Mitochondrial lipid pore in the mechanism of glutamate-induced calcium deregulation of brain neurons |
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Authors: | G D Mironova K N Belosludtsev A M Surin A S Trudovishnikov N V Belosludtseva V G Pinelis I A Krasilnikova B I Khodorov |
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Institution: | 1.Institute of Theoretical and Experimental Biophysics,Russian Academy of Sciences,Pushchino, Moscow oblast,Russia;2.Pushchino State University,Pushhcino, Moscow oblast,Russia;3.Institute of General Pathology and Pathophysiology,Russian Academy of Medical Sciences,Moscow,Russia;4.Scientific Center of Children Health,Russian Academy of Medical Sciences,Moscow,Russia |
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Abstract: | The work examines the mechanism of central nerve cell death upon stimulation of brain NMDA receptors with the stimulatory
mediator glutamate. A prolonged stimulation of neurons with glutamate is known to result in the disorder of Ca2+ homeostasis and severe mitochondrial depolarization followed by cell death. It has been shown that the overload of mitochondria
with Sr2+ leads to the release of the cation, medium alkalization, decrease of membrane potential and mitochondrial swelling, indicating
a nonspecific permeabilization of the mitochondrial membrane. The permeabilization, in our opinion, is caused by the activation
of Ca2+/Sr2+-dependent phospholipase A2 (PLA2), resulting in the formation of free palmitic and stearic acids in the mitochondrial membrane. These fatty acids bind Ca2+ with high affinity and the process of binding is accompanied by the formation of a transient lipid pore—a phenomenon demonstrated
earlier on both artificial and mitochondrial membranes. The inhibitors of PLA2 have been shown to suppress permeabilization of mitochondrial membranes. In the culture of granular cerebellum neurons, the
PLA2 inhibitors prolonged the lag of the delayed Sr2+ deregulation and membrane depolarization. On the basis of data obtained on isolated mitochondria and neurons we suppose that
the initial stages of glutamate-induced Ca2+ deregulation of neurons are underlain by the opening of lipid pores in brain mitochondria. |
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