bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2025–10–26
eleven papers selected by
Regina F. Fernández, Johns Hopkins University



  1. J Proteome Res. 2025 Oct 19.
      Depression is closely associated with brain energy metabolism; however, its metabolic characteristics and the mechanisms underlying energy dysregulation remain poorly understood. In this study, we employed an in vitro depression model using corticosterone (CORT)-induced astrocytes and applied stable isotope-resolved metabolomics (SIRM) to trace the metabolic fate of [U-13C6]-glucose, [U-13C3]-lactate, and [U-13C5]-glutamine. Metabolic flux analysis (MFA) was subsequently used to quantify intracellular fluxes. CORT exposure triggered substrate-specific metabolic reprogramming: glucose and lactate catabolism were impaired, whereas glutamine utilization was upregulated. Despite increased glucose uptake and glycolytic flux, most glucose-derived carbon was shunted toward excessive lactate production rather than entering the tricarboxylic acid (TCA) cycle, resulting in a net lactate efflux. Concurrently, glutaminolysis was enhanced to partially compensate for reduced oxidative metabolism. These findings indicate that while glucose remains the dominant energy substrate, its preferential diversion to aerobic glycolysis markedly diminishes ATP production. Collectively, this work provides novel insights into astrocytic energy dysfunction in depression and highlights potential metabolic targets for therapeutic strategies aimed at restoring cerebral energy homeostasis.
    Keywords:  aerobic glycolysis; astrocyte; depression; metabolic flux analysis; stable isotope-resolved metabolomics
    DOI:  https://doi.org/10.1021/acs.jproteome.5c00667
  2. J Neurochem. 2025 Oct;169(10): e70265
      Myelinating Schwann cells depend on precise metabolic regulation to support axonal function and maintain peripheral nerve integrity. Peripheral Myelin Protein 2 (PMP2), a fatty acid-binding protein enriched in myelinating Schwann cells, has been implicated in lipid metabolism and mitochondrial energy production. Here, we examine the role of PMP2 in regulating Schwann cell bioenergetics and myelination. Using both immortalized and primary Schwann cells, we show that PMP2 overexpression enhances mitochondrial ATP production. We also reveal that PMP2 alters metabolic dependencies during high metabolic demand, reducing Schwann cell reliance on glutamine while promoting greater metabolic adaptability under substrate restriction. Finally, PMP2 overexpression significantly increases myelination in vitro, indicating that PMP2-driven metabolic modulation supports the energetic demands of myelination. These findings position PMP2 as a key regulator of Schwann cell metabolism and a potential therapeutic target for demyelinating neuropathies.
    Keywords:  ATP; PMP2; Schwann cell; seahorse
    DOI:  https://doi.org/10.1111/jnc.70265
  3. J Neuroradiol. 2025 Oct 18. pii: S0150-9861(25)00153-1. [Epub ahead of print] 101395
      Most human physiological processes follow circadian rhythms such as glucose metabolism and neuronal activity, thereby playing a major role in brain metabolism regulation. Proton Magnetic Resonance Spectroscopy (1H-MRS) has become a valuable tool for quantification of brain metabolism in clinical settings. Nonetheless, only limited evidence of brain metabolism variation throughout the day has been found, restricted to specific brain regions or limited by a sample size. The aim of this study was to investigate time-of-day effect on brain metabolism in 1H-MRS of different brain regions associated with circadian rhythms in healthy adults. This prospective monocentric study included 39 healthy volunteers aged between 25 and 40 years. They underwent three 3T MRI examinations the same day at 7:30, 13:30 and 17:30. Two CSI MRS sequences were acquired to study brain regions of the basal ganglia and semi-oval center. A linear mixed model was used to investigate differences between session times, sex and brain hemisphere on acquired total Choline (tCho), total N-Acetyl-Aspartate (tNAA), and Lactate (Lac). Models showed a significant decrease in tCho/tNAA in the last session of -1.60% (p = 0.017) and a lower value of tCho/tCr of -9.74% (p = 0.014) and tCho/tNAA of -7.98% (p = 0.044) for women as compared with men. In the right hemisphere a higher value of tNAA/tCr of +2.84% (p < 0.001) was found, while tCho/tNAA was lower by -1.60% (p = 0.003) compared to the left hemisphere. The metabolite ratios under investigation were not affected by circadian rhythms, except for a small decrease of tCho/tNAA at 17:30. However, sex and brain hemispheres had a significant impact on brain metabolism. While brain MRS examination for most common metabolites could be carried out at any time of day, it is still important to consider the patient's sex and the side of the brain being examined.
    Keywords:  Brain Metabolism; Circadian Rhythm; Linear Mixed Model; Proton Magnetic Resonance Spectroscopy
    DOI:  https://doi.org/10.1016/j.neurad.2025.101395
  4. J Neurochem. 2025 Oct;169(10): e70262
      Lipids are emerging as key players in regulating neural stem cells and their progeny. Recent lipidomic profiling studies clearly illustrate the significance of lipids across cerebral cortical development and evolution. In this review, we identify the existing knowledge concerning the importance of lipids in cortex development and neurogenesis processes, with a special emphasis on ceramide-based sphingolipids. We then discuss the lipidation of factors that are relevant for cortex development and how their interaction with ceramides facilitates certain intracellular processes. We further summarize the importance of ceramides in different intracellular compartments and organelles, and finally discuss the alterations of sphingolipid metabolism in neurological disorders, particularly of neurodevelopmental origin.
    Keywords:  brain development; ceramides and sphingolipids; cerebral cortex; lipids; neurological disorders
    DOI:  https://doi.org/10.1111/jnc.70262
  5. Neurochem Res. 2025 Oct 25. 50(6): 337
      Astrocytes have important functions in the metabolism and antioxidative defence of the brain. Three redox pairs and the ratio of the reduced and oxidized partners in each pair are essential for astrocytic redox metabolism, GSx (glutathione (GSH) plus glutathione disulfide (GSSG)), NADx (NADH plus NAD+) and NADPx (NADPH plus NADP+). In order to elucidate the interactions between the three redox pairs in astrocytes, we first analysed the basal levels of the six redox co-substrates for cultured primary rat astrocytes by using sensitive and specific enzymatic cycling assays. In untreated cultures, the basal specific contents of GSx, NADPx and NADx were 44.7 ± 8.2 nmol/mg protein, 0.64 ± 0.09 nmol/mg protein and 2.91 ± 0.40 nmol/mg protein, with the reduced co-substrates accounting for 97 ± 3%, 37 ± 14% and 28 ± 10% of the total amounts, respectively. Exposure of cultured astrocytes to oxidative stress (100 µM H2O2 in the presence of the pentose-phosphate pathway inhibitor G6PDi-1) caused a rapid and severe but transient oxidation of GSH to GSSG. This increase was accompanied by a doubling of the total pool of NADPx on the expense of the cellular NADx pool, suggesting that NAD+ was phosphorylated to NADP+ under these conditions. Testing for NAD kinase (NADK) activity in lysates of cultured astrocytes revealed that the enzyme is present with a specific vmax activity of around 1 nmol/(min x mg protein) and has KM-values of 1.30 ± 0.19 mM for NAD+ and 2.71 ± 0.18 mM for ATP. Preincubation of astrocytes with thionicotinamide, the precursor for the cellular synthesis of the NADK inhibitor thio-NADP, prevented the transient oxidative stress-induced phosphorylation of NAD+ to NADP+. These data demonstrate that the NADPx pool can be increased in cultured astrocytes during oxidative stress by NADK-mediated phosphorylation of NAD+, providing experimental evidence for an additional interaction of the main astrocytic redox pairs during oxidative stress.
    Keywords:  Astrocytes; Glutathione; NAD kinase; Nicotinamide coenzymes; Oxidative stress
    DOI:  https://doi.org/10.1007/s11064-025-04588-4
  6. Exp Neurol. 2025 Oct 21. pii: S0014-4886(25)00371-1. [Epub ahead of print]396 115506
       OBJECTIVES: Currently there are no biomarkers to predict chronic neurobehavioral and neurocognitive deficits following a traumatic brain injury (TBI). We measured brain metabolite using magnetic resonance spectroscopy in a rat model of TBI to determine their potential as biomarkers of neurobehavioral/neurocognitive outcomes after TBI.
    METHODS: TBI or sham surgery was conducted in 11-12 weeks old Sprague Dawley (SD) rats. Rats underwent 1H-MRS at 1 week and 1 month following TBI. Behavioural evaluations were performed between 5 and 6 months post-TBI.
    RESULTS: TBI rats showed significantly elevated myoinositol as well as sustained reductions in N-acetyl aspartate (NAA), gamma-aminobutyric acid (GABA), and glutamate levels compared to the sham operated rats. Behavioural assessments revealed cognitive impairment and depression-like behaviour in the TBI rats. We categorized TBI rats with (TBI+) and without (TBI-) behavioural impairment based on their performance relative to the sham rats on each assessment. TBI+ rats with cognitive impairment showed elevated myoinositol and decreased levels of glutathione (GSH), glutamate, and total choline, compared to the TBI- rats. Furthermore, TBI+ rats with depression-like behaviour demonstrated increased myoinositol and glutamate alongside decreased NAA, total choline and total creatine levels compared to the TBI- rats. Logistic regression analysis showed that certain MRS measures had good sensitivity and specificity to distinguish between the TBI+ and TBI- rats (AUC for ROC curve = 0.75-0.9, p < 0.05).
    CONCLUSION: We identified specific early changes in brain metabolites that predict chronic behavioural impairments after TBI. These translational findings may help understand TBI pathophysiology and help to predict functional outcomes in the clinical settings.
    Keywords:  1H-MRS; Biomarker; Inflammation; Neuroimaging; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.expneurol.2025.115506
  7. Crit Care. 2025 Oct 24. 29(1): 450
       BACKGROUND: Lactate, traditionally viewed as a biomarker of hypoxia and severity in critical illness, has recently emerged as a potential therapeutic agent. Its roles extend beyond energy metabolism to include anti-inflammatory and signaling functions. This review explores the evolving evidence supporting lactates therapeutic application in critical care settings.
    MAIN BODY: We synthesize current knowledge on lactate physiology, including its production, transport, and metabolism across organs. Experimental models and clinical studies data suggest that exogenous lactate, particularly in the form of hypertonic sodium lactate (HSL), improves hemodynamics, reduces inflammation, and enhances organ function in sepsis, acute heart failure, and brain injury. Lactate administration shows promise in restoring metabolic homeostasis, improving microcirculation, and supporting cardiac and cerebral recovery. However, clinical studies in critical care remain limited, largely because lactate is predominantly regarded as a marker of poor prognosis rather than as a potential energy substrate with therapeutic value.
    CONCLUSION: Lactate-based therapy represents a paradigm shift in the management of critical illness. While preclinical data are promising, larger, well-designed randomized trials are needed to establish its safety, efficacy, and optimal indications. The therapeutic repositioning of lactate could complement or replace current resuscitation fluids and metabolic modulators in intensive care unit (ICU).
    Keywords:  Brain injury; Critical illness; Heart failure; Hypertonic sodium lactate; Lactate infusion; Metabolism; Resuscitation fluids; Sepsis
    DOI:  https://doi.org/10.1186/s13054-025-05665-4
  8. Neurotrauma Rep. 2025 ;6(1): 790-803
      Neuroinflammation is a nearly ubiquitous secondary injury process after traumatic brain injury (TBI) involving microglia. The time course of microglial functional transition between pro-inflammatory and anti-inflammatory states after mild TBI (mTBI) and the potential influence of sex in microglial response is not well-understood. To investigate interactions between sex and microglial activation states in the subacute post-mTBI period, we performed a morphological and phenotypic marker analysis on cells from male and female rats following closed head single impact (smTBI), repetitive impacts (rmTBI), or sham conditions at 24 h, 72 h, or 1 week postinjury. There was a significant increase in microglia population 24 h post-smTBI and at all time points for rmTBI in both male and female cells. Single-cell morphological analysis (24 microglia per animal) revealed no clear sex differences in microglial activation state. However, Sholl analysis demonstrated an increase in branching complexity for smTBI female cells at 24 h (area under the curve [AUC] 154 ± 2.1, p = 0.03) and at 72 h for rmTBI (AUC 229 ± 6.6, p = 0.006), but no increase in branching was observed in male cells. Principal component analysis similarly demonstrated that female cells formed distinct clusters at 72 h and 1 week, suggesting a change in morphology. There was an increase in anti-inflammatory marker, CD206, at 72 h for female cells in both smTBI and rmTBI groups. However, for males, most cells were KV1.3-positive (pro-inflammatory) even at 1 week in smTBI and rmTBI groups. Altogether, these data demonstrate microglial cells are pro-inflammatory 24 h after mTBI, but there is a robust difference between sexes, with female cells transitioning earlier from the pro-inflammatory state to the anti-inflammatory state compared with male cells. These results contribute to our understanding of sexual dimorphism associated with microglial recovery following mTBI and warrant further study of associated cellular pathways.
    Keywords:  microglia functional state; mild traumatic brain injury; morphological analysis; neuroinflammation; sex dimorphism
    DOI:  https://doi.org/10.1177/2689288X251377030
  9. J Alzheimers Dis. 2025 Oct 24. 13872877251389157
      BackgroundGlyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a well-known glycolytic enzyme that plays multiple roles in energy metabolism, cell growth, and cell death, and functions as a housekeeping protein. GAPDH has been identified as a potential target of citrullination, a calcium-dependent post-translational modification mediated by peptidylarginine deiminase (PAD), in which arginine residues are converted to citrulline. This modification has been implicated in various human pathologies.ObjectiveTo investigate the function and pathological relevance of citrullinated GAPDH.MethodsWe generated mouse monoclonal antibodies (mAbs) specific to citrullinated GAPDH and applied them in both in vitro systems and prion disease models.ResultsCitrullination of GAPDH at residues R200 and R248 was markedly increased in the brains of 22L scrapie-infected mice and sporadic Creutzfeldt-Jakob disease patients. Both full-length GAPDH and its fragments (∼25 kDa) were heavily citrullinated and highly expressed in neurons including Purkinje cells, astrocytes, and in plaque-like formation. In PAD2-expressing neuronal and astrocyte cell lines, citrullinated GAPDH predominantly accumulated in the nucleus and cytoplasm, with cell type-specific distribution patterns. Citrullinated GAPDH existed as both monomers and reversible oligomers, and citrullination did not alter its enzymatic activity. Immunoprecipitation demonstrated that GAPDH containing citrullinated forms interacts with prion protein. Tandem mass spectrometry analysis revealed that all arginine residues in GAPDH can be citrullinated by PAD2 in vitro. Interestingly, several asparagine and glutamine residues underwent deamidation during citrullination.ConclusionsOur findings suggest that post-translationally citrullinated GAPDH serve as a potential molecular signature of neurodegeneration, which could be easily assessed by newly generated mAbs.
    Keywords:  Alzheimer's disease; citrullination; glyceraldehyde 3-phosphate dehydrogenase; neurodegeneration; peptidylarginine deiminase; prion
    DOI:  https://doi.org/10.1177/13872877251389157
  10. Nat Metab. 2025 Oct 22.
      It has been shown that in most cells, low glucose leads to activation of AMP-activated protein kinase (AMPK) via the lysosomal glucose-sensing pathway, where glycolytic aldolase acts as the glucose sensor. Here, we show that ALDOC (aldolase C), the predominant isozyme of aldolase in mouse and rat oligodendrocyte precursor cells (OPCs), is acetylated at lysine 14, making the lysosomal glucose-sensing AMPK pathway unable to operate. We find that the blockage of AMPK activation is required for the proper proliferation and differentiation of OPCs into mature oligodendrocytes for myelination during development and for remyelination in areas of demyelination where the local glucose levels are low. Therefore, the acetylation of aldolase acts as a checkpoint for AMPK activation in response to low glucose to ensure the proliferation and differentiation of OPCs for myelination, and remyelination of demyelinated neurons.
    DOI:  https://doi.org/10.1038/s42255-025-01386-8
  11. Front Immunol. 2025 ;16 1648887
       Background: Microglia, the resident immune cells of the central nervous system (CNS), play pivotal roles in the onset and progression of various neurological disorders. Owing to their remarkable plasticity, microglia can adopt diverse phenotypic states in response to distinct microenvironmental cues. Over the past decades, accumulating evidence has demonstrated that immune cell metabolism critically regulates their polarization and effector functions through a process termed metabolic reprogramming, in which glucose metabolism is particularly central. Glycolytic reprogramming underlies the entire polarization process, and elucidating its mechanisms may enable targeted modulation of microglial activity to mitigate their deleterious effects in CNS pathologies, thereby offering novel therapeutic avenues for these diseases.
    Aim of the Review: This paper summarizes what is known about microglial polarization and glycolytic reprogramming and explores their important roles in the development of neurological diseases. The link between microglial metabolomics and epigenetics in neurological disorders requires further study.
    Key Scientific Concepts of the Review: Microglia exhibit distinct phenotypic states at different stages of central nervous system (CNS) disorders, and these polarization processes are closely coupled with glucose metabolic reprogramming. Proinflammatory microglia predominantly rely on glycolysis, whereas reparative or anti-inflammatory phenotypes primarily utilize oxidative phosphorylation. Targeting glycolytic pathways to limit the polarization of microglia toward proinflammatory states has emerged as a promising therapeutic strategy for CNS diseases.
    Keywords:  Warburg effect; glycolysis; lactylation; metabolic reprogramming; microglia; nervous system diseases
    DOI:  https://doi.org/10.3389/fimmu.2025.1648887