Cerebral glycolysis: a century of persistent misunderstanding and misconception

Since its discovery in 1780, lactate (lactic acid) has being blamed for almost any illness outcome in which its levels were elevated. Beginning in the mid 1980s, studies, both on muscle and brain tissues, have suggested that lactate plays a role in bioenergetics. However, great skepticism and, at times outright antagonism was exhibited by many to any perceived role of this monocarboxylate in energy metabolism. The present review attempts to trace the negative attitudes about lactate to the first four or five decades of research on carbohydrate metabolism and its dogma by which lactate is a useless anaerobic end-product of glycolysis. The main thrust here is the review of dozens of scientific publications, many by the leading scientists of their times, through the first half of the 20th century. Consequently, it is concluded that there exists a barrier, described by Howard Margolis as habit of mind, that many scientists find impossible to cross. The term suggests entrenched responses that ordinarily occur without conscious attention and that, even if noticed, are hard to change. Habit of mind has undoubtedly played a major role in the above mentioned negative attitudes toward this lactate. As early as the 1920s, scientists investigating brain carbohydrate metabolism had discovered that lactate can be oxidized by brain tissue preparations, yet their own habit of mind redirected them to believe that such an oxidation is simply a disposal mechanism of this poisonous compound. The last section of the review invites the reader to consider a postulated alternative glycolytic pathway in cerebral and, possibly, in most other tissues, where no distinction is being made between aerobic and anaerobic glycolysis; lactate is always the glycolytic end product. Aerobically, lactate is readily shuttled and transported into the mitochondrion, is converted to pyruvate via a mitochondrial lactate dehydrogenase (mLDH) and then entered the tricarboxylic acid (TCA) cycle

Cerebral Energy Metabolism: Measuring and Understanding Its Rate

The study of brain energy metabolism has taken second place to that of muscle ever since the dawn of this field of research. Consequently, each new discovery made using muscle tissue that advanced our understanding of the biochemistry of energy metabolic processes was attempted to be duplicated in brain tissue. It was only when the brain\u27s high energy needs were recognized that researchers realized its vulnerability to any mishap in its energy supplies and that this vulnerability may play a role in various brain disorders. Understanding of the mechanisms by which the brain deals with energy shortage is of utmost importance in shedding light on the fundamentals of brain disorders and their potential treatment. To achieve such understanding, accurate measurement of brain energy metabolic rates is necessary. This chapter summarizes the history of the current knowledge of the biochemical processes responsible for the production of adenosine triphosphate (ATP) in the brain. It briefly reviews the various techniques used to measure cerebral metabolic rates of oxygen (CMRO2) and glucose (CMRglucose), and elaborates on the potential of measuring the cerebral metabolic rate of lactate (CMRlactate) to improve our understanding of brain energy metabolism

Lactate, Not Pyruvate, Is the End Product of Glucose Metabolism via Glycolysis

Glucose is the monosaccharide utilized by most eukaryotes to generate metabolic energy, and in the majority of eukaryotic systems, glycolysis is the first biochemical pathway where glucose breaks down via a series of enzymatic reactions to produce relatively small amounts of adenosinetriphosphate (ATP). In 1940, the sequence of these glycolytic reactions was elucidated, a breakthrough that was recognized as the very first such elucidation of a biochemical pathway in history. Accordingly, the glycolytic breakdown of glucose ends up either with pyruvate as the final product under aerobic conditions or with lactate, to which pyruvate is being reduced, under anaerobic conditions. Consequently, pyruvate has been designated and is held to be the substrate of the mitochondrial tricarboxylic acid cycle, where it is completely oxidized into CO2 and H2O, while lactate has been defined and being held to as a useless dead-end product, poisonous at times, of which cells must discard off quickly. More than four decades after the glycolytic pathway has been elucidated, studies of both muscle and brain tissues have suggested that lactate is not necessarily a useless end product of anaerobic glycolysis and may actually play a role in bioenergetics. These studies have shown that muscle and brain tissues can oxidize and utilize lactate as a mitochondrial energy substrate. These results have been met with great skepticism, but a large number of publications over the past quarter of a century have strengthened the idea that lactate does play an important and, possibly, a crucial role in energy metabolism. These findings have shed light on a major drawback of the originally proposed aerobic version of the glycolytic pathway, that is, its inability to regenerate nicotinamide adenine dinucleotide (oxidized form) (NAD+), as opposed to anaerobic glycolysis that features the cyclical ability of the glycolytic lactate dehydrogenase (LDH) system to regenerate NAD+ upon pyruvate reduction to lactate. An examination of scientific investigations on carbohydrate metabolism of brain tissue in the 1920s and 1930s has already revealed that lactate can be readily oxidized. However, due to the prevailing dogma, according to which lactate is a waste product, its oxidation was assumed to be a possible mechanism of elimination. This chapter examines both old and new research data on glucose glycolysis both in muscle and in brain tissues. This chapter consolidates the available data in an attempt to form a more accurate and clear description of this universal and very important bioenergetic chain of reactions

Aerobic Production and Utilization of Lactate Satisfy Increased Energy Demands Upon Neuronal Activation in Hippocampal Slices and Provide Neuroprotection Against Oxidative Stress

Ever since it was shown for the first time that lactate can support neuronal function in vitro as a sole oxidative energy substrate, investigators in the field of neuroenergetics have been debating the role, if any, of this glycolytic product in cerebral energy metabolism. Our experiments employed the rat hippocampal slice preparation with electrophysiological and biochemical methodologies. The data generated by these experiments (a) support the hypothesis that lactate, not pyruvate, is the end-product of cerebral aerobic glycolysis; (b) indicate that lactate plays a major and crucial role in affording neural tissue to respond adequately to glutamate excitation and to recover unscathed post-excitation; (c) suggest that neural tissue activation is accompanied by aerobic lactate and NADH production, the latter being produced when the former is converted to pyruvate by mitochondrial lactate dehydrogenase (mLDH); (d) imply that NADH can be utilized as an endogenous scavenger of reactive oxygen species (ROS) to provide neuroprotection against ROS-induced neuronal damage

Glycolysis Paradigm Shift Dictates a Reevaluation of Glucose and Oxygen Metabolic Rates of Activated Neural Tissue

In 1988 two seminal studies were published, both instigating controversy. One concluded that “the energy needs of activated neural tissue are minimal, being fulfilled via the glycolytic pathway alone,” a conclusion based on the observation that neural activation increased glucose consumption, which was not accompanied by a corresponding increase in oxygen consumption (Fox et al., 1988). The second demonstrated that neural tissue function can be supported exclusively by lactate as the energy substrate (Schurr et al., 1988). While both studies continue to have their supporters and detractors, the present review attempts to clarify the issues responsible for the persistence of the controversies they have provoked and offer a possible rationalization. The concept that lactate rather than pyruvate, is the glycolytic end-product, both aerobically and anaerobically, and thus the real mitochondrial oxidative substrate, has gained a greater acceptance over the years. The idea of glycolysis as the sole ATP supplier for neural activation (glucose → lactate + 2ATP) continues to be controversial. Lactate oxidative utilization by activated neural tissue could explain the mismatch between glucose and oxygen consumption and resolve the existing disagreements among users of imaging methods to measure the metabolic rates of the two energy metabolic substrates. The postulate that the energy necessary for active neural tissue is supplied by glycolysis alone stems from the original aerobic glycolysis paradigm. Accordingly, glucose consumption is accompanied by oxygen consumption at 1–6 ratio. Since Fox et al. (1988) observed only a minimal if non-existent oxygen consumption compared to glucose consumption, their conclusion make sense. Nevertheless, considering (a) the shift in the paradigm of glycolysis (glucose → lactate; lactate + O2 + mitochondria → pyruvate → TCA cycle → CO2 + H2O + 17ATP); (b) that one mole of lactate oxidation requires only 50% of the amount of oxygen necessary for the oxidation of one mole of glucose; and (c) that lactate, as a mitochondrial substrate, is over eight times more efficient at ATP production than glucose as a glycolytic substrate, suggest that future studies of cerebral metabolic rates of activated neural tissue should include along with the measurements of CMRO2 and CMRglucose the measurement of CMRlactate

Aerobic Glycolysis: A DeOxymoron of (Neuro)Biology

The term ‘aerobic glycolysis’ has been in use ever since Warburg conducted his research on cancer cells’ proliferation and discovered that cells use glycolysis to produce adenosine triphosphate (ATP) rather than the more efficient oxidative phosphorylation (oxphos) pathway, despite an abundance of oxygen. When measurements of glucose and oxygen utilization by activated neural tissue indicated that glucose was consumed without an accompanied oxygen consumption, the investigators who performed those measurements also termed their discovery ‘aerobic glycolysis’. Red blood cells do not contain mitochondria and, therefore, produce their energy needs via glycolysis alone. Other processes within the central nervous system (CNS) and additional organs and tissues (heart, muscle, and so on), such as ion pumps, are also known to utilize glycolysis only for the production of ATP necessary to support their function. Unfortunately, the phenomenon of ‘aerobic glycolysis’ is an enigma wherever it is encountered, thus several hypotheses have been produced in attempts to explain it; that is, whether it occurs in cancer cells, in activated neural tissue, or during postprandial or exercise metabolism. Here, it is argued that, where the phenomenon in neural tissue is concerned, the prefix ‘aerobic’ in the term ‘aerobic glycolysis’ should be removed. Data collected over the past three decades indicate that L-lactate, the end product of the glycolytic pathway, plays an essential role in brain energy metabolism, justifying the elimination of the prefix ‘aerobic’. Similar justification is probably appropriate for other tissues as well

Aerobic Glycolysis: A DeOxymoron of (Neuro)Biology

The term ‘aerobic glycolysis’ has been in use ever since Warburg conducted his research on cancer cells’ proliferation and discovered that cells use glycolysis to produce adenosine triphosphate (ATP) rather than the more efficient oxidative phosphorylation (oxphos) pathway, despite an abundance of oxygen. When measurements of glucose and oxygen utilization by activated neural tissue indicated that glucose was consumed without an accompanied oxygen consumption, the investigators who performed those measurements also termed their discovery ‘aerobic glycolysis’. Red blood cells do not contain mitochondria and, therefore, produce their energy needs via glycolysis alone. Other processes within the central nervous system (CNS) and additional organs and tissues (heart, muscle, and so on), such as ion pumps, are also known to utilize glycolysis only for the production of ATP necessary to support their function. Unfortunately, the phenomenon of ‘aerobic glycolysis’ is an enigma wherever it is encountered, thus several hypotheses have been produced in attempts to explain it; that is, whether it occurs in cancer cells, in activated neural tissue, or during postprandial or exercise metabolism. Here, it is argued that, where the phenomenon in neural tissue is concerned, the prefix ‘aerobic’ in the term ‘aerobic glycolysis’ should be removed. Data collected over the past three decades indicate that L-lactate, the end product of the glycolytic pathway, plays an essential role in brain energy metabolism, justifying the elimination of the prefix ‘aerobic’. Similar justification is probably appropriate for other tissues as well

Glycolysis at 75: Is it time to tweak the first elucidated metabolic pathway in history?

Glycolysis, the pathway of enzymatic reactions responsible for the breakdown of glucose into two trioses and further into pyruvate or lactate, was elucidated in 1940. For more than seven decades, it has been taught precisely the way its sequence was proposed by Embden, Meyerhof and Parnas. Accordingly, two outcomes of this pathway were proposed, an aerobic glycolysis, with pyruvate as its final product, and an anaerobic glycolysis, identical to the aerobic one, except for an additional reaction, where pyruvate is reduced to lactate. Several studies in the 1980s have shown that both muscle and brain tissues can oxidize and utilize lactate as an energy substrate, challenging this monocarboxylate’s reputation as a useless end-product of anaerobic glycolysis. These findings were met with great skepticism about the idea that lactate could be playing a role in bioenergetics. In the past quarter of a century monocarboxylate transporters (MCTs) were identified and localized in both cellular and mitochondrial membranes. A lactate receptor has been identified. Direct and indirect evidence now indicate that the enzyme lactate dehydrogenase (LDH) resides not only in the cytosol, as part of the glycolytic pathway machinery, but also in the mitochondrial outer membrane. The mitochondrial form of the enzyme oxidizes lactate to pyruvate and concomitantly produces the reducing agent NADH. These findings have shed light on a major drawback of the originally proposed aerobic version of the glycolytic pathway i.e., its inability to regenerate NAD+, as opposed to anaerobic glycolysis that features the cyclical ability of regenerating NAD+ upon pyruvate reduction to lactate by the cytosolic form of LDH. The malate-aspartate shuttle (MAS), a major redox shuttle in the brain, was proposed as an alternative pathway for NAD+ generation for aerobic glycolysis. Nonetheless, would MAS really be necessary for that function if glycolysis always proceeds to the end-products, lactate and NAD+? An additional dilemma the originally proposed aerobic glycolysis presents has to do with the glycolytic pathway of erythrocytes, which despite its highly aerobic environment, always produces lactate as its end-product. It is time to reexamine the original, dogmatic separation of glycolysis into two distinct pathways and put to test the hypothesis of a unified, singular pathway, the end-product of which is lactate, the real substrate of the mitochondrial TCA cycle