Research over the past two decades has renewed the interest in lactate, no longer as a useless end product of anaerobic glycolysis in brain (and other tissues), but as an oxidative substrate for energy metabolism. While this topic would be considered blasphemy only three decades ago, much recent evidence indicates that lactate does play a major role in aerobic energy metabolism in the brain, the heart, skeletal muscle, and possibly in any other tissue and organ. Nevertheless, this concept has challenged the old dogma and ignited a fierce debate, especially among neuroscientists, pitting the supporters of glucose as the major oxidative energy substrate against those who support lactate as a possible alternative to glucose under certain conditions. Meanwhile, researchers working on energy metabolism in skeletal muscle have taken great strides toward bridging between these two extreme positions, while avoiding the high decibels of an emotional debate. Employing their findings along with the existing old and new data on cerebral energy metabolism, it is postulated here that lactate is the only major product of cerebral (and other tissues) glycolysis, whether aerobic or anaerobic, neuronal or astrocytic, under rest or during activation. Consequently, this postulate entails that lactate is a major, if not the only, substrate for the mitochondrial tricarboxylic acid cycle. If proven true, this hypothesis could provide better understanding of the biochemistry and physiology of (cerebral) energy metabolism, while holding important implications in the field of neuroimaging. Concomitantly, it could satisfy both ‘glucoseniks’ and ‘lactatians’ in the ongoing debate.

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.

The growing number of cellular and molecular pathways believed to be involved in mechanisms of ischemic cell death in the brain has spurred a similar growth in the number of potential neuroprotective modalities, the majority of which are pharmacological in nature. Preventing or minimizing the first few steps in the cascade of events leading to ischemic cell death would have a more profound effect on the postischemic outcome than intervention at later steps in that cascade. This logic is, of course, at the heart of the urgency in providing the stroke or cardiac arrest patient with the earliest possible neuroprotective treatment. For the purpose of assessing potential neuroprotective modalities, the use of a well-established cerebral hypoxic / ischemic model system is a prerequisite. In our studies, we have used two major approaches, in vitro and in vivo. We evaluated both agonists and antagonists of ionotropic glutamate receptor channels (IGRC) and their effects in exacerbating and attenuating, respectively, the posthypoxic / ischemic outcome. Other drugs were tested for their ability to block the L-type voltage-sensitive calcium channels (VSCC), which are responsible for calcium influx and overload upon hypoxia / ischemia. These two membrane protein entities, the IGRC and the VSCC, are believed to be involved in the early stages of the cellular cascade that leads to the demise of neurons posthypoxia / ischemia. Some of the drugs were also tested for possible interaction with each other searching for possible synergy. These and other published studies in the field are reviewed here.

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.

Some metabolic pathways involve two different cell components, for instance, cytosol and mitochondria, with metabolites traffic occurring from cytosol to mitochondria and vice versa, as seen in both glycolysis and gluconeogenesis. However, the knowledge on the role of mitochondrial transport within these two glucose metabolic pathways remains poorly understood, due to controversial information available in published literature. In what follows, we discuss achievements, knowledge gaps, and perspectives on the role of mitochondrial transport in glycolysis and gluconeogenesis. We firstly describe the experimental approaches for quick and easy investigation of mitochondrial transport, with respect to cell metabolic diversity. In addition, we depict the mitochondrial shuttles by which NADH formed in glycolysis is oxidized, the mitochondrial transport of phosphoenolpyruvate in the light of the occurrence of the mitochondrial pyruvate kinase, and the mitochondrial transport and metabolism of L-lactate due to the L-lactate translocators and to the mitochondrial L-lactate dehydrogenase located in the inner mitochondrial compartment.