title: Neuroglobin regulates hypoxic response of neuronal cells through Hif-1α- and Nrf2-mediated mechanism.
abstract: Oxygen sensing in hypoxic neurons has been classically attributed to cytochrome c oxidase and prolyl-4-hydroxylases and involves stabilization of transcription factors, hypoxia-inducible factor-1α (Hif-1α) and nuclear factor erythroid 2-related factor 2 (Nrf2) that mediate survival responses. On the contrary, release of cytochrome c into the cytosol during hypoxic stress triggers apoptosis in neuronal cells. We, here advocate that the redox state of neuroglobin (Ngb) could regulate both Hif-1α and Nrf2 stabilization and cytochrome c release during hypoxia. The hippocampal regions showing higher expression of Ngb were less susceptible to global hypoxia-mediated neurodegeneration. During normoxia, Ngb maintained cytochrome c in the reduced state and prevented its release from mitochondria by using cellular antioxidants. Greater turnover of oxidized cytochrome c and increased utilization of cellular antioxidants during acute hypoxia altered cellular redox status and stabilized Hif-1α and Nrf2 through Ngb-mediated mechanism. Chronic hypoxia, however, resulted in oxidation and degradation of Ngb, accumulation of ferric ions and release of cytochrome c that triggered apoptosis. Administration of N-acetyl-cysteine during hypoxic conditions improved neuronal survival by preventing Ngb oxidation and degradation. Taken together, these results establish a role for Ngb in regulating both the survival and apoptotic mechanisms associated with hypoxia.
authors.affiliation: High Altitude Physiology Laboratory, Defence Institute of High Altitude Research, Jammu and Kashmir, India.
authors.forename: Kalpana B
authors.initials: KB
authors.lastname: Hota
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Hota
authors.forename: Ravi B
authors.initials: RB
authors.lastname: Srivastava
authors.forename: Shashi B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D005914:Globins / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D000078787:Neuroglobin; D009474:Neurons / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D059748:Proteolysis; D017207:Rats, Sprague-Dawley
chemical_list: D016166:Free Radical Scavengers; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051267:NF-E2-Related Factor 2; D009419:Nerve Tissue Proteins; D000078787:Neuroglobin; C495637:Nfe2l2 protein, rat; D005914:Globins; D045304:Cytochromes c; D000111:Acetylcysteine