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 anti-oxidative 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 HT-22 neuronal cell line even with an 8 hr 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 Ca2+ 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 (BSO) toxicity. We found that tBHQ scavenged ROS, induced a rapid up-regulation of superoxide dismutase 2 (SOD2) expression and a delayed up-regulation of heme oxygenase 1 (HO-1) expression. In HT-22 cells with a knockdown of SOD2 expression, delayed treatment of 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.
- The American Society for Pharmacology and Experimental Therapeutics