bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2025–03–16
twenty-two papers selected by
Regina F. Fernández, Johns Hopkins University



  1. J Neurochem. 2025 Mar;169(3): e70029
      Synaptic homeostasis of the principal neurotransmitters glutamate and GABA is tightly regulated by an intricate metabolic coupling between neurons and astrocytes known as the glutamate/GABA-glutamine cycle. In this cycle, astrocytes take up glutamate and GABA from the synapse and convert these neurotransmitters into glutamine. Astrocytic glutamine is subsequently transferred to neurons, serving as the principal precursor for neuronal glutamate and GABA synthesis. The glutamate/GABA-glutamine cycle integrates multiple cellular processes, including neurotransmitter release, uptake, synthesis, and metabolism. All of these processes are deeply interdependent and closely coupled to cellular energy metabolism. Astrocytes display highly active mitochondrial oxidative metabolism and several unique metabolic features, including glycogen storage and pyruvate carboxylation, which are essential to sustain continuous glutamine release. However, new roles of oligodendrocytes and microglia in neurotransmitter recycling are emerging. Malfunction of the glutamate/GABA-glutamine cycle can lead to severe synaptic disruptions and may be implicated in several brain diseases. Here, I review central aspects and recent advances of the glutamate/GABA-glutamine cycle to highlight how the cycle is functionally connected to critical brain functions and metabolism. First, an overview of glutamate, GABA, and glutamine transport is provided in relation to neurotransmitter recycling. Then, central metabolic aspects of the glutamate/GABA-glutamine cycle are reviewed, with a special emphasis on the critical metabolic roles of glial cells. Finally, I discuss how aberrant neurotransmitter recycling is linked to neurodegeneration and disease, focusing on astrocyte metabolic dysfunction and brain lipid homeostasis as emerging pathological mechanisms. Instead of viewing the glutamate/GABA-glutamine cycle as individual biochemical processes, a more holistic and integrative approach is needed to advance our understanding of how neurotransmitter recycling modulates brain function in both health and disease.
    Keywords:  Alzheimer's disease; astrocytes; lipid metabolism; mitochondrial function; neurodegeneration; neurotransmitter recycling
    DOI:  https://doi.org/10.1111/jnc.70029
  2. bioRxiv. 2025 Feb 25. pii: 2025.02.24.639988. [Epub ahead of print]
      Glucose is a predominant fuel for the brain supporting its high energy demand associated with neuronal signaling and synaptic activity. Long-term potentiation (LTP) is required for learning and memory formation by generating long lasting increase in synaptic strength and signal transmission between two neurons. While the electrophysiological bases of LTP are well established, much less is known about the metabolic demands of neurons involved in LTP. Common protocols used to examine synaptic activity rely on high glucose concentrations which are far from physiological glucose levels found in the brain. Here we used primary hippocampal neurons cultured under physiological (2.5 mM) and high (25 mM) glucose to investigate the metabolic effects of chemically induced LTP. Physiological glucose was associated with neuronal survival while high glucose promoted "PAS granule" accumulation. Changes in glucose altered extracellular lactate and pyruvate concentrations and affected key intracellular metabolic intermediates and neurotransmitter levels in neuronal cells without depleting the TCA cycle. LTP induction was comparable, but mitochondrial and neurotransmitter response to LTP was differentially affected physiological and high glucose conditions. Glycogen phosphorylase inhibition had minimal effects in physiological glucose but impaired synaptic responses and altered metabolite dynamics in high glucose. Our findings demonstrate that neuronal mitochondrial metabolism is closely linked to synaptic plasticity and highlight the importance of studying neurophysiological activity physiologically relevant glucose conditions.
    DOI:  https://doi.org/10.1101/2025.02.24.639988
  3. bioRxiv. 2025 Feb 24. pii: 2025.02.19.639087. [Epub ahead of print]
      Hyperglycemia in poorly controlled diabetes is widely recognized as detrimental to organ dysfunction. However, the acute effects of hyperglycemia on brain metabolism and function are not fully understood. The potential protective benefit of ketone bodies on mitochondrial function in the brain has also not been well characterized. Here, we evaluated the acute effects of hyperglycemia and β-hydroxybutyrate (BHB) on brain metabolism by employing a novel approach leveraging adenosine triphosphate (ATP)-dependence of bioluminescence originating from luciferin-luciferase activity. Oxygen consumption rate was measured in ex vivo live brain punches to further evaluate mitochondrial function. Additionally, we investigated the functional relevance of BHB using an in vivo photothrombotic stroke model to assess its cerebroprotective effects. Our data demonstrate that brain metabolism in mice is affected by acute exposure to high glucose, at a level similar to consuming food or a beverage with high sucrose. This short-term effect of glucose exposure was reduced by co-administration with the ketone body BHB. Moreover, BHB significantly reduced infarct size in the brain stroke model, providing evidence for its functional protective role in the brain. These findings suggest that BHB may effectively mitigate the adverse effects of metabolic stress and ischemic events on brain metabolism and function.
    DOI:  https://doi.org/10.1101/2025.02.19.639087
  4. Int J Mol Sci. 2025 Feb 27. pii: 2104. [Epub ahead of print]26(5):
      The solute carrier family 1 member 4 (SLC1A4) gene encodes a neutral amino acid transporter, also referred to as alanine-serine-cysteine transporter 1, ASCT1, that helps maintain amino acid balance in the brain and periphery. In the brain, SLC1A4 plays an important role in transporting levo (L) and dopa (D) isomers of serine. L-serine is required for many cellular processes, including protein and sphingolipid synthesis, while D-serine is a co-agonist required for normal neurotransmission through N-methyl-D-aspartate receptors. Through its roles transporting L-serine across the blood-brain barrier and regulating synaptic D-serine levels, SLC1A4 helps establish and maintain brain health across the lifespan. This review examines the role of SLC1A4 in neurodevelopment and neurodegeneration and assesses the therapeutic potential of serine supplementation to treat neurodevelopmental symptoms associated with mutations in SLC1A4, as well as schizophrenia, depression, traumatic brain injury, and Alzheimer's and Parkinson's diseases.
    Keywords:  Alzheimer’s disease; SLC1A4; SPATCCM; neurodegeneration; neurodevelopment; serine homeostasis; solute carrier family 1 member 4 (SLC1A4) gene
    DOI:  https://doi.org/10.3390/ijms26052104
  5. Sci Transl Med. 2025 Mar 12. 17(789): eadn2635
      Traumatic brain injury (TBI) rapidly triggers proinflammatory activation of microglia, contributing to secondary brain damage post-TBI. Although the governing role of energy metabolism in shaping the inflammatory phenotype and function of immune cells has been increasingly recognized, the specific alterations in microglial bioenergetics post-TBI remain poorly understood. Itaconate, a metabolite produced by the enzyme aconitate decarboxylase 1 [IRG1; encoded by immune responsive gene 1 (Irg1)], is a pivotal metabolic regulator in immune cells, particularly in macrophages. Because microglia are macrophages of the brain parenchyma, the IRG1/itaconate pathway likely modulates microglial inflammatory responses. In this study, we explored the role of the IRG1/itaconate pathway in regulating microglial bioenergetics and inflammatory activation post-TBI using a mouse controlled cortical impact (CCI) model. We isolated microglia before and 4 and 12 hours after TBI and observed a swift but transient increase in glycolysis coupled with a prolonged disruption of mitochondrial metabolism after injury. Despite an up-regulation of Irg1 expression, itaconate in microglia declined after TBI. Microglia-specific Irg1 gene knockout (Irg1-Mi-KO) exacerbated metabolic changes, intensified proinflammatory activation and neurodegeneration, and worsened certain long-term neurological deficits. Supplementation with 4-octyl itaconate (OI) reinstated the use and oxidative metabolism of glucose, glutamine, and fatty acid, thereby enhancing microglial bioenergetics post-TBI. OI supplementation also attenuated proinflammatory activation and neurodegeneration and improved long-term neurological outcomes. These results suggest that therapeutically targeting the itaconate pathway could improve microglial energy metabolism and neurological outcomes after TBI.
    DOI:  https://doi.org/10.1126/scitranslmed.adn2635
  6. J Cereb Blood Flow Metab. 2025 Mar 13. 271678X251325805
      Demyelination is a common feature of neuroinflammatory and degenerative diseases of the central nervous system (CNS), such as multiple sclerosis (MS). It is often linked to disruptions in intercellular communication, bioenergetics and metabolic balance accompanied by mitochondrial dysfunction in cells such as oligodendrocytes, neurons, astrocytes, and microglia. Although current MS treatments focus on immunomodulation, they fail to stop or reverse demyelination's progression. Recent advancements highlight intercellular mitochondrial exchange as a promising therapeutic target, with potential to restore metabolic homeostasis, enhance immunomodulation, and promote myelin repair. With this review we will provide insights into the CNS intercellular metabolic decoupling, focusing on the role of mitochondrial dysfunction in neuroinflammatory demyelinating conditions. We will then discuss emerging cell-free biotherapies exploring the therapeutic potential of transferring mitochondria via biogenic carriers like extracellular vesicles (EVs) or synthetic liposomes, aimed at enhancing mitochondrial function and metabolic support for CNS and myelin repair. Lastly, we address the key challenges for the clinical application of these strategies and discuss future directions to optimize mitochondrial biotherapies. The advancements in this field hold promise for restoring metabolic homeostasis, and enhancing myelin repair, potentially transforming the therapeutic landscape for neuroinflammatory and demyelinating diseases.
    Keywords:  Extracellular vesicles (EVs); cell-free biotherapy; demyelination; mitochondria transfer; neuroinflammation
    DOI:  https://doi.org/10.1177/0271678X251325805
  7. Acta Pharmacol Sin. 2025 Mar 11.
      The acute phase of ischemic stroke is marked by a surge in matrix metalloproteinase-9 (MMP-9) activity. While integral to natural repair processes, MMP-9 exacerbates injury by breaking down the blood-brain barrier (BBB) and promoting edema and inflammation. MMP-9 is predominantly secreted by inflammatory cells such as neutrophils, macrophages and microglia soon after stroke onset. In this study we investigated the effects of MMP-9 inhibition via SB-3CT on astrocytic lipid metabolism, and its potential to enhance neuronal survival and recovery following ischemic stroke. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min, mice then were injected with SB-3CT (25 mg/kg, i.v.). On D3 post tMCAO, neurological outcomes were assessed, and whole brains were collected for analysis. Lipidomic analysis of brain tissue showed that SB-3CT treatment significantly restrained astrocytic cholesterol metabolism by modulating the sphingolipid and glycerophospholipid pathways. Specifically, SB-3CT reduced ceramide accumulation and promoted an increase in neuroprotective hexosylceramides, leading to enhanced neuronal survival and synaptic integrity. In addition, SB-3CT treatment reduced astrocytic and microglial reactivity, thereby mitigating neuroinflammation. In order to optimize the timing and dosage of MMP-9 inhibition to maximize the therapeutic efficacy, tMCAO mice were given three injections of SB-3CT on D0, D2 and D4 within 7 days after modeling. We found that prolonged MMP-9 inhibition alleviated astrogliosis, concurrently impaired neurological recovery and inhibited angiogenesis. These results demonstrate the critical role of lipid metabolism in MMP-9-mediated brain injury and the potential of SB-3CT as a therapeutic strategy for ischemic stroke by targeting astrocytic lipid metabolism.
    Keywords:  MMP-9; SB-3CT; astrocytic lipid metabolism; ischemic stroke; lipidomic analysis; sphingolipid metabolism
    DOI:  https://doi.org/10.1038/s41401-025-01505-x
  8. JIMD Rep. 2025 Mar;66(2): e12464
      This report details the case of an infant with confirmed propionic acidemia who presented with progressive neurological deterioration and recurrent episodes of metabolic decompensation with elevated lactate levels, but without hyperammonemia. The child's clinical course and neuroradiological findings increasingly deviated from the known clinical and neuroradiological spectrum of propionic acidemia. A rapid trio exome sequencing identified SLC19A3-related thiamine metabolism dysfunction syndrome 2 as a second genetic disease. The pathomechanisms of both diseases synergize in the impairment of brain energy metabolism, and the associated clinical phenotypes partially overlap, which explains the severe and atypical course of propionic acidemia in the reported case.
    Keywords:  SLC19A3; biotin‐thiamine‐responsive basal ganglia disease; hyperammonemia; lactate acidosis; neurological deterioration; propionic acidemia; propionic aciduria; thiamine metabolism dysfunction syndrome 2
    DOI:  https://doi.org/10.1002/jmd2.12464
  9. Ageing Res Rev. 2025 Mar 10. pii: S1568-1637(25)00072-8. [Epub ahead of print] 102726
      A key molecule in cellular metabolism, citrate is essential for lipid biosynthesis, energy production, and epigenetic control. The etiology of Alzheimer's disease (AD), a progressive neurodegenerative illness marked by memory loss and cognitive decline, may be linked to dysregulated citrate transport, according to recent research. Citrate transporters, which help citrate flow both inside and outside of cells, are becoming more and more recognized as possible participants in the molecular processes underlying AD. Citrate synthase (CS), a key enzyme in the tricarboxylic acid (TCA) cycle, supports mitochondrial function and neurotransmitter synthesis, particularly acetylcholine (ACh), essential for cognition. Changes in CS activity affect citrate availability, influencing energy metabolism and neurotransmitter production. Choline, a precursor for ACh, is crucial for neuronal function. Lipid metabolism, oxidative stress reactions, and mitochondrial function can all be affected by aberrant citrate transport, and these changes are linked to dementia. Furthermore, the two main pathogenic characteristics of AD, tau hyperphosphorylation and amyloid-beta (Aβ) aggregation, may be impacted by disturbances in citrate homeostasis. The goal of this review is to clarify the complex function of citrate transporters in AD and provide insight into how they contribute to the development and course of the illness. We aim to provide an in-depth idea of which particular transporters are dysregulated in AD and clarify the functional implications of these dysregulated transporters in brain cells. To reduce neurodegenerative processes and restore metabolic equilibrium, we have also discussed the therapeutic potential of regulating citrate transport. Gaining insight into the relationship between citrate transporters and the pathogenesis of AD may help identify new indicators for early detection and creative targets for treatment. This study offers hope for more potent ways to fight this debilitating illness and is a crucial step in understanding the metabolic foundations of AD.
    Keywords:  Alzheimer’s disease; acetylcholine; aging; citrate synthase; citrate transporter; therapeutic target
    DOI:  https://doi.org/10.1016/j.arr.2025.102726
  10. J Cereb Blood Flow Metab. 2025 Mar 12. 271678X251325039
      Extracellular vesicles (EVs) convey complex signals between cells that can be used to promote neuronal plasticity and neurological recovery in brain disease models. These EV signals are multimodal and context-dependent, making them unique therapeutic principles. This review analyzes how EVs released from various cell sources control neuronal metabolic function, neuronal survival and plasticity. Preferential sites of EV communication in the brain are interfaces between pre- and postsynaptic neurons at synapses, between astrocytes and neurons at plasma membranes or tripartite synapses, between oligodendrocytes and neurons at axons, between microglial cells/macrophages and neurons, and between cerebral microvascular cells and neurons. At each of these interfaces, EVs support mitochondrial function and cell metabolism under physiological conditions and orchestrate neuronal survival and plasticity in response to brain injury. In the injured brain, the promotion of neuronal survival and plasticity by EVs is tightly linked with EV actions on mitochondrial function, cell metabolism, oxidative stress and immune responses. Via the stabilization of cell metabolism and immune balance, neuronal plasticity responses are activated and functional neurological recovery is induced. As such, EV lay the ground for neuronal plasticity.
    Keywords:  Anti-inflammation; energy metabolism; exosome; immune modulation; mitochondria; oxidative stress; synaptic plasticity
    DOI:  https://doi.org/10.1177/0271678X251325039
  11. Commun Biol. 2025 Mar 11. 8(1): 410
      Methylmalonic aciduria (MMA) is an inborn error of metabolism resulting in loss of function of the enzyme methylmalonyl-CoA mutase (MMUT). Despite acute and persistent neurological symptoms, the pathogenesis of MMA in the central nervous system is poorly understood, which has contributed to a dearth of effective brain specific treatments. Here we utilised patient-derived induced pluripotent stem cells and in vitro differentiation to generate a human neuronal model of MMA. We reveal strong evidence of mitochondrial dysfunction caused by deficiency of MMUT in patient neurons. By employing patch-clamp electrophysiology, targeted metabolomics, and bulk transcriptomics, we expose an altered state of excitability, which is exacerbated by application of dimethyl-2-oxoglutarate, and we suggest may be connected to metabolic rewiring. Our work provides first evidence of mitochondrial driven neuronal dysfunction in MMA, which through our comprehensive characterisation of this paradigmatic model, enables first steps to identifying effective therapies.
    DOI:  https://doi.org/10.1038/s42003-025-07828-z
  12. J Lipid Res. 2025 Mar 10. pii: S0022-2275(25)00033-1. [Epub ahead of print] 100773
      Mammalian cells synthesize hundreds of different variants of their prominent membrane lipid phosphatidylcholine (PC), all differing in the side chain composition. This batch is constantly remodeled by the Lands cycle, a metabolic pathway replacing one chain at the time. Using the alkyne lipid lyso-phosphatidylpropargylcholine (LpPC), a precursor and intermediate in PC synthesis and remodeling, we study both processes in brain endothelial bEND3 cells. A novel method for multiplexed sample analysis by mass spectrometry is developed that offers high throughput and molecular species resolution of the propargyl-labeled PC lipids. Their time resolved profiles and kinetic parameters of metabolism demonstrate the plasticity of the PC pool and the acute handling of lipid influx in endothelial cells differs from that in hepatocytes. Side chain remodeling as a form of lipid cycling adapts the PC pool to the cells need and maintains lipid homeostasis. We estimate that endothelial cells possess the theoretical capacity to remodel up to 99% of their PC pool within 3.5 h using the Lands cycle. However, PC species are not subjected stochastically to this remodeling pathway as different species containing duplets of saturated, omega-3 and omega-6 side chains show different decay kinetics. Our findings emphasize the essential function of Lands cycling for monitoring and adapting the side chain composition of PC in endothelial cells.
    Keywords:  alkyne tracer; click; lipid cycling; lipidomics; lysophosphatdiylcholine; lysophospholipids; phospholipase; propargyl-PC
    DOI:  https://doi.org/10.1016/j.jlr.2025.100773
  13. bioRxiv. 2025 Mar 01. pii: 2025.02.25.640178. [Epub ahead of print]
    Alzheimer’s Disease Metabolomics Consortium
      Alzheimer's disease (AD) risk and progression are significantly influenced by APOE genotype with APOE4 increasing and APOE2 decreasing susceptibility compared to APOE3. While the effect of those genotypes was extensively studied on blood metabolome, less is known about their impact in the brain. Here we investigated the impacts of APOE genotypes and aging on brain metabolic profiles across the lifespan, using human APOE-targeted replacement mice. Biocrates P180 targeted metabolomics platform was used to measure a broad range of metabolites probing various metabolic processes. In all genotypes investigated we report changes in acylcarnitines, biogenic amines, amino acids, phospholipids and sphingomyelins during aging. The decreased ratio of medium to long-chain acylcarnitine suggests a reduced level of fatty acid β-oxidation and thus the possibility of mitochondrial dysfunction as these animals age. Additionally, aging APOE2/2 mice had altered branch-chain amino acids (BCAA) profile and increased their downstream metabolite C5 acylcarnitine, indicating increased branched-chain amino acid utilization in TCA cycle and better energetic profile endowed by this protective genotype. We compared these results with human dorsolateral prefrontal cortex metabolomic data from the Religious Orders Study/Memory and Aging Project, and we found that the carriers of APOE2/3 genotype had lower markers of impaired BCAA katabolism, including tiglyl carnitine, methylmalonate and 3-methylglutaconate. In summary, these results suggest a potential involvement of the APOE2 genotype in BCAA utilization in the TCA cycle and nominate these humanized APOE mouse models for further study of APOE in AD, brain aging, and brain BCAA utilization for energy. We have previously shown lower plasma BCAA to be associated with incident dementia, and their higher levels in brain with AD pathology and cognitive impairment. Those findings together with our current results could potentially explain the AD-protective effect of APOE2 genotype by enabling higher utilization of BCAA for energy during the decline of fatty acid β-oxidation.
    DOI:  https://doi.org/10.1101/2025.02.25.640178
  14. Cell Chem Biol. 2025 Feb 28. pii: S2451-9456(25)00035-2. [Epub ahead of print]
      Lysosomes are the central degradative organelle of mammalian cells and have emerged as major intersections of cellular metabolite flux. Macromolecules derived from dietary and intracellular sources are delivered to the acidic lysosomal lumen where they are subjected to degradation by acid hydrolases. Lipids derived from lipoproteins, autophagy cargo, or autophagosomal membranes themselves constitute major lysosomal substrates. Dysregulation of lysosomal lipid processing, defective export of lipid catabolites, and lysosomal membrane permeabilization underly diseases ranging from neurodegeneration to metabolic syndromes and lysosomal storage disorders. Mammalian cells are equipped with sophisticated homeostatic control mechanisms that protect the lysosomal limiting membrane from excessive damage, prevent the spillage of luminal hydrolases into the cytoplasm, and preserve the lysosomal membrane composition in the face of constant fusion with heterotypic organelles such as endosomes and autophagosomes. In this review we discuss the molecular mechanisms that govern lysosomal lipid homeostasis and, thereby, lysosome function in health and disease.
    Keywords:  contact sites; lipids; lysosomes; membrane homeostasis; phosphoinositides; signalling
    DOI:  https://doi.org/10.1016/j.chembiol.2025.02.003
  15. Dev Neurosci. 2025 Mar 11. 1-22
       BACKGROUND: Branched chain amino acid (BCAA) metabolism plays roles in various cellular processes, including energy homeostasis, anabolic signaling, and production of glutamate, the primary excitatory neurotransmitter. Emerging evidence also suggests BCAA metabolism has relationships to inflammatory and hypoxic cellular responses. Recent work in adult and adolescent clinical populations has suggested that BCAA dietary supplementation may improve outcomes associated with traumatic brain injury (TBI). Given these links, examining the putative mechanisms and potential therapeutic applications of modulating dietary BCAA content in the context of inflammatory and hypoxic developmental brain injury may reveal mechanisms for intervention in affected infants.
    SUMMARY: Inflammatory and hypoxic brain injury influence the dynamics of BCAA metabolism in the fetal brain. Inflammatory insults to the developing brain may increase BCAA catabolism downstream of the branched chain ketoacids (BCKAs). The effect of altered BCAA metabolism on the pathophysiology of inflammatory developmental brain injury is currently unclear but may play a role in microglial response. Hypoxic brain injury seems to increase BCAA concentration in fetal brain, possibly because of re-amination of BCKAs to the parent BCAAs, or via increased protein breakdown during hypoxia.
    KEY MESSAGES: The apparent relationship between aberrant BCAA metabolism and inflammation or hypoxia warrants consideration of BCAA supplementation or restriction as a strategy for attenuating developmental brain injury that is associated with these pathologic events. This approach could entail alterations of maternal diet during pregnancy or the feeding of infant formula that is fortified with or restricted in BCAA. These types of interventions have been safely and effectively employed in cases of inborn errors of BCAA metabolism, suggesting feasibility in infant populations. Both in vitro and pre-clinical work is necessary to elucidate how BCAA supplementation or restriction may affect the sequelae of inflammatory and hypoxic developmental brain injury.
    DOI:  https://doi.org/10.1159/000545099
  16. Cell Death Dis. 2025 Mar 12. 16(1): 173
      Mohr-Tranebjaerg syndrome (MTS) is a rare X-linked recessive neurodegenerative disorder caused by mutations in the Translocase of Inner Mitochondrial Membrane 8A (TIMM8A) gene, which encodes TIMM8a, a protein localized to the mitochondrial intermembrane space (IMS). The pathophysiology of MTS remains poorly understood. To investigate the molecular mechanisms underlying MTS, we established induced pluripotent stem cells (iPSCs) from a male MTS patient carrying a novel TIMM8A mutation (c.225-229del, p.Q75fs95*), referred to as MTS-iPSCs. To generate an isogenic control, we introduced the same mutation into healthy control iPSCs (CTRL-iPSCs) using the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRISPR/Cas9), resulting in mutant iPSCs (MUT-iPSCs). We differentiated the three iPSC lines into neurons and evaluated their mitochondrial function and neuronal development. Both MTS- and MUT-iPSCs exhibited impaired neuronal differentiation, characterized by smaller somata, fewer branches, and shorter neurites in iPSC-derived neurons. Additionally, these neurons showed increased susceptibility to apoptosis under stress conditions, as indicated by elevated levels of cytochrome c and cleaved caspase-3. Mitochondrial function analysis revealed reduced protein levels and activity of complex IV, diminished ATP synthesis, and increased reactive oxygen species (ROS) generation in MTS- and MUT-neurons. Furthermore, transmission electron microscopy revealed mitochondrial fragmentation in MTS-neurons. RNA sequencing identified differentially expressed genes (DEGs) involved in axonogenesis, synaptic activity, and apoptosis-related pathways. Among these DEGs, coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2), which encodes a mitochondrial IMS protein essential for mitochondrial homeostasis, was significantly downregulated in MTS-neurons. Western blot analysis confirmed decreased CHCHD2 protein levels in both MTS- and MUT-neurons. Overexpression of CHCHD2 rescued mitochondrial dysfunction and promoted neurite elongation in MTS-neurons, suggesting that CHCHD2 acts as a downstream effector of TIMM8a in the pathogenesis of MTS. In summary, loss-of-function of TIMM8a leads to a downstream reduction in CHCHD2 levels, collectively impairing neurogenesis by disrupting mitochondrial homeostasis. TIMM8a mutation (p.Q75fs95*) leads to mitochondrial dysfunction and neuronal defects in iPSC-derived neurons from patient with Mohr-Tranebjaerg syndrome, which are rescued by overexpression of CHCHD2. TIMM8a translocase of inner mitochondrial membrane 8a, CHCHD2 coiled-coil-helix-coiled-coil-helix domain-containing protein 2, MTS Mohr-Tranebjaerg syndrome, I mitochondrial complex I, II mitochondrial complex II, III mitochondrial complex III, IV mitochondrial complex IV, Q coenzyme Q10, Cyt c cytochrome c.
    DOI:  https://doi.org/10.1038/s41419-025-07472-9
  17. Proc Natl Acad Sci U S A. 2025 Mar 11. 122(10): e2416433122
      Understanding the key drivers of brain aging is essential for effective prevention and treatment of neurodegenerative diseases. Here, we integrate human brain and physiological data to investigate underlying mechanisms. Functional MRI analyses across four large datasets (totaling 19,300 participants) show that brain networks not only destabilize throughout the lifetime but do so along a nonlinear trajectory, with consistent temporal "landmarks" of brain aging starting in midlife (40s). Comparison of metabolic, vascular, and inflammatory biomarkers implicate dysregulated glucose homeostasis as the driver mechanism for these transitions. Correlation between the brain's regionally heterogeneous patterns of aging and gene expression further supports these findings, selectively implicating GLUT4 (insulin-dependent glucose transporter) and APOE (lipid transport protein). Notably, MCT2 (a neuronal, but not glial, ketone transporter) emerges as a potential counteracting factor by facilitating neurons' energy uptake independently of insulin. Consistent with these results, an interventional study of 101 participants shows that ketones exhibit robust effects in restabilizing brain networks, maximized from ages 40 to 60, suggesting a midlife "critical window" for early metabolic intervention.
    Keywords:  aging; brain; fMRI; insulin; neuron
    DOI:  https://doi.org/10.1073/pnas.2416433122
  18. Ann Neurol. 2025 Mar 14.
       OBJECTIVE: The goal was to examine the effect of sociodemographic variables, Alzheimer's disease (AD) clinical stages and pathology on brain metabolism in Down syndrome (DS).
    METHODS: We included 71 euploid healthy controls (HC) and 105 adults with DS (67 asymptomatic, 12 prodromal, and 26 with dementia) from the Down-Alzheimer Barcelona Neuroimaging Initiative. Participants underwent [18F]fluorodeoxyglucose positron emission tomography, 3 Tmagnetic resonance imaging, and lumbar puncture to measure cerebrospinal fluid (CSF) biomarkers (ratio beween amyloid β peptide 42 and 40, phosphorylated tau 181, and neurofilament light chain [NfL]). Voxel-wise analyses in SPM12 examined the effects of age, sex, intellectual disability, Alzheimer's clinical stage, and CSF biomarkers on brain metabolism.
    RESULTS: In HC, brain metabolism decreased with age primarily in the frontal lobe. By contrast, a more distributed pattern of metabolic loss was observed in DS with age, predominating in temporoparietal regions. Compared to asymptomatic DS participants, those at the prodromal stage exhibited medial parietal hypometabolism, which later extended to other temporoparietal and frontal regions at the dementia stage. In asymptomatic individuals, we observed a widespread hypometabolism compared to HC, mainly in medial frontal and parietal regions. All CSF biomarkers were closely associated with hypometabolism in regions affected by the disease, with the strongest association observed for NfL in medial parietal structures.
    INTERPRETATION: The brain metabolic decline in DS with age reflects Alzheimer's pathological processes and involves temporoparietal regions in a similar pattern to that found in other forms of AD. Hypometabolism is more tightly related to CSF NfL levels than to core AD biomarkers. ANN NEUROL 2025.
    DOI:  https://doi.org/10.1002/ana.27226
  19. Heliyon. 2025 Feb 28. 11(4): e42735
      Microglia, the immune cells of the central nervous system (CNS), play key roles in neurogenesis, myelination, synaptic transmission, immune surveillance, and neuroinflammation. Inflammatory responses in microglia can lead to oxidative stress and neurodegeneration, contributing to diseases like Parkinson's and Alzheimer's. The enzyme glucose-6-phosphate dehydrogenase (G6PD) is essential for producing nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), which neutralizes oxidative stress. G6PD deficiency has been linked to several disorders, including neurological conditions. Our study shows that G6PD deficiency in microglia reduces NADPH levels, disrupting redox balance and lysosomal function. To address this, we explored alternative metabolic pathways by targeting enzymes like isocitrate dehydrogenase 1 (IDH1) and malic enzyme 1 (ME1), both crucial for NADPH production. Supplementing metabolites such as citric and malic acid improved NADPH levels, while small molecules like dieckol and resveratrol enhanced IDH1 and ME1 expression. The combination of these approaches restored redox homeostasis and lysosomal function, offering potential therapeutic strategies for G6PD deficiency.
    Keywords:  G6PD deficiency; Metabolites; Oxidative stress; Phytochemicals; Therapeutics
    DOI:  https://doi.org/10.1016/j.heliyon.2025.e42735
  20. Nat Commun. 2025 Mar 10. 16(1): 2353
      Proper neuronal development, function and survival critically rely on mitochondrial functions. Yet, how developing neurons ensure spatiotemporal distribution of mitochondria during expansion of their dendritic arbor remained unclear. We demonstrate the existence of effective mitochondrial positioning and tethering mechanisms during dendritic arborization. We identify rhotekin2 as outer mitochondrial membrane-associated protein that tethers mitochondria to dendritic branch induction sites. Rhotekin2-deficient neurons failed to correctly position mitochondria at these sites and also lacked the reduction in mitochondrial dynamics observed at wild-type nascent dendritic branch sites. Rhotekin2 hereby serves as important anchor for the plasma membrane-binding and membrane curvature-inducing F-BAR protein syndapin I (PACSIN1). Consistently, syndapin I loss-of-function phenocopied the rhotekin2 loss-of-function phenotype in mitochondrial positioning at dendritic branch induction sites. The finding that rhotekin2 deficiency impaired dendritic branch induction and that a syndapin binding-deficient rhotekin2 mutant failed to rescue this phenotype highlighted the physiological importance of rhotekin2 functions for neuronal network formation.
    DOI:  https://doi.org/10.1038/s41467-025-57399-0
  21. Brain Behav Immun. 2025 Mar 09. pii: S0889-1591(25)00102-3. [Epub ahead of print]127 110-111
      
    Keywords:  Cognition; Kynurenic acid; Kynurenine; Mood disorders; Quinolinic acid; Schizophrenia
    DOI:  https://doi.org/10.1016/j.bbi.2025.03.017
  22. Sci Rep. 2025 Mar 08. 15(1): 8127
      Despite extensive research on neuroimaging correlates of human brain aging, there is little mechanistic insight into how they are linked to loss of brain function. Previous studies on the role of cerebral blood flow (CBF) in supporting brain function have focused on delivery of nutrients, namely oxygen and glucose. However, CBF is required also to clear the byproducts of energy metabolism, namely CO2 and protons. With the goal of determining whether age-associated reduction in regional CBF may lead to abnormal brain partial pressure of carbon dioxide (pCO2) and pH levels that are sufficient to alter brain activity and cognitive function, we applied a recently introduced homeostatic modeling of nutrients and waste products to human neuroimaging PET data acquired in young and older adults (Goyal et al. in Cell Metab 26(2):353-360, 2017). Our results demonstrate that age-associated reductions in CBF, in the presence of virtually unaltered oxygen consumption rates, show concurrent regional age-associated increases in pCO2 and associated pH acid-shifts of possible functional relevance. We conclude that the implications of altered vascular health in older adults needs to be revisited in light of its central role in removing waste products from energy metabolism at resting state and, in future studies, during external stimulations.
    DOI:  https://doi.org/10.1038/s41598-025-90342-3