Introduction
In the nineteenth century, approximately 80 years after Scheele discovered lactate (La-) (Kompanje et al., 2007), Louis Pasteur observed an interesting phenomenon with yeast. He noticed that yeast cells that can survive with or without oxygen, called facultative yeast cells, grew more when exposed to oxygen compared to when they were under anaerobic conditions. Interestingly, when oxygen was present, these cells consumed less sugar and produced less alcohol through fermentation (Pasteur, 1861).
Prior to this discovery, Pasteur (1858) had already identified that some types of yeast fermented sugar into lactate (La-) only under anaerobic conditions, not in the presence of oxygen. This fascinating occurrence, which applies to both alcohol and lactate fermentation, became known as the Pasteur Effect (Barnett and Entian, 2005).
Similar phenomena were later observed in skeletal muscle and whole animals. For instance, Fletcher and Hopkins (1907) found that lactate accumulated in anaerobic frog muscles at rest. When these muscles were stimulated, the concentration of lactate increased rapidly. However, when the fatigued muscles were allowed to recover in an oxygen-rich environment, the lactate disappeared. These observations mirrored the behavior of yeast cells. Subsequently, Meyerhof conducted conclusive experiments that demonstrated glycogen as the precursor of lactate in isolated muscles. By the early 1940s, researchers had fully elucidated the glycolytic pathway (Meyerhof, 1942; Brooks and Gladden, 2003). This framework, along with other studies on hypoxia, established the traditional dogma: pyruvate is the end product of glycolysis under aerobic conditions, while lactate is produced when oxygen is insufficient. Schurr (2006) explored this dogma from the perspective of brain metabolism.
It is widely accepted that when intracellular oxygen (O2) levels drop to approximately 0.5 Torr or below, oxidative phosphorylation becomes limited, resulting in a condition called dysoxia. This limitation leads to the production and accumulation of lactate (Connett et al., 1990). However, Stainsby and Welch (1966) reported lactate efflux from contracting muscles that appeared to be well-oxygenated. In subsequent experiments, Jöbsis and Stainsby (1968) observed lactate production and release from contracting skeletal muscles in dogs, even when the NAD+/NADH redox couple indicated adequate oxygen supply. Another study by Connett et al. (1986), utilizing myoglobin cryomicrospectroscopy to determine PO2 in contracting dog gracilis muscle, revealed increasing lactate efflux without evidence of dysoxia. The lowest PO2 values recorded were generally around 2 Torr. Richardson et al. (1998) employed proton magnetic resonance spectroscopy (MRS) to measure myoglobin saturation and intracellular PO2 levels in humans during graded exercise. Simultaneously, they determined lactate efflux through arteriovenous concentration differences and blood flow. Surprisingly, lactate efflux was observed at intracellular PO2 levels of approximately 3 Torr, which should not have been limiting oxidative phosphorylation. Véga et al. (1998) also reported lactate release from isolated, stimulated nerve tissue even under aerobic conditions.
These findings, alongside other abundant circumstantial evidence, suggest that net lactate production and efflux from cells can occur even in the presence of oxygen (Gladden, 2004a,b). In fact, Brooks (2000) proposed that lactate is produced continuously in fully oxygenated cells and tissues. Schurr (2006) delved into this proposition in detail, proposing that lactate is the final step of glycolysis and is formed in brain tissue and likely many other tissues as well. Subsequently, Schurr and Payne (2007) and Schurr and Gozal (2012) provided experimental evidence supporting this idea in hippocampal brain slices. In this article, we embrace this concept and introduce the Cytosol-to-Mitochondria Lactate Shuttle, anchored by basic biochemical principles.
In conclusion, under anaerobic conditions, yeast produces lactate as a waste product. However, even with sufficient oxygen, lactate can still be produced and released from cells. This challenges the traditional notion that lactate is solely a byproduct of insufficient oxygen. Understanding these processes can help shed light on the role of lactate in various biological systems.
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