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Open Access Highly Accessed Research article

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

Francesco A Massucci1, Mauro DiNuzzo23, Federico Giove23, Bruno Maraviglia34, Isaac Perez Castillo5, Enzo Marinari36 and Andrea De Martino367*

Author Affiliations

1 Departament d’Enginyeria Quimica, Universitat Rovira i Virgili, 43007 Tarragona, Spain

2 Magnetic Resonance for Brain Investigation Lab, Enrico Fermi Center, Roma, Italy

3 Dipartimento di Fisica, Sapienza Università di Roma, P.le Aldo Moro 2, 00185 Roma, Italy

4 Fondazione Santa Lucia, Roma, Italy

5 Department of Mathematics, King’s College London, Strand, London, WC2R 2LS, UK

6 Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Roma, Italy

7 CNR–IPCF, Unità di Roma Sapienza, Roma, Italy

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BMC Systems Biology 2013, 7:103  doi:10.1186/1752-0509-7-103

Published: 10 October 2013

Abstract

Background

The 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.

Results

We 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.

Conclusions

These 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.

Keywords:
Brain energetics; Lactate shuttle; Metabolic modeling; Glutamate-glutamine cycle; Glucose partitioning; OGI