cellular respiration - Why is a lack of oxygen fatal to cells?

In animals temporary anaerobic respiration leads to the breakdown of the pyruvate formed by glycolysis into lactate. The buildup of lactate in the bloodstream is accompanied by a large number of protons causing lactic acidosis, which is detrimental to the health of the organism. This is one of the main suggestions I have come across for why a lack of oxygen is fatal to cells, however the LD₅₀ for lactic acid as referenced by the COSHH MSDS seem awfully high (even if the route is by ingestion rather than directly into the bloodstream) for this to be a cause of cell death:

Toxicological Data on Ingredients: ORAL (LD50): Acute:

3543 mg/kg [Rat (Lactic Acid (CAS no. 50-21-5))].

4875 mg/kg [Mouse (Lactic Acid (CAS no. 50-21-5))].

I also wonder if this is a larger problem for an organism as a whole rather than on a cellular level.

The alternative, I suppose, is that glycolysis alone does not provide sufficient ATP for vital cellular processes to occur. If this is the case, which ATP requiring processes are most vital for the short term survival for a cell?

Answer

Here's an illustrated example in neurons:

ATP, of course, is generated by aerobic respiration. The critical biochemical reaction in the brain that is halted due to lack of ATP (and therefore O2) is the glutmaine synthetase reaction, which is very important for the metabolism and excretion of nitrogenous wastes:

The body uses this reaction to dump excess ammonia (which is a metabolic waste product) on glutamate to make glutamine. The glutamine is then transported via the circulatory system to the kidney, where the terminal amino group is hydrolyzed by glutaminase, and the free ammonium ion is excreted in the urine.

Therefore, as you'd expect, under hypoxic conditions in the brain, excess ammonia builds up which is very toxic to the cells. Neurons are also highly metabolically active, which means they generate more waste products. A buildup of nitrogenous waste products in the cell (and bloodstream) can be potentially fatal due to it's effects on pH (screws up enzymes and a whole slew of biochemical reactions).

In addition, the buildup of ammonia will cause glutamate dehydrogenase to convert ammonia + aKG to glutamate, which depletes the brain of alpha-ketoglutarate (key intermediate in TCA cycle). This basically creates a logjam in the central metabolic cycle which further depletes the cell of energy.

This is just one example of many. Of course, there are many, many other critical metabolic processes that require ATP (i.e. the Na+/K+ ATPase pump that regulates neuronal firing and osmotic pressure), but nitrogen metabolism was the first that came to mind :)