= ОБЗОРЫ
УДК 577.25
FUELING BRAIN NEURONAL ACTIVITY
© 2012 Yu. Zilberter, P. Bregestovski
INSERM-U751, Université de la Méditerranée, 13285Marseille, France; e-mail: yuri.zilberter@univmed.fr Received 05.09.2011
The energy requirements of the brain are amazingly high. The brain represents about 2% of the body weight, but it receives 15% of the total blood flow provided by the cardiovascular system and consumes at least 25% circulating glucose plus 20% oxygen available in the body at rest. The cornerstone feature of the brain energy metabolism is its tight coupling with neuronal activity. An abnormality in the sequence of events allowing neurons to be adequately supplied with the necessary energy could have dramatic consequences exemplified in the neurodegenerative diseases such as epilepsy and Alzheimer's disease. In this paper, we review the current views on the main pathways of neuronal energy supply.
Keywords: neurons, glucose, lactate, astrocyte—neuron lactate shuttle.
GLUCOSE AND LACTATE AS THE BRAIN FUELS
For decades, glucose has been considered as the main, if not exclusive, energy substrate for the adult brain. Indeed, glucose is the main energy substrate in the blood pumpted to the adult brain. However, in some cases the alternative substrates significantly contribute to the brain energy supply. First of all, this is the case of the early development. Prior to birth, the fetal lactate uptake is about half of the fetal glucose uptake and provides a major substrate for oxidative fetal metabolism [1, 2]. At birth, the transplacental supply of nutrients is terminated, so the crucial changes in the energy supply take place. Lactate appears to be an important energy substrate in the immediate newborn period [1, 2]. The rate of lactate utilization by neurons in the early neonatal rat brain is significantly higher than that of p-hydroxybutyrate (BHB, the predominant ketone body (KB) in the blood [3]), or glucose [4—6]. Once the onset of suckling takes place, KBs become the major fuel for rat brain development [7, 8]. In the postnatal developing rat brain, blood glucose levels are close to those in adults [9, 10]. However, glucose utilization is limited to only about 20% of the adult levels [11—13]. Until maturation of enzymatic systems required for glucose oxidation is completed, other energy substrates, including KBs and lactate, make up the energy substrate balance [12, 14, 15]. Indeed, the immature rat brain utilizes KBs so effecient-ly that they contribute at least 30% of the energy demands [8].
In the human neonate, glucose oxidation can only supply about 70% of the estimated energy needs of the brain, emphasizing the need for alternative energy substrates such as KBs and lactate. The newborn brain is capable of extracting and utilizing KBs at the rate
about 5- to 40-fold greater than that of infant or adult brain. Lactate appears to be an important energy substrate for the infant in the immediate newborn period. At this time, the presence of abundant lactate probably accounts for the observed paradox that even as blood glucose values transiently fall to very low levels, the babies remain in good health and show no symptoms that suggest cerebral fuel deficiency.
Although lactate has been known for almost 80 years to serve as an oxidative energy source in the adult brain [16], the work of Hill et al. [17] on skeletal muscle, which characterized lactate as a waste-product of anaerobic exercise, has been mostly responsible for the lactate's bad reputation. For many years, most scientists agreed that lactate is useless end product of anaerobic energy metabolism, which at times can become harmful. For instance, the concept appeared that lactate accumulation in muscle tissue is responsible for muscle fatigue. This concept has been convincingly disproved recently [18]. In the brain, lactate was considered as the major exacerbating factor of cerebral ischemic damage.
However, a number of recent studies have provided evidence that lactate is an important cerebral oxidative energy substrate and required overall reinterpretation of the role of lactate in neuronal functions. Although many of these results have been obtained in the in vitro experiments, the ultimate prove of lactate significance in the brain has been demonstrated in vivo. Using mi-crodialysis measurements and high-resolution nuclear magnetic resonance, Gallagher et al. [19] directly demonstrated that the human brain is able to aerobi-cally utilize lactate as an energy source (see also [20, 21]). Wiss et al. [22] showed in anaesthetised rats that under hypoglycemic conditions neurons rely on lactate as an energy substrate. They also demonstrated
that lactate is preferred by neurons over glucose if both substrates are available. Finally, Suzuki et al. [23] found in freely moving rats that learning leads to a significant increase in extracellular lactate levels in hippocampus that is deprived of glycogen, an energy reserve selectively localized in astrocytes. The authors showed that astrocytic glycogen breakdown and lactate release are essential for the long-term memory formation. Therefore, at present the role of lactate as energy substrate and utilization of lactate by neuronal networks during their activation in the mature brain are reliably established.
INTRACELLULAR LACTATE SHUTTLE
Lactate as well as ketone bodies is a physiological member of the family of compounds known as mono-carboxylates. Since they are hydrophilic molecules, they cannot cross the cellular membranes by ordinary diffusion. Thus, specific transporters are required for these compounds to be released and taken up by cells of different types. A family of proton-linked carriers collectively known as monocarboxylate transporters (MCTs) has been identified in recent years. MCTs are found in various tissues including the brain where three isoforms, MCT1, MCT2, and MCT4, have been described [24, 25]. At the cellular level, MCT1 is expressed by endothelial cells of microvessels as well as by astrocytes. MCT4 expression appears to be specific for astrocytes. By contrast, the predominant neuronal monocarboxylate transporter is MCT2. Therefore, the family of monocarboxylate transporters provides an efficient way of lactate (as well as pyruvate and KBs) uptake by different cell types.
The "lactate shuttle" hypothesis was initially formulated for skeletal muscles [26]. Realization that lac-tate can be formed in and released from diverse tissues such as skeletal muscle, liver and skin under resting conditions countered the long-held belief that lactate is formed as the result of oxygen-limited metabolism. Rather, the lack of evidence that limitation in oxygen supply causes lactate production, together with the overwhelming evidence that it is formed in circumstances of adequate oxygen supply, led to the conclusion that the reasons of substrate supply are responsible for the lactate formation [25]. The concept of a "lactate shuttle" stated that during hard exercise, as well as other conditions of accelerated glycolysis, the glycolytic flux in muscle involves lactate formation regardless of the state of oxygenation. Further, according to the lactate shuttle concept, lactate represents the major means of distributing carbohydrate potential energy for oxidation and gluconeogenesis. According to the lactate shuttle hypothesis, the formation and distribution of lactate represents the key tools by which the coordination of intermediary metabolism in diverse tissues and different cells within tissues can be accomplished.
The "intracellular lactate shuttle" hypothesis was introduced when it was realized that mitochondria isolated from rat heart, skeletal muscle and liver can oxidize lactate directly. Therefore, it was suggested that for such oxidation mitochondria need a symport like MCT and lactate dehydrogenase (LDH), both of which were shortly identified [27, 28]. Subsequently, the ability of isolated muscle mitochondria to oxidize lactate [28] and intramitochondrial localization of LDH [29, 30] have been confirmed. Additionally, the mitochondrial lactate/pyruvate transporter in muscle has been identified as MCT1 [27, 29, 30].
The concept of intracellular lactate shuttle with regard to neuronal energy metabolism was further elaborated by A. Schurr [31, 32]. He suggested that in the brain, either at rest conditions or during activation, both under aerobic and anaerobic conditions, glycoly-sis always proceeds to its final step, the LDH reaction and the formation of lactate. Consequently, this hypothesis entails that lactate is the oxidative substrate for the mitochondrial TCA cycle. This hypothesis is based on the following considerations: as it is firmly established, the glycolytic pathway begins with the phosphorylation of glucose and ends with the formation of lactate unless oxygen is present; otherwise, gly-colysis stops short of its last enzymatic step, namely, LDH, ending with pyruvate, the substrate that enters the mitochondrial tricarboxylic acid (TCA, or Krebs) cycle. Although exceptions to the aerobic sequence have been documented, where aerobic glycolysis proceeds to form lactate, for instance in red blood cells, heart muscle, and retina [31], the prevailing notion is that, under ample oxygen supply, pyruvate, not lactate, is the final product of glycolysis. However, the assumption that under aerobic conditions, pyruvate conversion to acetyl-CoA, a reaction that takes place in the mitochondrion, is somehow thermodynamical-ly preferable over pyruvate conversion to lactate is unsubstantiated. This assumption would have some basis if the glycolytic enzymes, substrates and products were, as was believed for many years, floating freely in a cytosol that behaves like an aqueous medium. Only such notion would explain the classic representation of the branched glycolytic chain, where one substrate/product, pyruvate, does not behave according to the rules of thermodynamics in the
Для дальнейшего прочтения статьи необходимо приобрести полный текст. Статьи высылаются в формате PDF на указанную при оплате почту. Время доставки составляет менее 10 минут. Стоимость одной статьи — 150 рублей.