Energy metabolism and glutamate-glutamine cycle in the brain: a stoichiometric modeling perspective

Abstract

BackgroundThe energetics of cerebral activity critically relies on the functional and metabolic interactions between neurons and astrocytes. Important open questions include the relation between neuronal versus astrocytic energy demand, glucose uptake and intercellular lactate transfer, as well as their dependence on the level of activity.ResultsWe have developed a large-scale, constraint-based network model of the metabolic partnership between astrocytes and glutamatergic neurons that allows for a quantitative appraisal of the extent to which stoichiometry alone drives the energetics of the system. We find that the velocity of the glutamate-glutamine cycle (Vcyc) explains part of the uncoupling between glucose and oxygen utilization at increasing Vcyc levels. Thus, we are able to characterize different activation states in terms of the tissue oxygen-glucose index (OGI). Calculations show that glucose is taken up and metabolized according to cellular energy requirements, and that partitioning of the sugar between different cell types is not significantly affected by Vcyc. Furthermore, both the direction and magnitude of the lactate shuttle between neurons and astrocytes turn out to depend on the relative cell glucose uptake while being roughly independent of Vcyc.ConclusionsThese findings suggest that, in absence of ad hoc activity-related constraints on neuronal and astrocytic metabolism, the glutamate-glutamine cycle does not control the relative energy demand of neurons and astrocytes, and hence their glucose uptake and lactate exchange.

Glutamine-Glutamate Cycle Flux Is Similar in Cultured Astrocytes and Brain and Both Glutamate Production and Oxidation Are Mainly Catalyzed by Aspartate Aminotransferase

“…However, this potential argument against AAT activity is invalid because of spatial separation between cytosolic glutamate formation and mitochondrial degradation, removal of synthesized glutamate by glutamine formation and of α-KG by TCA cycle activity as well as temporal separation during exposure to high and low extracellular glutamate concentrations shown by modeling. A recent study performing stoichiometric modeling concluded that the well-known increase in glycolysis compared to oxidative metabolism (decreased OGI) during brain activation can be partly (but not completely) explained by an increase in glutamate-glutamine cycling [108], with a doubling of cycle flux when the ratio between rates of oxidative and glycolytic metabolism decreases from 5.5 to 4.25. This indicates that cycle activity must vary greatly from moment to moment in concert with brain activation or lack thereof.…”

Effects of Systemic Metabolic Fuels on Glucose and Lactate Levels in the Brain Extracellular Compartment of the Mouse

“…A competing hypothesis, the neuron-to-astrocyte lactate shuttle (NALS) (Mangia et al, 2009), is based on a number of arguments that center on the different characteristics of GLUT1, the glucose transporter found on the epithelial cells of blood vessels and on astrocytes, and GLUT3, the transporter found mainly on the neuropil of neurons (Chih et al, 2001; Chih and Roberts, 2003; Mangia et al, 2009, 2011; Massucci et al, 2013). GLUT1 has a high affinity for glucose (Heyes, 2010) and is also capable of transporting other hexose at a much-reduced rate (Gould et al, 1991).…”

GLT‐1 mediates exercise‐induced fatigue through modulation of glutamate and lactate in rats

“…The transient increase in lactate level during exercise might be a consequence of energetic processes that complement healthy brain processes . The subsequent decrease in lactate concentration observed during the latter stages of strenuous activity imply that exercise‐induced fatigue may be due to depletion of an energy source; the lactate in neurons is further oxidized to produce glutamate . This metabolic process further increases the extracellular glutamate concentration.…”