A prolonged stimulation of brain NMDA receptors with glutamate is known to result in a delayed Ca2+ deregulation (DCD) and mitochondrial depolarization (MD), which eventually cause the neuron death. Here we found that the initial stages of glutamate-induced DCD are underlain by the opening of lipid pore in brain mitochondria. It was obtained that the overload of mitochondria with Sr2+ leads to a nonspecific permeabilization of the mitochondrial membrane. The permeabilization can be caused by the activation of Ca2+/Sr2+-dependent phospholipase A2 (PLA2), resulting in the formation of free palmitic and stearic acids. These fatty acids bind Ca2+ with high affinity, and the binding process 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 mitochondria and prolong the lag of the delayed Sr2+ deregulation and MD in the culture of cerebellum granular neurons. This work was supported by the Government of RF (No. 14.Z50.31.0028).