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

[whatdidigetinto]

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I can understand why lactic acid increase but not why glutamate increases.

 

[OberynMartell]

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.

 

[Phloston]

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.

 

[Phloston]

Btw, no one picked up on the fact that I said niacin, not thiamine.

Woops.

 

[whatdidigetinto]

Thanks Phloston that makes a whole lotta sense. Nice bridging between biochemistry and pathology too.

 

[thecalccobra]

Nice explanation.