title: Sequential Upregulation of Superoxide Dismutase 2 and Heme Oxygenase 1 by tert-Butylhydroquinone Protects Mitochondria during Oxidative Stress.
abstract: Oxidative stress is linked to mitochondrial dysfunction in aging and neurodegenerative conditions. The transcription factor nuclear factor E2-related factor 2 (Nrf2)-antioxidant response element (ARE) regulates intracellular antioxidative capacity to combat oxidative stress. We examined the effect of tert-butylhydroquinone (tBHQ), an Nrf2-ARE signaling pathway inducer, on mitochondrial function during oxidative challenge in neurons. tBHQ prevented glutamate-induced cytotoxicity in an HT-22 neuronal cell line even with an 8-hour exposure delay. tBHQ blocked glutamate-induced intracellular reactive oxygen species (ROS) and mitochondrial superoxide accumulation. It also protected mitochondrial function under glutamate toxicity, including maintaining mitochondrial membrane potential, mitochondrial Ca(2+) hemostasis, and mitochondrial respiration. Glutamate-activated, mitochondria-mediated apoptosis was inhibited by tBHQ as well. In rat primary cortical neurons, tBHQ protected cells from both glutamate and buthionine sulfoximine toxicity. We found that tBHQ scavenged ROS and induced a rapid upregulation of superoxide dismutase 2 (SOD2) expression and a delayed upregulation of heme oxygenase 1 (HO-1) expression. In HT-22 cells with a knockdown of SOD2 expression, delayed treatment with tBHQ failed to prevent glutamate-induced cell death. Briefly, tBHQ rescues mitochondrial function by sequentially increasing SOD2 and HO-1 expression during glutamate-mediated oxidative stress. This study is the first to demonstrate the role of tBHQ in preserving mitochondrial function during oxidative challenge and provides a clinically relevant argument for using tBHQ against acute neuron-compromising conditions.
authors.affiliation: Department of Physiology and Pharmacology, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, West Virginia.
authors.forename: Jiahong
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Physiology and Pharmacology, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, West Virginia.
authors.forename: Xuefang
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Physiology and Pharmacology, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, West Virginia jwsimpkins@hsc.wvu.edu.
authors.forename: James W
authors.initials: JW
authors.lastname: Simpkins
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000633:toxicity; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006873:Hydroquinones / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000099156:Superoxide Dismutase 2
chemical_list: D018698:Glutamic Acid; D051547:Heme Oxygenase-1; D006873:Hydroquinones; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C018855:2-tert-butylhydroquinone