Why do uncouplers of ETC (aspirin) cause lactic acidosis?

[Ven0m]

Uncoupling agents of the ETC make the ETC run faster and increase O2 consumption, but ATP production is decreased because all those H+ ions are going to waste. So if the ETC is running faster, doesn't this mean more pyruvate is being converted by pyruvate dehydrogenase into acetyl-CoA, put into citric acid cycle, and the resulting NADH into ETC? If more pyruvate was indeed converted into acetyl-CoA, instead of into lactate, then where's all the lactic acid coming from? Doesn't the ETC have to be "backed up" in order for anaerobic glycolysis to occur? (for example, in CO poisoning there's no O2, so electrons can't flow, NADH can't be oxidized back to NAD, so lactate dehydrogenase replenishes the NAD by reducing pyruvate to lactate --> lactic acidosis).

Or is it because faster ETC causes increased O2 consumption, which makes other tissues hypoxic --> they switch to anaerobic glycolysis (just a guess)?

Goljan said overdose of salicylates like aspirin are a cause of lactic acidosis (p. 112, 4th edition), so I'm trying to find the mechanism

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[Ven0m]

inhibited the TCA

What I'm trying to find out is how they inhibit the TCA, is there a specific enzyme they inhibit or what

 

[TheIllusionist]

Decrease in O2 from more rapid consumption causes feedback loops to result in more anerobic respiration which generates more lactic acid.Btw, since the ETC is no longer producing ATP, the lack of ATP is one of the major changes in feedback drivers for all of these processes.

The body tries to compensate by blowing off more CO2 to offset this acid base balanc. The body knows there is more CO2 because the medulla can detect and increase in the partial pressure of blood CO2 because the partial pressure of blood O2 has fallen due to increased consumption and the two gases follow a zero sum type equilibrium system izn accordance with Dalton's law of partial pressures. The other driver is salicylates directly changing thresholds at which the medulla feels the need to tell the lungs blow off CO2, which results in blowing it off even at lower levels than the normal set point. This is what causes a beyond a normal compensatory reaction. Pregnancy and LPS do tbis which is why both result in a respiratory alkalosis.

The end is an anion gap metabolic acidosis with respiratory alkalosis cocomitant. The anion gap as stated above is due to the bicarb consumption from the increased presensce of keto acids, latic acids, etc from increased lipolysis and anerobic respiration as the body enters an anoxic state.

 

[Ven0m]

Decrease in O2 from more rapid consumption causes feedback loops to result in more anerobic respiration which generates more lactic acid

This is what I was guessing - the increased systemic tissue consumption of O2 eventually causes systemic hypoxia which then would prevent the ETC from running (since O2 is no longer there to serve as the final electron acceptor). Because the ETC has stopped, this depletes intracellular NAD+. Because NAD+ is depleted, glyceraldehyde-3P dehydrogenase (a key enzyme of glycolysis) cannot run, which would halt glycolysis if it weren't for lactate dehydrogenase's presence to replenish the NAD+ from the excess NADH, thereby allowing glyceraldehyde-3P and thus glycolysis to keep running, but as anaerobic glycolysis --> lactic acidosis.

I'm going with that explanation because a decrease in ATP would indeed stimulate PFK-1, which increases the rate of glycolysis, however, the final product of glycolysis is pyruvate - and there are two routes it can go. Either converted to lactate (if NAD+ is low), or acetyl-CoA (if NAD+ is not low). So idk how a decrease in ATP would increase pyruvate's conversion to lactate, seeing as that depends on the NADH/NAD ratio (this is all just from kaplan biochem so if I'm wrong tell me lol)