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.
Highlights
GLYCOLYSIS IS PREFERENTIALLY INCREASED DURING BRIEF BRAIN ACTIVATIONGlucose metabolism is a two-stage process in which glucose initially is converted to pyruvate during glycolysis and pyruvate subsequently is completely oxidized in the tricarboxylic acid (TCA) cycle
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 as during operation of conventional MAS
Under resting conditions brain metabolism in the adult brain occurs almost exclusively as complete oxidative metabolism of glucose (Siesjö, 1978; Shulman et al, 2001; Patel et al, 2014) in both neurons and astrocytes, which show similar rates of oxidative metabolism of glucose. These two cell types are connected by the glutamate-glutamine cycle, which carries glutamate synthesized in astrocytes to neurons to cover their entire supply of transmitter glutamate and GABA, which cannot be synthesized in neurons (Bringmann et al, 2013; Schousboe et al, 2013; Hertz and Rothman, 2016, 2017)
Summary
Glucose metabolism is a two-stage process in which glucose initially is converted to pyruvate during glycolysis and pyruvate subsequently is completely oxidized in the tricarboxylic acid (TCA) cycle. Under resting conditions OGI is generally close to (or slightly below) the theoretical value of 6, indicating complete oxidation of glucose almost exclusively via glycolysis to pyruvate and subsequent oxidation of pyruvate in the TCA cycle This would a priori be expected to be the case during energy-requiring brain activation due to the much higher ATP yield during pyruvate oxidation. Lin et al (2009) showed that the large initial preferential increase in blood flow and in glycolysis is transient and almost abolished after ∼20 min (Figure 1) This was done by comparing the relationship between relative cerebral blood flow (δCBF) and relative cerebral metabolic rate of oxygen (δCMRO2) during continuous visual stimulation (21 min at 8 Hz) with functional magnetic resonance imaging (fMRI) and simultaneously measuring of blood oxygenation level-dependent (BOLD) signals, CBF and cerebral blood volume (CBV). Measurements of brain glucose and lactate in visual cortex have indicated a long lasting increase in CMRglc (Prichard et al, 1991; Sappey-Marinier et al, 1992; Chen et al, 1993; Frahm et al, 1996)
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