Fri. Apr 19th, 2024

I have shown [117], monocarboxylate transporters favour the movement of lactate out of the astrocyte and into the neuron in both the cell body and the postsynaptic density. They further posited that lactate would move from the astrocyte to the neuron to TGR-1202 cost supplement the energy needs of the neuron (figure 3b), an idea that generated much controversy [5,118?21]. Unfortunately, these discussions have tended to ignore the elegant details of that relationship. I briefly highlight some of the most interesting features of this symbiotic relationship between neurons and astrocytes. When lactate enters a neuron its conversion to pyruvate and entry into oxidative phosphorylation captures only part of the story. It is not a simple choice by the neuron to select between glucose and lactate for its energy production but, rather, the challenge for the neuron is to maintain energy production while at the same time increasing the availability of glucose for biosynthesis and neuroprotection. Overlooked by most neuroscientists is one of the important functions performed by glycolysis which is to provide substrate for biosynthesis [21,103,122].Biosynthesis via glycolysis proceeds largely via the pentose phosphate pathway (figure 3b), where glucose-derived carbon is used for the synthesis of nucleotides, lipids and proteins. This is important not only for actively proliferating cancer cells, where the role of aerobic glycolysis has been explored in great detail [123], but for the basal turnover and remodelling of neuronal connections in the service of memory and learning (e.g. [103,124,125]). This expanded view of aerobic glycolysis in a symbiotic relationship between neuron and astrocyte has been dubbed the reverse Miransertib supplier Warburg effect [126] (figure 3b) in reference to the original work of Otto Warburg on the role of aerobic glycolysis in cell proliferation [127]. This same relationship is seen in axons where the supporting cell is the oligodendrocyte [20]. There is an additional fascinating twist to the reverse Warburg effect [126] which involves the redox state of the neuron. When lactate enters the neuron and is converted to pyruvate it shifts the NAD?NADH equilibrium to a more reduced state which turns off glycolysis at a critical step between biosynthesis pathways and energy generation (i.e. the conversation of glyceraldehyde-3-phosphate to 1,3 bisphosphoglycerate mediated by GAPDH; figure 3b). This has been dubbed a redox switch [128], designed to facilitate glycolysis-mediated biosynthesis in the neuron without sacrificing its mandatory energy requirements which are conveniently supplied by lactate from an adjacent astrocyte. With a potential role for aerobic glycolysis in cellular biosynthesis in the human brain, it is important to ask what evidence we have for this hypothesis. To pursue the hypothesis put forth above that elevated aerobic glycolysis is associated with biosynthesis, we explored its regional variability in relation to gene expression [103] and found that aerobic glycolysis correlates with the persistence of gene expression typical of infancy (transcriptional neotony). In brain regions with the highest aerobic glycolysis levels (figure 3a), we found increased gene expression related to synapse formation and growth. By contrast, regions high in oxidative glucose metabolism express genes related to mitochondria and synaptic transmission. Our results suggest that brain aerobic glycolysis in the resting state supports developmental processes, p.I have shown [117], monocarboxylate transporters favour the movement of lactate out of the astrocyte and into the neuron in both the cell body and the postsynaptic density. They further posited that lactate would move from the astrocyte to the neuron to supplement the energy needs of the neuron (figure 3b), an idea that generated much controversy [5,118?21]. Unfortunately, these discussions have tended to ignore the elegant details of that relationship. I briefly highlight some of the most interesting features of this symbiotic relationship between neurons and astrocytes. When lactate enters a neuron its conversion to pyruvate and entry into oxidative phosphorylation captures only part of the story. It is not a simple choice by the neuron to select between glucose and lactate for its energy production but, rather, the challenge for the neuron is to maintain energy production while at the same time increasing the availability of glucose for biosynthesis and neuroprotection. Overlooked by most neuroscientists is one of the important functions performed by glycolysis which is to provide substrate for biosynthesis [21,103,122].Biosynthesis via glycolysis proceeds largely via the pentose phosphate pathway (figure 3b), where glucose-derived carbon is used for the synthesis of nucleotides, lipids and proteins. This is important not only for actively proliferating cancer cells, where the role of aerobic glycolysis has been explored in great detail [123], but for the basal turnover and remodelling of neuronal connections in the service of memory and learning (e.g. [103,124,125]). This expanded view of aerobic glycolysis in a symbiotic relationship between neuron and astrocyte has been dubbed the reverse Warburg effect [126] (figure 3b) in reference to the original work of Otto Warburg on the role of aerobic glycolysis in cell proliferation [127]. This same relationship is seen in axons where the supporting cell is the oligodendrocyte [20]. There is an additional fascinating twist to the reverse Warburg effect [126] which involves the redox state of the neuron. When lactate enters the neuron and is converted to pyruvate it shifts the NAD?NADH equilibrium to a more reduced state which turns off glycolysis at a critical step between biosynthesis pathways and energy generation (i.e. the conversation of glyceraldehyde-3-phosphate to 1,3 bisphosphoglycerate mediated by GAPDH; figure 3b). This has been dubbed a redox switch [128], designed to facilitate glycolysis-mediated biosynthesis in the neuron without sacrificing its mandatory energy requirements which are conveniently supplied by lactate from an adjacent astrocyte. With a potential role for aerobic glycolysis in cellular biosynthesis in the human brain, it is important to ask what evidence we have for this hypothesis. To pursue the hypothesis put forth above that elevated aerobic glycolysis is associated with biosynthesis, we explored its regional variability in relation to gene expression [103] and found that aerobic glycolysis correlates with the persistence of gene expression typical of infancy (transcriptional neotony). In brain regions with the highest aerobic glycolysis levels (figure 3a), we found increased gene expression related to synapse formation and growth. By contrast, regions high in oxidative glucose metabolism express genes related to mitochondria and synaptic transmission. Our results suggest that brain aerobic glycolysis in the resting state supports developmental processes, p.