Glutamate is the major excitatory neurotransmitter in the brain, and it is widely accepted to play a role in synaptic plasticity and excitotoxic cell death. Glutamate binds to several receptors, including ionotropic N-methyl-d-Aspartate receptor (NMDAR), which is essential in synaptic plasticity and excitotoxicity. This receptor is a calcium channel that is located in synaptic and extrasynaptic sites, triggering different signalling cascades in each case. The calcium entry through extrasynaptic NMDARs is linked to calcium overload in the mitochondria in neurons in vitro. The mitochondria, besides their role in ATP production in the cell, participate in calcium homeostasis, acting as a buffering organelle. Disruption of mitochondrial calcium homeostasis has been linked to neuronal death either by triggering apoptosis or driven by the opening of the mitochondrial transition pore. These cell-death mechanisms contribute to the pathophysiology of diverse diseases such as neurodegenerative Alzheimer’s disease or Parkinson’s disease, and acute neuropathological conditions such as stroke or traumatic brain injury. In this review, we will address the available evidence that positions the mitochondria as an essential organelle in the control of calcium-mediated toxicity, highlighting its role from the perspective of specific NMDAR signalling microdomains at the level of the central synapse.

谷氨酸是大脑中主要的兴奋性神经递质，被广泛认为在突触可塑性和兴奋性毒性细胞死亡中发挥作用。谷氨酸与几种受体结合，包括离子型N-甲基-d-天冬氨酸受体 (NMDAR)，它对突触可塑性和兴奋性毒性至关重要。该受体是一种钙通道，位于突触和突触外位点，在每种情况下触发不同的信号级联。通过突触外 NMDAR 进入的钙与体外神经元线粒体中的钙超载有关。线粒体除了在细胞内产生 ATP 中的作用外，还参与钙稳态，充当缓冲细胞器。线粒体钙稳态的破坏与神经元死亡有关，要么通过触发细胞凋亡，要么由线粒体过渡孔的开放驱动。这些细胞死亡机制有助于多种疾病的病理生理学，例如神经退行性阿尔茨海默病或帕金森病，和急性神经病理学状况，例如中风或外伤性脑损伤。在这篇综述中，我们将讨论将线粒体定位为控制钙介导毒性的重要细胞器的现有证据，从中央突触水平的特定 NMDAR 信号微域的角度突出其作用。