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Cited by 371Neuroscience and Neuropharmacology ResearchCancer, Hypoxia, and MetabolismMetabolism, Diabetes, and Cancer

Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism

Open access
Yellen, Gary·2018·Journal of Cell Biology
DOI 10.1083/jcb.201803152PMC PMC6028533
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Abstract

The brain’s energy demands are remarkable both in their intensity and in their moment-to-moment dynamic range. This perspective considers the evidence for Warburg-like aerobic glycolysis during the transient metabolic response of the brain to acute activation, and it particularly addresses the cellular mechanisms that underlie this metabolic response. The temporary uncoupling between glycolysis and oxidative phosphorylation led to the proposal of an astrocyte-to-neuron lactate shuttle whereby during stimulation, lactate produced by increased glycolysis in astrocytes is taken up by neurons as their primary energy source. However, direct evidence for this idea is lacking, and evidence rather supports that neurons have the capacity to increase their own glycolysis in response to stimulation; furthermore, neurons may export rather than import lactate in response to stimulation. The possible cellular mechanisms for invoking metabolic resupply of energy in neurons are also discussed, in particular the roles of feedback signaling via adenosine diphosphate and feedforward signaling by calcium ions.

AI snapshot

Written from the paper’s full text.

TL;DR

Yellen reviews how neuronal metabolism acutely balances glycolysis and oxidative phosphorylation during stimulation, arguing that activated neurons increase glucose rather than lactate utilization and that the classical astrocyte-to-neuron lactate shuttle does not provide the primary neuronal energy source during activation. It also outlines unresolved mechanisms controlling glycolysis/oxphos coupling, including ADP/Ca²⁺ signaling and cytosolic NADH redox.

Key findings

  • In resting brain, glycolysis and oxphos are near matched: the oxygen–glucose index is ∼5.5 in gray matter versus an ideal stoichiometry of 6, and the brain is ∼2% of body mass but consumes ∼20% of the daily energy budget; neurons account for most (∼80–90%) of the brain’s energy demand.
  • During stimulation, there is transient uncoupling: local blood flow increases by ∼50% with commensurate local glucose consumption, but oxygen utilization increases much less, on the order of 5%, reducing OGI to ∼5; lactate rises locally and can be exported with strong stimuli such as seizures.
  • Evidence favors direct neuronal glycolysis during activation rather than lactate uptake: stimulation increased glucose metabolism over twofold while lactate metabolism declined in cultured neurons, and neuronal cytosolic NADH/NAD⁺ transients in hippocampal/cortical neurons rise for ∼2–3 min and are blocked by glycolysis inhibition but not by MCT or LDH blockade, suggesting neurons normally export lactate when stimulated.
  • The ANLS hypothesis remains controversial: astrocytes are more glycolytic at rest with higher cytosolic NADH/NAD⁺, and lactate shuttling may support resting or ischemic conditions, but the paper states there is no affirmative evidence that astrocyte-to-neuron lactate movement occurs during ordinary brain activation.

Methods

  • Review/perspective article, not primary research; it synthesizes biochemical, imaging, genetic, and metabolic literature.
  • Discusses studies using cultured neurons and astrocytes, acute brain slices, in vivo rodent cortex/hippocampus, retina, white matter, Drosophila, and human PET/MRS/functional imaging.
  • Main analysis is a narrative synthesis organized around two questions: the balance between glycolysis and oxphos in brain cells, and the cellular mechanisms responsible for acute control of glycolysis and oxphos in neurons.

Limitations

  • The paper states many caveats for OGI measurements: pentose phosphate pathway and glycogen synthesis can consume glucose without oxygen; stress, stimulus strength, region definition, lactate oxidation in surrounding tissue, and β-adrenergic blockade can affect results; ANLS evidence often argues feasibility rather than direct occurrence.
  • The paper states that understanding of oxphos-related mitochondrial signals and the trigger for neuronal glycolysis is incomplete; mechanisms may vary with stimulation degree, glucose/O₂ conditions, and cell type, and more compartment- and cell-specific studies are needed.
  • Evident from the text: as a review, it presents no systematic search or meta-analysis and no new primary data; conclusions depend on cited studies with differing preparations and limitations, including glucose analogues with different transport properties, MCT blockers that also affect mitochondrial pyruvate uptake, and culture conditions that may alter metabolic behavior.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1083/jcb.201803152

Cites

128 of 128 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 148 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Neurons comprise most (∼80-90%) of the energy demand of the brain.

    “the focus will be on neurons which comprise most (∼80–90%) of the energy demand of the brain (Attwell and Laughlin, 2001; Yu et al., 2017).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Attwell and Laughlin, 2001 source

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    • cites Yu et al., 2017

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  • Interpretationcitation

    If unstimulated tissue in the periphery or within the stimulated region is capable of oxidative metabolism of excess lactate, including its contribution will normalize the OGI.

    “For instance, if the unstimulated tissue in the periphery or even within the stimulated region is capable of oxidative metabolism of the excess lactate (Madsen et al., 1999; Gandhi et al., 2009), then including the contribution from this tissue will normalize the OGI.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Madsen et al., 1999 source

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    • cites Gandhi et al., 2009 source

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  • Interpretationreasoning

    OGI may be exaggerated or suppressed depending on how the stimulated region is defined.

    “Second, OGI may be exaggerated or suppressed depending on how the stimulated region is defined.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Lactate can be exported from the brain with stronger stimuli such as epileptic seizures.

    “This is supported by measurements showing local elevation of brain lactate levels with stimulation (Korf and de Boer, 1990; Hu and Wilson, 1997; Mazuel et al., 2017) and even lactate export from the brain (e.g., Duffy et al., 1975, with stronger stimuli such as epileptic seizures).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Duffy et al., 1975 source

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  • Interpretationreasoning

    Experiments in support of the ANLS often argue for its feasibility rather than providing direct evidence that it occurs.

    “Experiments in support of the ANLS often argue for its feasibility rather than providing direct evidence that it occurs.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 18
  • May combine two claims. 38

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The astrocyte-to-neuron lactate shuttle (ANLS) hypothesis has been quite controversial for a long time.

    “The ANLS hypothesis has been quite controversial for a long time (Chih et al., 2001; Gjedde and Marrett, 2001; Hertz, 2004; Mangia et al., 2011; Dienel, 2012, 2017; Bak and Walls, 2018; Barros and Weber, 2018; see also Dienel [2017] for strong arguments against ANLS at the tissue level).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Chih et al., 2001 source

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    • cites Gjedde and Marrett, 2001

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    • cites Hertz, 2004 source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Uncoupling between glycolysis and oxidative metabolism is the norm for all organs except the brain.

    “Recent work on in vivo metabolite fluxes argues that uncoupling between glycolysis and oxidative metabolism is the norm for all organs except the brain (Hui et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hui et al., 2017 source

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  • May combine two claims.

    Interpretationreasoning

    The additional glucose consumption during regional brain stimulation is not stoichiometrically matched by oxygen; glucose is metabolized nonoxidatively by glycolysis without oxidative phosphorylation.

    “But the increase in oxygen utilization is much less, on the order of 5%, indicating that the additional glucose consumption is not stoichiometrically matched by oxygen but rather that glucose is metabolized nonoxidatively by glycolysis without oxphos.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Multiple studies exhibit net production of lactate from glucose in activated brain, arguing that glycolysis without oxidative phosphorylation constitutes a component of the reduced OGI.

    “Nevertheless, multiple studies exhibit net production of lactate from glucose in activated brain, arguing that glycolysis without oxphos constitutes a component of the reduced OGI (Korf and de Boer, 1990; Hu and Wilson, 1997; Mazuel et al., 2017).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Korf and de Boer, 1990

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    • cites Hu and Wilson, 1997

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    • cites Mazuel et al., 2017 source

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  • May combine two claims.

    Premisecitation

    Other organs readily export lactate derived from glucose metabolism and readily use circulating lactate for oxidative metabolism.

    “Other organs readily export the lactate they derive from glucose metabolism, and they readily use circulating lactate for their oxidative metabolism.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hui et al., 2017 source

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  • May combine two claims.

    Premisecitation

    During regional brain stimulation, local blood flow increases by ∼50% and local glucose consumption increases commensurately.

    “With regional stimulation (e.g., of the visual cortex by a flashing checkerboard pattern), positron electron tomography studies reveal that local blood flow increases by ∼50% and that there is a commensurate increase in local glucose consumption.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The expected stoichiometry for complete glucose oxidation is six O2 molecules consumed per glucose molecule.

    “The expected stoichiometry for this process is that six O2 molecules will be consumed for each glucose molecule.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The pentose phosphate pathway and glycogen synthesis can both result in net utilization of glucose without molecular oxygen, thereby reducing the OGI.

    “First, in addition to glycolysis, the pentose phosphate pathway and glycogen synthesis can both result in net utilization of glucose without molecular oxygen, thereby reducing the OGI.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In separately cultured astrocytes and neurons, glutamate application to cultured astrocytes triggers [3H]-2-deoxyglucose uptake and lactate release, and neurons are capable of consuming lactate as a fuel.

    “For instance, the initial demonstration of feasibility was from separately cultured astrocytes and neurons: glutamate application to cultured astrocytes triggers [3H]-2-deoxyglucose (2-DG; [3H]–2-DG) uptake and lactate release, and neurons are capable of consuming lactate as a fuel (Magistretti et al., 1993; Pellerin and Magistretti, 1994).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Magistretti et al., 1993 source

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    • cites Pellerin and Magistretti, 1994

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    Premisecitation

    Two recent in vivo studies monitoring glucose analogue accumulation in somatosensory cortex during whisker stimulation used two different glucose analogues and obtained opposite results.

    “Two recent in vivo studies monitored glucose analogue accumulation in somatosensory cortex during whisker stimulation; they used two different glucose analogues and obtained opposite results.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Chuquet et al., 2010 source

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    • cites Lundgaard et al., 2015 source

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    • The authors state this as an assumption: Uptake of 2-DG-based tracers and, in some cases, their phosphorylation by hexokinase parallels glucose utilization.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Glycolysis is one of the most ancient metabolic pathways with a wide variety of allosteric and phosphorylation-based controls.

    “Glycolysis is one of the most ancient metabolic pathways with a wide variety of allosteric and phosphorylation-based controls (Mulukutla et al., 2010; Icard and Lincet, 2012).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Mulukutla et al., 2010 source

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    • cites Icard and Lincet, 2012

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  • May combine two claims.

    Interpretationcitation

    The Bouzier-Sore et al. (2006) study was done with unstimulated neurons and did not test whether preferential use of lactate was enhanced by activation.

    “Importantly, this study was done with unstimulated neurons and did not test whether the preferential use of lactate was enhanced by activation as proposed (Bouzier-Sore et al., 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bouzier-Sore et al., 2006 source

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  • May combine two claims.

    Premisecitation

    In vitro glycolytic behavior can change with choice of culture media and astrocyte coculture.

    “In vitro glycolytic behavior can change with choice of culture media (Sünwoldt et al., 2017) and astrocyte coculture (Mamczur et al., 2015), but gene expression data from acutely dissociated brain cells indicate that neurons are well equipped for glycolysis, with higher levels of mRNA expression than astrocytes for most glycolytic enzymes (Fig. 1, left).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Sünwoldt et al., 2017 source

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    • cites Mamczur et al., 2015 source

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  • May combine two claims.

    Premisecitation

    Proteomics data show an overall deficit of MCTs in neurons, but they are from cells in culture.

    “although again, the transporters are both equilibrative, and transcriptomics show comparable levels of MCT1 in both neurons and astrocytes (Fig. 1, left; the proteomics data on the right show an overall deficit of MCTs in neurons, but they are from cells in culture).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fig. 1

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  • May combine two claims.

    Interpretationcitation

    Extracellular lactate supports basal metabolism in neurons but not stimulated activity.

    “Similar experiments using graded neuronal stimulation by NMDA, which produced moderate submicromolar increases in cytosolic calcium, showed that activation increased glucose metabolism over twofold, whereas lactate metabolism declined, consistent with a role for extracellular lactate supporting basal metabolism in neurons but not stimulated activity (Bak et al., 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bak et al., 2009 source

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  • May combine two claims.

    Premisecitation

    In cultured neurons, graded NMDA stimulation producing moderate submicromolar increases in cytosolic calcium increased glucose metabolism over twofold, whereas lactate metabolism declined.

    “Similar experiments using graded neuronal stimulation by NMDA, which produced moderate submicromolar increases in cytosolic calcium, showed that activation increased glucose metabolism over twofold, whereas lactate metabolism declined, consistent with a role for extracellular lactate supporting basal metabolism in neurons but not stimulated activity (Bak et al., 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bak et al., 2009 source

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  • May combine two claims.

    Premisecitation

    PFKFB3 is posttranslationally down-regulated in neurons and thus cannot participate in glycolytic stimulation.

    “Although one specific enzyme for up-regulation of glycolysis, the bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (isoform PFKFB3), is posttranslationally down-regulated in neurons and thus cannot participate in glycolytic stimulation (Herrero-Mendez et al., 2009; Bolaños, 2016), this rules out only one of many mechanisms that neurons can use to stimulate glycolysis.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Herrero-Mendez et al., 2009 source

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    • cites Bolaños, 2016 source

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  • May combine two claims.

    Premisecitation

    The NADHCYT transients decrease with inhibition of glycolysis but not of the MAS.

    “The NADHCYT transients decrease with inhibition of glycolysis but not of the MAS, indicating that increased neuronal glycolysis upon stimulation is the main cause of the NADHCYT transients.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Díaz-García et al., 2017 source

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  • May combine two claims.

    Premisenone given

    Neighboring cells are capable of maintaining very different NADHCYT redox, and at rest, the high NADHCYT of astrocytes does not drive neighboring neurons to a correspondingly high level.

    “However, neighboring cells are capable of maintaining very different NADHCYT redox, and at rest, the high NADHCYT of astrocytes does not drive neighboring neurons to a correspondingly high level.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    A deliberate review of the evidence with an optimized model concluded that neurons provide about a third of their own lactate/pyruvate during brain activation, with the other two thirds from astrocytes.

    “A deliberate review of the evidence with an optimized model concluded that neurons provide about a third of their own lactate/pyruvate during brain activation, with the other two thirds from astrocytes (Hyder et al., 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hyder et al., 2006 source

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    • The authors state this as an assumption: Acetate is metabolized only in glia.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    The very active malate-aspartate shuttle (MAS) of neurons could transfer reducing equivalents not only from neuronal glycolysis but also from astrocytic glycolysis.

    “In essence, the very active malate–aspartate shuttle (MAS) of neurons could transfer reducing equivalents not only from neuronal glycolysis but also from astrocytic glycolysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Knockdown of glycolytic enzymes in Drosophila neurons did not affect the viability or the general behavior of flies.

    “In Drosophila melanogaster, glycolysis appears to be more essential in glial cells than it is in neurons; knockdown of glycolytic enzymes in neurons did not affect the viability or the general behavior of flies, whereas knockdown in glial cells produced noticeable phenotypic changes (Volkenhoff et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Volkenhoff et al., 2015 source

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  • May combine two claims.

    Premisecitation

    In the retina, photoreceptors perform aerobic glycolysis and export lactate, which is then oxidized by Müller cells.

    “the opposite appears to be true: photoreceptors perform aerobic glycolysis and export lactate, which is then oxidized by Müller cells (Hurley et al., 2015; Kanow et al., 2017).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hurley et al., 2015 source

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    • cites Kanow et al., 2017 source

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  • May combine two claims.

    Premisecitation

    Upon whisker stimulation in anesthetized rats, 6-NBDG uptake into both cell types tended to increase, though only significantly for astrocytes.

    “Baseline accumulation of the analogue into astrocytes and neurons was similar; upon whisker stimulation in anesthetized rats, uptake into both cell types tended to increase, though only significantly for astrocytes (Chuquet et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chuquet et al., 2010 source

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    • The authors state this as an assumption: Uptake of 2-DG-based tracers and, in some cases, their phosphorylation by hexokinase parallels glucose utilization.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The acute metabolic response to neuronal activity has not been studied in Drosophila.

    “The acute metabolic response to neuronal activity has not been studied.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    At present, there are no data to indicate whether there is significant redox exchange between astrocytes and neurons through lactate-pyruvate exchange.

    “At present, there are no data to indicate whether there is significant redox exchange between astrocytes and neurons through lactate–pyruvate exchange.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Moderate chemical stimulation produced a strong increase in labeling of glutamate from labeled glucose and a decrease in incorporation of label from labeled lactate, inconsistent with significant lactate utilization by neurons during stimulation.

    “Moderate chemical stimulation produced a strong increase in the labeling of glutamate from labeled glucose and a decrease in the incorporation of label from labeled lactate, inconsistent with significant lactate utilization by neurons during stimulation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Bak et al., 2009 source

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    • cites Bak et al., 2012 source

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  • May combine two claims.

    Interpretationcitation

    Higher resting NADHCYT predisposes astrocytes to higher resting lactate/pyruvate ratios and higher resting lactate levels.

    “Consistent with most of the cultured cell studies, in resting brain or in quiescent brain slice astrocytes appear to be more glycolytic than neurons, with higher resting cytosolic NADH/NAD+ (NADHCYT) ratios (Mongeon et al., 2016) that predispose them to higher resting lactate/pyruvate ratios and higher resting lactate levels (Mächler et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mächler et al., 2016 source

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  • May combine two claims.

    Premisecitation

    Müller cells are deficient in pyruvate kinase, the final enzyme in the glycolytic pathway, and have limited ability to convert glucose to lactate.

    “Müller cells are deficient in pyruvate kinase, the final enzyme in the glycolytic pathway, and have limited ability to convert glucose to lactate (Lindsay et al., 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lindsay et al., 2014 source

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  • May combine two claims.

    Premisecitation

    In cultured neurons, unlabeled lactate does not diminish the increased utilization of labeled glucose with stimulation, but it does reduce labeling from glucose at rest.

    “Furthermore, although in cultured neurons, unlabeled lactate does not diminish the increased utilization of labeled glucose with stimulation, it does reduce labeling from glucose at rest (Bak et al., 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bak et al., 2009 source

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  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    In neuronal cell bodies, stimulation leads to enhanced neuronal glucose metabolism.

    “In neuronal cell bodies, stimulation leads to enhanced neuronal glucose metabolism,”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The absence of mitochondria from dendritic spines makes it questionable whether the role of MCTs is to support astrocyte-to-neuron movement of lactate rather than efflux of lactate produced by aerobic glycolysis in spines.

    “But the absence of mitochondria from dendritic spines does make it questionable whether the role of MCTs, which may be inserted into spine membranes together with AMPA receptors (Bergersen et al., 2001), is to support astrocyte-to-neuron movement of lactate rather than efflux of lactate produced by aerobic glycolysis in the spines.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bergersen et al., 2001 source

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  • Classified as probably not a substantial claim.

    Interpretationnone given

    Both the increased O2 consumption and the initial NAD(P)H dip are generally agreed to reflect increased ETC activity upon mitochondrial depolarization.

    “Both the increased O2 consumption and the initial NAD(P)H dip are generally agreed to reflect increased ETC activity upon mitochondrial depolarization,”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Ca2+ handling is itself metabolically expensive, so elevated [Ca2+] is usually accompanied by an elevation in ADP.

    “A complication in dissecting the roles of these two avenues for metabolic regulation is that Ca2+ handling is itself metabolically expensive, so elevated [Ca2+] is usually accompanied by an elevation in ADP.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    We do not have a complete understanding of the oxphos-related mitochondrial signals that result from neuronal excitation.

    “Clearly, we do not have a complete understanding of the oxphos-related mitochondrial signals that result from neuronal excitation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    In some myelinated axons, metabolic support from glia may be essential during stimulation.

    “whereas in some myelinated axons, metabolic support from glia may be essential during stimulation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Both ADP and Ca2+ can regulate glycolysis and oxphos rates via multiple mechanisms.

    “Both of these agents can regulate glycolysis and oxphos rates via multiple mechanisms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The feedforward effect of Ca2+ would increase the rate of matrix NADH production and thereby increase the supply of electrons for the ETC, leading to mitochondrial hyperpolarization.

    “This feedforward effect of Ca2+ would increase the rate of matrix NADH production (and thus the NAD(P)H signal) and thereby increase the supply of electrons for the ETC, leading to mitochondrial hyperpolarization (Ivannikov and Macleod, 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ivannikov and Macleod, 2013

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  • May combine two claims.

    Interpretationreasoning

    Depolarization and proton movements accompanying ADP or Ca2+ entry will diminish ΔμH and allow the stalled ETC to function again, consuming O2 and matrix NADH.

    “The depolarization and proton movements accompanying ADP or Ca2+ entry will diminish ΔμH and allow the stalled ETC to function again, consuming O2 and matrix NADH (Fig. 2).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    There is no affirmative evidence that lactate movement from astrocytes to neurons occurs during the ordinary function of the brain, particularly during brain stimulation.

    “However, there is no affirmative evidence that lactate movement from astrocytes to neurons occurs during the ordinary function of the brain, particularly during brain stimulation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The NAD(P)H overshoot in slices did not disappear with prolonged elimination of extracellular Ca2+, although the mitochondrial Ca2+ transient did disappear.

    “However, it is hard to reconcile this with the clear finding by Shuttleworth et al. (2003) that the NAD(P)H overshoot in slices did not disappear with the prolonged elimination of extracellular Ca2+, although the mitochondrial Ca2+ transient did disappear.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shuttleworth et al., 2003 source

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  • May combine two claims.

    Interpretationreasoning

    ADP can be considered a feedback metabolic signal, whereas Ca2+ can function as a feedforward signal to anticipate energetic costs before they are incurred.

    “ADP can be considered a feedback metabolic signal—energetic costs have been incurred and must be paid for—whereas Ca2+ can function as a feedforward signal to anticipate energetic costs before they are incurred.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    For glycolysis and oxphos to run at different rates, there must be slippage or uncoupling at the interface between them: lactate-pyruvate partitioning controlled by the NADHCYT ratio.

    “Also, for glycolysis and oxphos to run at different rates, there must be slippage or uncoupling at the interface between them: lactate-pyruvate partitioning controlled by the NADHCYT ratio.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both ADP and Ca2+ produce depolarization of the mitochondrial membrane potential (Δψ) and the related mitochondrial proton driving force (ΔμH).

    “Proximally, both produce depolarization (diminution) of the mitochondrial membrane potential (Δψ) and the related mitochondrial proton driving force (ΔμH; Fig. 2 A).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Nicholls and Ferguson, 2002

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    • cites Salway, 2004

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  • May combine two claims.

    Interpretationreasoning

    The MAS is the primary route for moving reducing equivalents across the mitochondrial inner membrane because NADH itself does not cross.

    “The shuttle is the primary route for moving reducing equivalents across the mitochondrial inner membrane (because NADH itself does not cross).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Elevated NADHCYT by itself can both affect glucose flux through glycolysis and shunt pyruvate toward lactate and away from utilization for oxphos.

    “Both of these effects suggest that elevated NADHCYT by itself can both affect glucose flux through glycolysis and shunt pyruvate toward lactate and away from utilization for oxphos.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Neurons possess many mitochondria and rely chronically on them as a major source of ATP.

    “Neurons possess many mitochondria and rely chronically on them as a major source of ATP (Hall et al., 2012),”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hall et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Upon neuronal stimulation, the classical ANLS hypothesis does not apply; instead, there is an increase in neuronal glycolysis accompanied by a smaller increase in neuronal oxphos.

    “the most direct evidence argues that upon neuronal stimulation, the classical ANLS hypothesis does not apply and that instead, there is an increase in neuronal glycolysis accompanied by a smaller increase in neuronal oxphos.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Glycolysis produces NADH at the GAPDH step, and this NADH will accumulate unless recycled by LDH or by malate dehydrogenase, usually as the first step in the MAS.

    “First, glycolysis produces NADH at the GAPDH step. This NADH will accumulate in the cell (and ultimately inhibit continued glycolysis) unless it is recycled by one of two recycling routes. The first is LDH: conversion of NADH to NAD+ coordinately with production of lactate from pyruvate; this is the primary mechanism by which cells can perform glycolysis without oxphos, as it deprives mitochondria”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In dentate granule neurons, MCT inhibition led to higher peaks of NADHCYT as well as smaller dips in glucose, suggesting that elevated NADHCYT also exerted back pressure on glycolysis.

    “In dentate granule neurons, MCT inhibition led to higher peaks of NADHCYT as well as smaller dips in glucose, suggesting that the elevated NADHCYT also exerted back pressure on glycolysis, presumably on the GAPDH equilibrium (Díaz-García et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Díaz-García et al., 2017 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    The mechanisms engaged by neuronal excitation can vary with the degree of stimulation and with the environmental conditions of [glucose] and [O2] during experiments, which usually vary from the in vivo condition, and may also vary with cell type.

    “The mechanisms that are engaged by neuronal excitation can vary with the degree of stimulation and with the environmental conditions of [glucose] and [O2] during experiments, which usually vary from the in vivo condition, and the mechanisms may also vary with cell type.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Interconversion between pyruvate and lactate by LDH requires coordinate interconversion between NADH and NAD+, and the rate of glycolysis depends on recycling of NADH to NAD+, so the NADHCYT ratio is a key parameter for uncoupling.

    “Because interconversion between pyruvate and lactate by LDH requires coordinate interconversion between NADH and NAD+, and because the rate of glycolysis depends on some form of recycling of NADH to NAD+, the NADHCYT ratio is a key parameter for the uncoupling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Fast-twitch muscle, requiring the greatest acute supply of energy, tends to be far more glycolytic and to have fewer mitochondria than the slow-twitch muscle used for postural control.

    “fast-twitch muscle, requiring the greatest acute supply of energy, tends to be far more glycolytic and to have fewer mitochondria than the slow-twitch muscle used for postural control (Crow and Kushmerick, 1982; Spriet, 1989).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Crow and Kushmerick, 1982

      Not checked in the free run.

    • cites Spriet, 1989

      Not checked in the free run.

53 of 53

  • The authors state this as an assumption.

    Uptake of 2-DG-based tracers and, in some cases, their phosphorylation by hexokinase parallels glucose utilization.

    “Glucose uptake by neurons and astrocytes can be monitored with tracers based on 2-DG, relying on the assumption that uptake of the tracers and (in some cases) their phosphorylation by hexokinase parallels glucose utilization.”

  • The authors state this as an assumption.

    Acetate is metabolized only in glia.

    “However, this conclusion depends on the assumption that acetate is metabolized only in glia; a recent study of acetate metabolism in brain slices showed a substantial ability of neurons to metabolize acetate directly, which calls the compartment-specific modeling into question (Rowlands et al., 2017).”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Neuronal activity and glucose utilization have previously been shown to exist in a near 1:1 stoichiometric relationship.

    “neuronal activity and glucose utilization have previously been shown to exist in a near 1:1 stoichiometric relationship72”

    From APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice (2020) · cites this paper as [72]

    In “The source of neuronal energy during activation” (page unavailable), the review reports that neuronal stimulation increased glucose metabolism more than twofold, supporting a link between activity and glucose use. It does not report a near 1:1 stoichiometric relationship between them. Its separate discussion of stoichiometry concerns oxygen and glucose use in the resting brain, not neuronal activity and glucose use. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Neuron and astrocyte are coupled in glucose oxidation.

    “As the two most abundant, and energetically most essential cell types in the brain, neuron and astrocyte are coupled in not only glucose oxidation (Magistretti and Allaman, 2018; Yellen, 2018), but also lipid metabolism (Barber and Raben, 2019).”

    From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Yellen, 2018

    In “The source of neuronal energy during activation” (page unavailable), Yellen describes possible exchange of glucose-derived metabolic products between astrocytes and neurons, but says there are no data showing significant exchange at rest. “Some key puzzles to solve” adds that the best direct evidence during neuronal stimulation favors neurons using glucose themselves, rather than the classical astrocyte-to-neuron lactate shuttle. The unqualified claim that the cells are coupled in glucose oxidation therefore overstates the paper’s position. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • The capacity in performing glycolysis and OXPHOS varies between neurons and astrocytes.

    “The capacity in performing glycolysis and OXPHOS varies between neuron and astrocyte (Magistretti and Allaman, 2018; Yellen, 2018).”

    From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Yellen, 2018

    In “The source of neuronal energy during activation” (page unavailable), Yellen reports that astrocytes appear more glycolytic than neurons at rest and describes differences in their glycolytic-enzyme expression. Those passages support a difference in glycolytic behavior, but they do not establish a comparative capacity for oxidative phosphorylation between the two cell types. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The high metabolic need of the brain cannot be met by glycolytic activity; neurons rely on the tricarboxylic acid cycle and oxidative phosphorylation housed in mitochondria to produce ATP.

    “The high metabolic need of the brain cannot be met by glycolytic activity. Rather, neurons rely on the tricarboxylic acid cycle and oxidative phosphorylation housed in mitochondria to produce ATP [72,120].”

    From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [72]

Cites

Flagged first, then by citations

3 of the 131 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. Clarke, 1994, Circulation and energy metabolism of the brain, 637
  2. Nelson, 2017, Lehninger Principles of Biochemistry.
  3. Nicholls, 2002, Bioenergetics 3.

Cited by

Sorted by citations

Related

Authors
Yellen, G.
Affiliations
Harvard University (US)
Corresponding author
Yellen, Gary
ORCID
Yellen, Gary
Venue
Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2018-05-11
Volume
217
Issue
7
Pages
2235-2246
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.201803152
PMC
PMC6028533
OpenAlex
W2801615083
Semantic Scholar
ff7241917ffdf6751decf262f5a2edcbd2217b86
Cited by
371
References
131
Citations by year
2026: 39 · 2025: 46 · 2024: 46 · 2023: 55 · 2022: 49 · 2021: 54 · 2020: 42 · 2019: 28 · 2018: 12
FWCI
4.40
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (R01 NS055031, DP1 EB016985, R01 NS102586, R01 GM124038)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
neuronal energy metabolism, aerobic glycolysis, mitochondrial uncoupling, brain energy demand, lactate metabolism, calcium signaling
MeSH terms
Adenosine Diphosphate, Animals, Astrocytes, Brain, Calcium, Energy Metabolism, Glucose, Glycolysis, Humans, Neurons, Oxidative Phosphorylation, Lactic Acid

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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