912:Hydroxyquinolines; D064800:Prolyl-Hydroxylase Inhibitors; D017382:Reactive Oxygen Species; D051701:Activating Transcription Factor 4; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; C522721:PHD1 protein, mouse; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases