Glutamine-mediated protection from neuronal cell death depends on mitochondrial activity |
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Authors: | EV Stelmashook ER Lozier ES Goryacheva P Mergenthaler SV Novikova DB Zorov NK Isaev |
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Institution: | 1. Institute of Neurology, Department of Brain Research, Russian Academy of Medical Sciences, 105064 Moscow, Russia;2. A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, 119992 Moscow, Russia;3. Department of Experimental Neurology, Center for Stroke Research, Charite Universitetsmedizin Berlin, Germany |
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Abstract: | The specific aim of this study was to elucidate the role of mitochondria in a neuronal death caused by different metabolic effectors and possible role of intracellular calcium ions (Ca2+]i) and glutamine in mitochondria- and non-mitochondria-mediated cell death. Inhibition of mitochondrial complex I by rotenone was found to cause intensive death of cultured cerebellar granule neurons (CGNs) that was preceded by an increase in intracellular calcium concentration (Ca2+]i). The neuronal death induced by rotenone was significantly potentiated by glutamine. In addition, inhibition of Na/K-ATPase by ouabain also caused Ca2+]i increase, but it induced neuronal cell death only in the absence of glucose. Treatment with glutamine prevented the toxic effect of ouabain and decreased Ca2+]i. Blockade of ionotropic glutamate receptors prevented neuronal death and significantly decreased Ca2+]i, demonstrating that toxicity of rotenone and ouabain was at least partially mediated by activation of these receptors. Activation of glutamate receptors by NMDA increased Ca2+]i and decreased mitochondrial membrane potential leading to markedly decreased neuronal survival under glucose deprivation. Glutamine treatment under these conditions prevented cell death and significantly decreased the disturbances of Ca2+]i and changes in mitochondrial membrane potential caused by NMDA during hypoglycemia. Our results indicate that glutamine stimulates glutamate-dependent neuronal damage when mitochondrial respiration is impaired. However, when mitochondria are functionally active, glutamine can be used by mitochondria as an alternative substrate to maintain cellular energy levels and promote cell survival. |
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Keywords: | Glutamine Neurons Mitochondria |
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