Integration between Glycolysis and Glutamate-Glutamine Cycle Flux May Explain Preferential Glycolytic Increase during Brain Activation, Requiring Glutamate

Abstract

The 1988 observation by Fox et al. (1988) that brief intense brain activation increases glycolysis (pyruvate formation from glucose) much more than oxidative metabolism has been abundantly confirmed. Specifically glycolytic increase was unexpected because the amount of ATP it generates is much smaller than that formed by subsequent oxidative metabolism of pyruvate. The present article shows that preferential glycolysis can be explained by metabolic processes associated with activation of the glutamate-glutamine cycle. The flux in this cycle, which is essential for production of transmitter glutamate and GABA, equals 75% of brain glucose utilization and each turn is associated with utilization of ~1 glucose molecule. About one half of the association between cycle flux and glucose metabolism occurs during neuronal conversion of glutamine to glutamate in a process similar to the malate-aspartate shuttle (MAS) except that glutamate is supplied from glutamine, not formed from α-ketoglutarate (αKG) as during operation of conventional MAS. Regular MAS function is triggered by one oxidative process in the cytosol during glycolysis causing NAD+ reduction to NADH. Since NADH cannot cross the mitochondrial membrane (MEM) for oxidation NAD+ is re-generated by conversion of cytosolic oxaloacetate (OAA) to malate, which enters the mitochondria for oxidation and in a cyclic process regenerates cytosolic OAA. Therefore MAS as well as the “pseudo-MAS” necessary for neuronal glutamate formation can only operate together with cytosolic reduction of NAD+ to NADH. The major process causing NAD+ reduction is glycolysis which therefore also must occur during neuronal conversion of glutamine to glutamate and may energize vesicular glutamate uptake which preferentially uses glycolytically derived energy. Another major contributor to the association between glutamate-glutamine cycle and glucose utilization is the need for astrocytic pyruvate to generate glutamate. Although some oxidative metabolism occurs during glutamate formation it is only one half of that during normal tricarboxylic acid (TCA) cycle function. Glutamate’s receptor stimulation leads to potassium ion (K+) release and astrocytic uptake, preferentially fueled by glycolysis and followed by release and neuronal re-accumulation. The activation-induced preferential glycolysis diminishes with continued activation and is followed by an increased ratio between oxidative metabolism and glycolysis, reflecting oxidation of generated glutamate and accumulated lactate.

The intertwined roles of circadian rhythmsand neuronal metabolism fueling drug reward and addiction

“…NAD + , a byproduct of lactate production, is an essential metabolic and redox cofactor crucial for the generation of ATP [126,127]. NAD + is also important in maintaining brain energy homeostasis, calcium transport, and mitochondrial respiration [127–129].…”

Additional mechanisms for brain activation failure due to reduced glucose metabolism—a commentary on Zilberter and Zilberter: The vicious circle of hypometabolism in neurodegenerative diseases

“…The reason for this unexpected metabolic response was unknown, but it is consistent with an increase in lactate in activated brain (Hossmann & Linn, ; Prichard, ; Prichard, Petroff, Ogino, & Shulman, ) and exit of lactate to extracellular fluid, blood, and the lymphatic system (Dienel & Cruz, ). It has also repeatedly been confirmed (reviewed by Dienel & Cruz, ; Hertz & Chen, ). The preferential upregulation of glycolysis is prevented by propranolol, an inhibitor of both β 1 ‐ and β 2 ‐adrenergic receptors (Schmalbruch, Linde, Paulson, & Madsen, ).…”

“…The process was shown in cultured neurons by Palaiologos et al (), and supporting evidence was obtained by Bak et al () in isolated brain mitochondria. From Hertz and Chen () with permission…”

“…Remarkably, lactate produced from glycogen also exits astrocytes more easily than glucose-derived lactate (Walls, Heimburger, Bouman, Schousboe, & Waagepetersen, 2009). This lactate is essential for signaling of extracellular lactate and a minute lactate uptake in neurons-activities that are necessary for neuronal contributions to learning (Hertz & Chen, 2017;Steinman, Gao, & Alberini, 2016;Suzuki et al, 2011;Tang et al, 2014).…”

Does shuttling of glycogen‐derived lactate from astrocytes to neurons take place during neurotransmission and memory consolidation?

“…The mitochondrial malate–aspartate shuttle (MAS) transfers reducing equivalents from cytosolic NADH into the mitochondria where it enters the electron transport chain to produce ATP, and this process is required to produce pyruvate as oxidative fuel. A similar mechanism, called the pseudo‐MAS, was proposed by Leif Hertz (Hertz & Chen, ) to carry out the conversion of glutamine to glutamate in neurons prior to its entry into the transmitter pool and participation in the glutamate–glutamine cycle (Figures and b). The mechanism of the pseudo‐MAS involves conversion in the outer mitochondrial membrane of glutamine by glutaminase to form glutamate that enters the mitochondrial matrix in exchange with aspartate.…”