Abstract
Glutamate-induced cytotoxicity is partially mediated by enhanced oxidative stress. The objectives of the present study are to determine the effects of glutamate on mitochondrial membrane potential, oxygen consumption, mitochondrial dynamics and autophagy regulating factors and to explore the protective effects of selenium against glutamate cytotoxicity in murine neuronal HT22 cells. Our results demonstrated that glutamate resulted in cell death in a dose-dependent manner and supplementation of 100 nM sodium selenite prevented the detrimental effects of glutamate on cell survival. The glutamate induced cytotoxicity was associated with mitochondrial hyperpolarization, increased ROS production and enhanced oxygen consumption. Selenium reversed these alterations. Furthermore, glutamate increased the levels of mitochondrial fission protein markers pDrp1 and Fis1 and caused increase in mitochondrial fragmentation. Selenium corrected the glutamate-caused mitochondrial dynamic imbalance and reduced the number of cells with fragmented mitochondria. Finally, glutamate activated autophagy markers Beclin 1 and LC3-II, while selenium prevented the activation. These results suggest that glutamate targets the mitochondria and selenium supplementation within physiological concentration is capable of preventing the detrimental effects of glutamate on the mitochondria. Therefore, adequate selenium supplementation may be an efficient strategy to prevent the detrimental glutamate toxicity and further studies are warranted to define the therapeutic potentials of selenium in animal disease models and in human.
Highlights
Glutamate toxicity is a major contributor to neuronal cell death in stroke and other neurodegenerative diseases including Parkinson’s and Alzheimer’s disease [1]
Glutamate treatment resulted in dose-dependent cell death in HT22 cells when measured 24 h after exposure resulting about 80% of mortality at 4 mM concentration. Glutamate (4 mM) concentration
The present study demonstrates that glutamate toxicity is linked to mitochondrial membrane hyperpolarization, increased production of reactive oxygen species (ROS), elevated mitochondrial oxygen consumption, disturbance of mitochondrial dynamic balance towards fission and activation of autophagy
Summary
Glutamate toxicity is a major contributor to neuronal cell death in stroke and other neurodegenerative diseases including Parkinson’s and Alzheimer’s disease [1]. Glutamate-induced cell death is mediated by receptor-initiated excitotoxicity [2] and non-receptor mediated oxidative toxicity [3]. Oxidative glutamate toxicity is initiated by high concentrations of extracellular glutamate that prevent cystine uptake into the cells via the cystine/glutamate antiporter system, resulting in depletion of intracellular cysteine and glutathione [3]. Glutathione depletion induces excessive accumulation of reactive oxygen species (ROS) resulting in oxidative stress. Depletion of antioxidant or excessive accumulation of ROS has detrimental effects on mitochondrial structure and function. Oxidative stress and mitochondrial dysfunction are considered as primary events in glutamate induced oxytosis [5], the precise mechanisms are not clear
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