Ippei Kawano
“Lactic acidosis” is among the more basic clinical concepts taught in medical school, but this term is hugely misleading. In our uni’s online biochem textbook (from 3rd faculty), lactate formation is rather shamelessly listed under “anaerobic glycolysis in muscles and erythrocytes” as a “proton-producing reaction”. Strictly speaking, this is not incorrect — but rather, it is leading to the misunderstanding that lactate is somehow a metabolic “waste” that is produced “only under anaerobic conditions” that causes “acidosis”. Some textbooks even go further to say “exercise leads muscles to make lactic acid” — now that expression is completely wrong.
Why?
1. At physiological pH, there’s virtually no “lactic acid” in the body, only lactate (conjugate base!!) — if you look at the last step of glycolysis, the carboxylic acid group of pyruvate is already deprotonated. The step of lactic acid generation rather consumes (!) acid by NADH oxidation.
2. Glycolysis per se does not produce acid, but acid is produced by ATP hydrolysis. Note that the hydrolysis of ester, thioester, and phosphoanhydride (of ATP) do produce H+. So only if the net 2 ATP is quickly hydrolyzed, such as in exercising muscle, H+ is produced.
3. Some studies do show the stoichiometric relationship between lactate and H+ is 1:1 during exercise as support for lactic acid generation. But this can also be explained by the net 2ATP hydrolysis of glycolysis producing 2H+.
4. Lactate is ubiquitously produced under both aerobic and anaerobic conditions as a redox-balanced product of glycolysis, and is quickly cleared by the TCA cycles all over the whole body. The textbook view of “glucose to pyruvate, pyruvate to acetyl-CoA to TCA” is missing the lactate step. Lactate is a ubiquitous fuel, not a waste.
The state of lactate accumulation should be considered as reduced clearance by OXPHOS, rather than toxic waste buildup; therefore, the true stress in lactic acidosis is not “lactic acid” but OXPHOS defect. (Turning it around, serum lactate may be used as a biomarker for OXPHOS activity.)
