1.2 Neuron/Astrocyte Metabolic Interactions
1.2.4 Lactate Shuttle
Among the metabolic substrates the brain processes, lactate has been the center of much attention in recent years. Lactate is present in the extracellular space in concentrations similar to those of glucose (between 0.5 and 1.5 mM) 104. While it has long been considered the dead end of anaerobic processes, this view has drastically changed in light of growing evidence indicating that it represents another important energy source for the brain105-107. In many emerging models, lactate is even regarded as the product of glycolysis rather than pyruvate108. The main evidence for this is the discovery of a mitochondrial lactate oxidation complex, reported in neurons among many other cell types, which would allow lactate entry and oxidation in the mitochondria itself101. This complex, and the metabolic cooperation it implies between neurons and astrocytes, has been evolutionarily conserved from Drosophila
melanogaster through the mammalian brain101,109,110.
Both astrocytes and neurons have the capacity to fully oxidize glucose and/or lactate, and both contain roughly equivalent numbers of mitochondria across various regions of the brain11,80,111. However, neurons and astrocytes preferentially utilize different metabolic pathways under physiological conditions and have different cell type-specific expression patterns of key genes regulating energy metabolism11,90,112 (Figure 1.5). Consistent with their higher energy requirements, neurons sustain oxidative metabolism at an elevated rate
compared to glia113-115. Intriguingly, neurons efficiently use lactate as an energy substrate and
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will preferentially utilize it over glucose when both substrates are present81,115,116. Conversely, astrocytes preferentially metabolize glucose due to their elevated expression and maintenance of the enzyme 6-phosphofructose-2-kinase/fructose-2,6-bisphosphatase-3 (Pfkfb3), which, oddly, is subjugated to constant proteasomal degradation after its production in neurons112,117. The enzyme is a potent activator of the key glycolytic enzyme phosphofructokinase-1 (PFK), and is responsible for upregulating glycolytic rate during periods of metabolic stress117. Additionally, astrocytes and neurons differentially group their mitochondrial respiratory chain (MRC)
complexes. In astrocytes most complex I is uncoupled from supercomplexes, resulting in less efficient mitochondrial respiration, while neurons embed most of their complex I into their
Figure 1.7: Key astrocyte/axon metabolic components.
Glucose is transported from vessels via GLUT1 transporter, then uptaken by astrocytes via GLUT1 and, to a lesser degree, axons via GLUT3.
Astrocytes form glucose into glycogen stores via glycogen synthase (GS) and mobilize it by glycogen phosphorylase (GP). Via glycolysis, glucose is metabolized into pyruvate, which is metabolized by lactate dehoydrogenase A (LDHA) into lactate, making ATP and NADH. Monocarboxylate transporters 1 and 4 (MCT1/4) transport lactate into the extracellular space, where it is uptaken by axonal MCT2. Lactate is then converted back into pyruvate by lactate dehydrogenase B (LDHB).
Pyruvate is metabolized in mitochondria, producing large sums of ATP along with CO2, NADH, and H2O.
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supercomplexes for increased efficiency118. As a result, neurons and astrocytes function as a compartmentalized metabolic unit, cooperating to distribute energy in an efficient manner.
Due to these different metabolic profiles, astrocytes uptake far more glucose than they fully reduce. It is estimated that astrocytes account for only 5-15% of the brain’s energy
expenditure119, but are responsible for approximately half of glucose uptake and even increase that proportionally with activity120-122. A central point of the astrocyte-neuron lactate shuttle hypothesis provides a simple explanation for this discrepancy: astrocytes transfer energy substrates to neurons to compensate for their high activity levels123. The model states that neuronal activity increases extracellular glutamate, which is taken up by Na+-dependent mechanism by glial glutamate transporters. The resulting increase in Na+ activates the Na+/K+ ATPase, thereby increasing ATP consumption, glucose uptake, and glycolysis in astrocytes. This leads to a large increase in lactate production, which is released into the extracellular space and subsequently taken up by neurons for use in oxidative phosphorylation. Through this
mechanism, neurons are able to sustain their elevated rates of energy consumption without dependence on glycolysis itself.
Astrocyte support of neuronal function is further supported by recent studies demonstrating that mice presenting a haploinsufficiency of the neuron-specific glucose
transporter GLUT3 do not present any neurological or brain energy metabolism abnormalities.
Further, their brain glucose utilization does not differ from that of wild-type animals124,125. In contrast, haploinsufficiency for GLUT1, which is absent in neurons but highly expressed in astrocytes, results in a severe neurological phenotype126. Certainly, there is abundant evidence
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for a net transfer of energy from astrocytes to neurons; the astrocyte-neuron lactate shuttle is the most widely accepted model for this energy transfer.
In white matter, the astrocyte-neuron lactate shuttle involves a third cell type:
oligodendrocytes. Much of an axon’s surface is covered by oligodendrocytes and their myelin, limiting the capacity for astrocytes to transfer metabolites through the extracellular space. To compensate, oligodendrocytes function as an intermediary by shuttling lactate from the extracellular space through monocarboxylate transporter 1 (MCT1)127. The oligodendrocytes themselves do not utilize the lactate – inhibiting cytochrome C oxidase, a key component of mitochondrial oxidative phosphorylation, does not influence oligodendrocyte survival after development128. Rather, the lactate is again shuttled into the periaxonal space through MCT1, where neuronal MCT2 transporters then shuttle it into axons5. How the intermediary
oligodendrocytes alter their metabolic support through neuropathology, however, remains unknown.