Review ArticleGlia-neuron energy metabolism in health and diseases: New insights into the role of nervous system metabolic transporters
Introduction
Neurons and glia are the primary cellular components that perform the functions of the central and peripheral nervous system (CNS and PNS, respectively). Glia maintain tissue homeostasis, form myelin, regulate development, and contribute to diverse neuropathophysiologies in the CNS and the PNS. Besides providing structural and metabolic support to neurons, glia also contribute to recovery following neuronal injuries. Neurons transmit signals over long distances through their axons; and these axons require an enormous energy supply to maintain their function. Axons are closely associated with glial cells that support their function and prevent degeneration.
Research over the last decades has shown that the brain is an organ of unusually high metabolic demand that utilizes 20% of the total glucose and 20% of the total oxygen in the human body (Magistretti and Allaman, 2015). Studies have reported glucose as the obligatory energy substrate for brain, where it is almost fully oxidized (Kety and Schmidt, 1948; Sokoloff, 1960). Similarly, further studies at the whole organ level have provided some refinements to this view, suggesting that ketone bodies fulfill the energy requirements of the brain under particular conditions, including fasting, uncontrolled diabetes and breast-fed newborn babies (Magistretti, 1999). Additionally, several studies over the last few years have illustrated the significance of lactate as an energy substrate for the brain (Baltan, 2015; Castillo et al., 2015; Machler et al., 2016; Matsui et al., 2017; Magistretti and Allaman, 2018). Specifically, findings from in vitro and in vivo studies demonstrate that lactate sustains neuronal activity during glucose deprivation (Wyss et al., 2011; Sobieski et al., 2018). The astrocyte-neuron lactate shuttle hypothesis (ANLSH) suggests that astrocyte-derived L-lactate is taken up by neurons via monocarboxylate transporters (MCTs), metabolic transporters for monocarboxylates, and used as an energy substrate, possibly in preference to glucose. Though it was proposed over twenty years ago (Magistretti et al., 1993; Pellerin and Magistretti, 1994), ANLSH remains controversial and not fully accepted. A recent study claims that during fasting conditions, glucose contributes indirectly (via circulating lactate) to tissue TCA metabolism in all tissues except the brain (Hui et al., 2017). Additionally, a study modeling the kinetic characteristics and cellular concentrations of the neuronal glucose and lactate transporters opposes the ANLSH primarily due to the fact that neuronal glucose transporter, GLUT3, has higher affinity for glucose than the astrocytic counterpart, GLUT1, an, indicating that glucose may be primarily transported to and consumed by neurons (Simpson et al., 2007). Finally, studies suggest that neurons have the capacity to boost their own glycolysis and potentially export rather than import lactate during brain activation or in response to stimulation (Diaz-Garcia et al., 2017; Yellen, 2018). This article addresses these controversies and reviews different aspects of glia-axon energy metabolism in health and diseases of the nervous system focusing on neural energy substrates consumption and metabolism, and their transporters.
Section snippets
Fuels to neural cells: glucose, its “by-product” lactate, and occasionally acetate too!
About 20% of our circulating glucose enters the brain, suggesting that glucose is the primary energy source for the brain. For some time, it had been accepted without reservation that all brain metabolic pathways are subsequent to glucose until the proposition of the ANLSH (Magistretti, 2008, Pellerin and Magistretti, 2012). The ANLSH challenged this precept, stating that activity-dependent uptake of glucose takes place in astrocytes that subsequently metabolize the glucose anaerobically to
Glucose transporters ensure efficient glucose uptake by neural cells
Glucose is transported across the cell membrane by facilitative diffusion mediated by members of the GLUT family, which belongs to the major facilitator superfamily of membrane transporters (Pao et al., 1998; Thorens and Mueckler, 2010). Most of the GLUTs catalyze the ATP-dependent bidirectional transfer of glucose across membranes. GLUT 1-4 are the well-studied/established glucose transporters and have distinct regulatory and/or kinetic properties, suggesting their cell-specific role. GLUT1
Monocarboxylate transporters are widely expressed metabolic transporters in central and peripheral nervous systems
The existence of glia-axon metabolic interactions in the CNS and PNS is most likely mediated by the monocarboxylate transporters (MCTs) (Fig. 2 and Fig. 3). MCTs are extracellular membrane channels that can transport monocarboxylates (such as lactate, pyruvate and ketone bodies), along with protons, down their concentration gradient across membranes (Garcia et al., 1994). MCTs are vital for metabolic shuttling between glia and neurons and facilitate the functioning of lactate as a preferred
Conclusions
It is now more than half a century since glia were acknowledged to contribute to neuronal energy metabolism. Glia are now widely recognized as dynamic cells that sense neuronal metabolic changes and regulate metabolism by transferring metabolites from glia to neurons. Both central and peripheral neurons alternate between glucose and lactate as an effective energy source, but prefer lactate during increased energy demand. Astrocytes and oligodendrocytes in the CNS, and potentially Schwann cells
Acknowledgements
This work was supported by the National Institutes of Health (R01NS086818).
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