Glia-neuron energy metabolism in health and diseases: New insights into the role of nervous system metabolic transporters

Abstract

The brain is, by weight, only 2% the volume of the body and yet it consumes about 20% of the total glucose, suggesting that the energy requirements of the brain are high and that glucose is the primary energy source for the nervous system. Due to this dependence on glucose, brain physiology critically depends on the tight regulation of glucose transport and its metabolism. Glucose transporters ensure efficient glucose uptake by neural cells and contribute to the physiology and pathology of the nervous system. Despite this, a growing body of evidence demonstrates that for the maintenance of several neuronal functions, lactate, rather than glucose, is the preferred energy metabolite in the nervous system. Monocarboxylate transporters play a crucial role in providing metabolic support to axons by functioning as the principal transporters for lactate in the nervous system. Monocarboxylate transporters are also critical for axonal myelination and regeneration. Most importantly, recent studies have demonstrated the central role of glial cells in brain energy metabolism. A close and regulated metabolic conversation between neurons and both astrocytes and oligodendroglia in the central nervous system, or Schwann cells in the peripheral nervous system, has recently been shown to be an important determinant of the metabolism and function of the nervous system. This article reviews the current understanding of the long existing controversies regarding energy substrate and utilization in the nervous system and discusses the role of metabolic transporters in health and diseases of the nervous system.

Keywords: Acetate; Axon; Energy metabolism; Glia; Glucose; Glucose transporters; Lactate; Metabolic transporters; Monocarboxylate transporters.

Fig. 1.

Fuels to neural cells. Glucose, its “by-product” lactate, and occasionally acetate are fuels to neural cells.

Fig. 2.

Glia-neuron metabolic interactions in the CNS are most likely mediated by monocarboxylate and glucose transporters (MCTs and GLUTs, respectively). Astrocytes and oligodendrocytes take up glucose from blood circulation through GLUT1. Glycolysis breaks down glucose to pyruvate, which can either be converted to lactate or metabolized further in mitochondria via oxidative metabolism. Astrocytes can also store the capillary glucose as glycogen, which can then be metabolized to lactate. Astrocyte or oligodendrocyte-derived intracellular lactate can exit the cell through MCT1 and/or MCT4. Neurons take up the extracellular lactate through MCT2. Neuron can also take up glucose from blood circulation or extracellular space through GLUT3. Glc-6-P; glucose-6-phosphate, GlyS; glycogen synthase, GlyP; glycogen phosphorylase, LDH; lactate dehydrogenase.

Fig. 3.

Differential expression of monocarboxylate and glucose transporters (MCTs and GLUTs, respectively) in peripheral nerve. MCT1, MCT2, and MCT4 are the major MCTs in peripheral nerves, and they each have distinct patterns of expression. MCT1 is highly expressed in perineurial cells within the perineurium. MCT1 and MCT4 are expressed in Schwann cells. GLUT1 and GLUT3 are the major GLUTs in peripheral nerves, and they each have distinct patterns of expression. GLUT1, which is highly expressed in sciatic nerves, is localized to the perineurium and to some endo- and epineurial capillaries. Schwann cells express GLUT1, primarily in the paranodal region and Schmidt-Lanterman incisures. GLUT3 is expressed in neurons, perineurium, endoneurial capillaries, and paranodal Schwann cells. The expression pattern of MCTs and GLUTs in peripheral nerves suggest their crucial involvement in metabolite transport in the peripheral nervous system.