Mild excitotoxic insult allow NMDAR activation by ambient concentrations of glutamate. This leads to increased mitochondrial [Ca2+] and free radical production, yet relatively preserved ATP generation. Consequently, the mitochondria can release cytochrome c (Cytc), caspase 9, apoptosis inducing factor (AIF), and other mediators that lead to apoptosis.
After severe insults e.g. ischaemia, NMDAR activation is enhanced resulting in increased intracellular calcium levels. This activates nitric oxide synthase (NOS), which increases mitochondrial Ca(2+) and superoxide generation followed by formation of peroxynitrite (ONOO-). This free radical causes DNA and cellular damage, leasing to the activation of poly-ADP-ribose polymerase (PARS). Mitochondrial calcium accumulation and oxidative damage lead to activation of the permeability transition pore (PTP) that is linked to excitotoxic cell death.