Energy Metabolism of the Brain

McKenna, Mary C.; Dienel, Gerald A.; Sonnewald, Ursula; Waagepetersen, Helle S.; Schousboe, Arne

doi:10.1016/b978-0-12-374947-5.00011-0

Cited by 144 publications

(279 citation statements)

References 161 publications

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“…Our comparative study showed that the NSC glutamine dependence is no longer present after its differentiation into astrocytes. NSC-derived astrocytes secreted glutamine (the rate was higher when cultured in glutamine-free medium), showing that even in the absence of neurons, these cells are able to recapitulate an important feature of the glutamate-glutamine cycle between neurons and astrocytes in the brain [5,19]. Noteworthy, astrocytes took up glutamate from the medium at a similar rate of glutamine secretion (Table S1).…”

Section: Modulation Of Consumption and Production Rates During Astrocmentioning

confidence: 90%

Quantification of Metabolic Rearrangements During Neural Stem Cells Differentiation into Astrocytes by Metabolic Flux Analysis

et al. 2016

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Proliferation and differentiation of neural stem cells (NSCs) have a crucial role to ensure neurogenesis and gliogenesis in the mammalian brain throughout life. As there is growing evidence for the significance of metabolism in regulating cell fate, knowledge on the metabolic programs in NSCs and how they evolve during differentiation into somatic cells may provide novel therapeutic approaches to address brain diseases. In this work, we applied a quantitative analysis to assess how the central carbon metabolism evolves upon differentiation of NSCs into astrocytes. Murine embryonic stem cell (mESC)-derived NSCs and astrocytes were incubated with labelled [1-13 C]glucose and the label incorporation into intracellular metabolites was followed by GC-MS. The obtained 13 C labelling patterns, together with uptake/secretion rates determined from supernatant analysis, were integrated into an isotopic non-stationary metabolic flux analysis ( 13 C-MFA) model to estimate intracellular flux maps. Significant metabolic differences between NSCs and astrocytes were identified, with a general downregulation of central carbon metabolism during astrocytic differentiation. While glucose uptake was 1.7-fold higher in NSCs (on a per cell basis), a high lactate-secreting phenotype was common to both cell types. Furthermore, NSCs consumed glutamine from the medium; the highly active reductive carboxylation of alpha-ketoglutarate indicates that this was converted to citrate and used for biosynthetic purposes. In astrocytes, pyruvate entered the TCA cycle mostly through pyruvate carboxylase (81%). This pathway supported glutamine and citrate secretion, recapitulating well described metabolic features of these cells in vivo. Overall, this fluxomics study allowed us to quantify the metabolic rewiring accompanying astrocytic lineage specification from NSCs.

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Section: Modulation Of Consumption and Production Rates During Astrocmentioning

confidence: 90%

Quantification of Metabolic Rearrangements During Neural Stem Cells Differentiation into Astrocytes by Metabolic Flux Analysis

et al. 2016

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“…A possible confounding factor to the interpretation of the labelling patterns described earlier would be the presence of extensive pyruvate recycling [27,28]. …”

Section: Pyruvate Recyclingmentioning

confidence: 99%

Neuron–Astrocyte Interactions, Pyruvate Carboxylation and the Pentose Phosphate Pathway in the Neonatal Rat Brain

et al. 2013

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Glucose and acetate metabolism and the synthesis of amino acid neurotransmitters, anaplerosis, glutamate-glutamine cycling and the pentose phosphate pathway (PPP) have been extensively investigated in the adult, but not the neonatal rat brain. To do this, 7 day postnatal (P7) rats were injected with [1-C]glucose and [1,2-C]acetate and sacrificed 5, 10, 15, 30 and 45 min later. Adult rats were injected and sacrificed after 15 min. To analyse pyruvate carboxylation and PPP activity during development, P7 rats received [1,2-C]glucose and were sacrificed 30 min later. Brain extracts were analysed using Hand C-NMR spectroscopy. The neonatal brain contained lower levels of glutamate, aspartate and N-acetylaspartate but similar levels of GABA and glutamine compared to adults. Metabolism of [1-C]glucose at the acetyl CoA stage was reduced much more than that of [1,2-C]acetate. The transfer of glutamate from neurons to astrocytes was greatly reduced while transfer of glutamine from astrocytes to glutamatergic neurons was relatively higher compared to adults. However, transport of glutamine from astrocytes to GABAergic neurons was lower. Using [1,2-C]glucose it could be shown that despite much lower pyruvate carboxylation, relatively more pyruvate from glycolysis was directed towards anaplerosis than pyruvate dehydrogenation in astrocytes compared to reports from the adult brain. Moreover, the ratio of PPP/glucose metabolism was higher in P7 compared to adult brain. Our findings indicate that only the part of the glutamateglutamine cycle that transfers glutamine from astrocytes to neurons is operating in the After uptake into the cell, glucose (via pyruvate from glycolysis) and acetate can be converted to the TCA cycle substrate acetyl CoA. It has been reported that glucose oxidation is lower and that the average time the metabolites stay in the TCA cycle before conversion to substances such as neurotransmitters glutamate and thereafter γ-amino butyric acid (GABA) is longer in the neonatal compared to the adult brain [7]. This is in part attributed to the low levels of enzymes for pyruvate metabolism and oxidative glucose metabolism in the postnatal period [8].Pyruvate carboxylase, the brain's exclusive anaplerotic enzyme [9], is present in astrocytes only [10], and is of major importance for glial metabolic support of neurotransmission. Pyruvate carboxylase content is low in the neonatal period and increases 15-fold up to young adult age (postnatal day 30-40) when the level reaches a plateau [8].Most of the glutamate in the brain is found in neurons and is released into the synapse after depolarisation [11]. The ability of astrocytes to take up glutamate from the synapse and convert it into glutamine by the astrocyte specific enzyme glutamine synthetase [12] is vital for normal metabolic homeostasis and as a defence mechanism against excitotoxicity [13]. The subsequent transfer of glutamine from astrocytes to neurons for deamidation to glutamate closes the glutamate-

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“…[2,6,7]. Most of the glucose utilized by brain neurons is oxidized in mitochondria, and this requires a substantial transfer of reducing equivalents from cytosolic NADH to mitochondria through MAS [8]. In vivo, AGC1 may largely be present in neurons [9] although both mRNA and functional protein has been detected in freshly isolated mouse astrocytes [10], and aralar was identified as an interaction partner to the astrocytic glutamate transport, .…”

Section: Introductionmentioning

confidence: 99%

Fluctuations in Cytosolic Calcium Regulate the Neuronal Malate–Aspartate NADH Shuttle: Implications for Neuronal Energy Metabolism

Satrústegui

Bak

2015

Neurochem Res

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The malate-aspartate NADH shuttle (MAS) operates in neurons and other cells to translocate reducing equivalents from the cytosol to the mitochondrial matrix, thus allowing a continued flux through the glycolytic pathway and metabolism of extracellular lactate. Recent discoveries have taught us that MAS is regulated by fluctuations in cytosolic Ca 2? levels, and that this regulation is required to maintain a tight coupling between neuronal activity and mitochondrial respiration and oxidative phosphorylation. At cytosolic Ca 2? fluctuations below the threshold of the mitochondrial calcium uniporter, there is a positive correlation between Ca 2? and MAS activity; however, if cytosolic Ca 2? increases above the threshold, MAS activity is thought to be reduced by an intricate mechanism. The latter forces the neurons to partly rely on anaerobic glycolysis producing lactate that may be metabolized subsequently, by neurons or other cells. In this review, we will discuss the evidence for Ca 2? -mediated regulation of MAS that have been uncovered over the last decade or so, together with the need for further verification, and examine the metabolic ramifications for neurons.

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Energy Metabolism of the Brain

Cited by 144 publications

References 161 publications

Quantification of Metabolic Rearrangements During Neural Stem Cells Differentiation into Astrocytes by Metabolic Flux Analysis

Quantification of Metabolic Rearrangements During Neural Stem Cells Differentiation into Astrocytes by Metabolic Flux Analysis

Neuron–Astrocyte Interactions, Pyruvate Carboxylation and the Pentose Phosphate Pathway in the Neonatal Rat Brain

Fluctuations in Cytosolic Calcium Regulate the Neuronal Malate–Aspartate NADH Shuttle: Implications for Neuronal Energy Metabolism

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