Why is there an increase in glutamate during hypoxic or ischemic cell injury?

This forum made possible through the generous support of SDN members, donors, and sponsors. Thank you.
No oxygen means no final electron acceptor, meaning no ATP generation. No ATP generation means pumps like Na/K pump don't work (as one example). This depolarizes the cell because the gradient can't be maintained. Depolarization leads to glutamate firing (it's an excitatory neurotransmitter in the brain). This is something called "glutamate toxicity" or excitotoxicity.

This in turn leads to increased cytosolic calcium, which can activate endonucleases, phospholiases, proteases, etc. and punch holes in the mitochondria. This leads to leaking of cytochrome c, which activates caspaces.
 
Hypoxia --> decreased activity of the TCA cycle --> accumulation of TCA intermediates, including alpha-KG.

Since alpha-KG + NH4+ <--> glutamate + H2O ,

increased alpha-KG shifts the equilibrium to the right, which means increased glutamate.

This equilibrium is why niacin deficiency in alcoholics leads to neuroexcitotoxicity; alpha-KG builds up due to loss of the dehydrogenase activity.
 
Top