title: Bid-mediated mitochondrial damage is a key mechanism in glutamate-induced oxidative stress and AIF-dependent cell death in immortalized HT-22 hippocampal neurons.
abstract: Glutamate toxicity involves increases in intracellular calcium levels and enhanced formation of reactive oxygen species (ROS) causing neuronal dysfunction and death in acute and chronic neurodegenerative disorders. The molecular mechanisms mediating glutamate-induced ROS formation are, however, still poorly defined. Using a model system that lacks glutamate-operated calcium channels, we demonstrate that glutamate-induced acceleration of ROS levels occurs in two steps and is initiated by lipoxygenases (LOXs) and then significantly accelerated through Bid-dependent mitochondrial damage. The Bid-mediated secondary boost of ROS formation downstream of LOX activity further involves mitochondrial fragmentation and release of mitochondrial apoptosis-inducing factor (AIF) to the nucleus. These data imply that the activation of Bid is an essential step in amplifying glutamate-induced formation of lipid peroxides to irreversible mitochondrial damage associated with further enhanced free radical formation and AIF-dependent execution of cell death.
authors.affiliation: Institute for Pharmacology and Toxicology, Philipps University Marburg, Karl-von-Frisch-Strasse 1, Marburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Tobaben
authors.forename: J
authors.initials: J
authors.lastname: Grohm
authors.forename: A
authors.initials: A
authors.lastname: Seiler
authors.forename: M
authors.initials: M
authors.lastname: Conrad
authors.forename: N
authors.initials: N
authors.lastname: Plesnila
authors.forename: C
authors.initials: C
authors.lastname: Culmsee
mesh_terms: D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002461:Cell Line, Transformed; D018698:Glutamic Acid / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D058945:Lipoxygenases / Q000737:chemistry / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D051033:Apoptosis Inducing Factor; D051023:BH3 Interacting Domain Death Agonist Protein; D016859:Lipoxygenase Inhibitors; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D058945:Lipoxygenases