Pyruvate to lactate how many atp

The higher the lactic acid concentration, the quicker the rigor mortis sets in. Moreover, Fletcher and Hopkins [ 25 ] have shown that in the presence of oxygen, the survival of the excised muscle was prolonged and so did the acceleration of the disposal of lactate from it. These researchers highlighted the recognition that the body has the means to rid itself from muscular lactate and that there is ample evidence that such disposal is most efficient under oxidative conditions.

Thus, the dogma of lactate as a muscular product responsible for fatigue and rigor, one that aerobic conditions enhance its disposal, was already well entrenched among scientists at the beginning of the twentieth century. It is still entrenched today among athletes and their coaches. Hill [ 7 , 8 ] went even further than Fletcher by suggesting that the role of oxygen in muscle contracture is twofold, to decrease the duration of heat production and to remove lactate from it.

Hill argued that the measured heat production of lactate oxidation was much lower than the calculated value of its complete combustion. It is somewhat perplexing that a scientist of the stature of Hill would argue that if lactate were a fuel, all the energy of its oxidation would be released as heat.

The leading investigators in the field at the time actually concluded that lactate is a separate entity from the one that is oxidized during muscle respiration and which yields energy and CO 2.

Moreover, they held that the energy yielded in respiration is utilized for lactate disposal. By the s [ 28 , 29 ], the central theme of these studies and many others had been muscle tissue and its glycolytic formation of lactate. The process had been postulated to always be anaerobic and mainly through the breakdown of glycogen.

In addition, when aerobic oxidation takes place, it occurs only after the muscle contracts and its main purpose is the removal of accumulated lactate and its accompanied acidosis. The relationship between lactate and glycogen in muscle and, eventually, in other tissues, including brain, has been a complicating issue in the understanding of glycolysis.

While the muscular conversion of glycogen to lactate is still in dispute today [ 30 ], both Nobel laureates had a long-lasting influence on this field of research. Since the majority of scientists in the field of carbohydrate metabolism in those days studied muscle tissue, their interpretation of and opinions about the results of their studies greatly influenced those who studied carbohydrate metabolism of other tissues, especially brain.

Thus, the small scientific community that investigated cerebral glycolysis in the late s and early s adopted the opinions of their peers in the field of muscle glycolysis and accepted the popular dogma, according to which, lactate is a useless end product that the brain eliminates via oxidation.

That concept stood against their own notion that the results of their studies could indicate lactate oxidative utilization by brain tissue. While Hill and Meyerhof were the leading scientists in the field of muscle carbohydrate metabolism in the s and s, E. Holmes was their counterpart in the field of cerebral carbohydrate metabolism. The latter was joined by his wife, B. First, they showed that brain carbohydrates are not the source of brain lactate; however, the brain is capable of forming lactate from added glucose [ 31 ].

In their second study, they determined that brain lactate levels fall when there was a fall in blood sugar level, which results in shortage of glucose in the brain [ 32 ].

In the third paper of the series, the Holmes found that brain tissue in room temperature or under anaerobic conditions does not exhibit a significant increase in lactate level or a significant fall in glycogen level, but that under aerobic conditions, lactate rapidly disappears, while glycogen level remains unchanged [ 33 ].

Thus, the Holmes established that glucose is the precursor of lactate in the brain and that under aerobic conditions, brain lactate content decreases.

Additionally, these investigators showed that brain lactate is formed from glucose supplied by the blood and that its levels rise and fall with blood glucose levels, under both hypo- and hyperglycemic conditions.

Moreover, they showed that the diabetic brain is not different from the normal brain, where lactate formation and its removal under aerobic conditions are concerned [ 34 ].

By , Ashford joined Holmes and the two were able to demonstrate that the disappearance of lactate and the consumption of oxygen are correlated, which, in essence, indicates an aerobic utilization of lactate by brain tissue. Furthermore, these investigators also showed that sodium fluoride NaF , the first known glycolytic inhibitor, blocked both glucose conversion to lactate and oxygen consumption.

Holmes [ 35 ] showed in brain gray matter preparation that oxygen consumption was completely inhibited by NaF in the presence of glucose. However, when lactate was used instead of glucose, oxygen consumption was not inhibited by NaF. Consequently, Holmes concluded that the conversion of glucose to lactate must take place prior to its oxidation by brain gray matter. These results and their straightforward conclusion have been completely ignored for over eight decades.

This ignorance is especially glaring when one considers the fact that by the time the glycolytic pathway was elucidated in , Holmes and Ashford papers were already available for at least a decade [ 35 , 36 ] and should have been taken into account prior to the announcement of that elucidation.

Hence, 76 years ago, we could have been presented with somewhat different view of the glycolytic pathway instead of the one in which, depending on the presence or absence of oxygen, ends up with either pyruvate or lactate, respectively. Krebs and Johnson were careful to place a question mark following their suggestion that pyruvate is the TCA cycle substrate. Thus, the work by the Holmes couple [ 31 — 34 ], Ashford and Holmes [ 36 ] and Holmes and Ashford [ 41 ] on brain carbohydrate metabolism has been ignored and remained obscure even today, due mainly to habit of mind [ 23 ].

This habit of mind prevents many scientists from accepting more recent data that challenge the old dogma of a glycolytic pathway that has two possible outcomes, aerobic and anaerobic. Nevertheless, we must not forget that in , both the fact that the TCA cycle enzymes are located in mitochondria and the role these organelles play in respiration were unknown. Also unknown at the time was the fact that mitochondria contain in their membrane the enzyme lactate dehydrogenase LDH , which can convert lactate to pyruvate [ 42 — 51 ].

Ignorance is understandable where the general public is concerned as both coaches and athletes continue, unabated, to blame lactic acid for muscle pain following anaerobic effort, even as recently as during the Rio Olympic games despite the fact that this claim has been refuted [ 52 ]. Nevertheless, ignorance cannot explain the persistence of the dogmatic aerobic and anaerobic glycolysis concept among scientists, since the knowledge available today does not support this dogma.

Hence, the choice by many scientists to ignore or circumvent this knowledge Is most probably due to habit of mind [ 23 ]. The preceding sections have attempted to explain why the pioneers who formulated the glycolytic pathway decided to branch it into two types, aerobic and anaerobic.

It is clear from the review of the studies that led to this formulation that these pioneers had to overcome several hurdles while gathering the existing information, including, among others, contradictory results and some unknowns.

Nevertheless, their formulation of glycolysis has remained unchanged until this day, regardless of some major predicaments it created as the field of energy metabolism has progressed over the years. Many biochemical pathways have been redrawn as research progresses over time, and yet, the one pathway that has never been subjected to any redrawing throughout its 76 year history has been the glycolytic pathway. The reluctance of many scientists in the field to suggest corrections to or even consider its reformulation is unexplainable.

Most importantly, the originally drawn pathway forces those who object to any reformulation which circumvents the more straightforward one according to which the glycolytic pathway always terminates with lactate production. It stands in complete disagreement with the fact that the glycolytic pathway of erythrocytes, the richest of all tissues in oxygen concentration, produces largely lactate from glucose and only minimal amounts of pyruvate [ 53 ].

Despite the fact that red blood cell glycolytic pathway is identical to that of other tissues, it produces lactate, both in the presence and absence of oxygen. However, for an unexplained reason, aerobic glycolysis of all other oxygenated tissues supposedly produces mainly pyruvate. Understandably, this paradox has remained unresolved throughout the second half of the twentieth century.

However, the cumulative data gathered since the late s are more than sufficient to suggest that this paradox is actually a misconception. Hence, it is bewildering that the majority of scientists in the field of energy metabolism prefer to accept such a paradox, rather than to correct a deficient formula of this biochemical pathway.

Dienel and colleagues have published several studies and reviews over the years adamantly rejecting the postulate that lactate may be utilized oxidatively instead of glucose, since glucose is an obligatory energy substrate in the brain. Under such circumstances, any NADH is formed in the mitochondria, not in the cytoplasm. LDH localization in the mitochondrial membrane and that mitochondria are capable of utilizing lactate as a substrate of the TCA cycle have been demonstrated by many investigators [ 42 — 51 , 57 ].

For those who insist that the original formulation of the glycolytic pathway is correct and accurate, the existence of membranous mitochondrial LDH presents a real dilemma, since one must question the role of such enzyme there, as it is unlikely for the reduction of pyruvate to lactate. Consequently, an aggressive push back was mounted against the findings of Brooks et al. That reaction affords this portion of glycolysis its cyclical capacity.

Under aerobic conditions, lactate is the main substrate of the TCA cycle and, as such, must be considered as the main molecule coupling between the glycolytic and the TCA cycle pathways, one in the cytosol and the other in the mitochondrion, respectively. This in turn could circumvent the need for the proposed function of the malate-aspartate shuttle MAS; but see Ref.

Under anaerobic conditions, glycolysis continues to function unabated, resulting in lactate accumulation, as the TCA cycle is nonfunctional Figure 2. When lactate is accumulating, under anaerobic conditions, it becomes upon return to aerobic conditions the principal energy substrate until its levels are falling back to their minimal, normal levels [ 57 , 61 — 63 ]. A schematic illustration of the glycolytic pathway as has been proposed based on numerous studies over the past three decades where glycolysis has only one end product, lactate, whether under aerobic or anaerobic conditions.

Under aerobic conditions O 2 , lactate is being utilized, being the substrate of mitochondrial lactate dehydrogenase mLDH , which converts it to pyruvate that enters the TCA cycle. Under anaerobic conditions N 2 , lactate is accumulated in the cytosol.

Lactate is a glycolytic metabolite that has earned a negative reputation ever since its discovery over two centuries ago. Consequently, with the progress of biochemistry and the elucidation of the different pathways of carbohydrate metabolism and bioenergetics, medical or physiological conditions where lactate appeared to accumulate have been assumed to potentially be harmful or damaging.

As a result, the medical literature still emphasizes the benefit of reactions or treatments that could minimize lactate concentration. However, under anaerobic conditions, only 2 mol of ATP can be produced. Aerobic glycolysis occurs in 2 steps.

The first occurs in the cytosol and involves the conversion of glucose to pyruvate with resultant production of NADH. This process alone generates 2 molecules of ATP.

If oxygen is available, then the free energy contained in NADH is further released via reoxidization of the mitochondrial electron chain and results in the release of 30 more mol of ATP per mol of glucose. However, when oxygen is in short supply, this NADH is reoxidized instead by reducing pyruvate to lactate.

This severely limits the amount of ATP formed per mole of glucose oxidized when compared with aerobic glycolysis. In situations where there is an imbalance of oxygen usage and oxygen delivery, for example in sepsis or heart failure, anaerobic glycolysis occurs and results in lactate accumulation and results in inefficient glucose usage and inadequate ATP production.