bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2026–06–28
39 papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Metabolic Brain Disorders: Prodromes, Symptoms, and Syndromes.
  2. Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.
  3. Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration.
  4. A combination of ketones and NAD+ precursor preserves white matter integrity in mild cognitive impairment.
  5. Quantitative determination of longitudinal CNS cholesterol loss during myelin damage and repair.
  6. Ceramide-rich extracellular vesicles as pathogenic biomarkers in traumatic brain injury.
  7. Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
  8. Plasma Membrane Remodeling During Microglial Activation: A Hypothesis Linking Microglial Shape and Lipid Droplet Formation.
  9. Metabolic crosstalk in the ageing brain: astrocyte-neuron coupling as a target for homeostatic restoration and therapy.
  10. Metabolic Assessment in Human Pluripotent Stem Cell-Derived Cerebral Organoids Using HR-MAS NMR Spectroscopy.
  11. Mitochondrial Dysfunction in Autism and Attention-Deficit/Hyperactivity Disorder: Evidence from Genetic, Biochemical, and Neuroimaging Approaches.
  12. Influence of Ketogenic Diet Lipid Composition on Anxiety-Like Behavior and Neurometabolic Profile in Healthy Rats.
  13. TOMM40 '523' genotype induces sex- and tissue- specific differences in cholesterol and triglyceride levels in an APOE-TOMM40 humanized mouse model.
  14. SIRT3/AARS2 regulates SOD2 lactylation to determine neuronal fate in TBI.
  15. EXPRESS: Intercellular Mitochondrial Transfer in Ischemic Stroke: Emerging Roles of Microglia.
  16. Phospholipid Remodeling as a Key Regulator of Ferroptosis.
  17. Compensatory Intercellular Mitochondrial Transfer Improves Bioenergetics in P301L Tau-Affected Neuronal Cells.
  18. Extracellular vesicles (EVs) in neurodevelopment: The emerging role of lipids.
  19. A Subset of Caveolin-1 Interacts with a Fraction of Acyl-CoA:Cholesterol Acyltransferase 1 (ACAT1/SOAT1) at an Endoplasmic Reticulum Subdomain to Attenuate Cholesteryl Ester Biosynthesis.
  20. Metabolism-weighted brain connectome reveals synaptic integration and vulnerability to neurodegeneration.
  21. Norepinephrine regulates hippocampal mitochondrial biogenesis via β2-adrenergic receptor signaling and PGC-1α.
  22. 1-Deoxysphingolipids Require Very-Long-Chain Ceramide Synthesis to Induce ER Stress and Cytotoxicity.
  23. Bioenergetic failure in diabetic peripheral neuropathy: from glucotoxicity to multidimensional metabolic imbalance.
  24. ACLY alleviates cerebral ischemia/reperfusion injury by reducing oxidative stress and enhancing mitochondrial function via histone acetylation.
  25. Investigating the relationship between ATP synthase and the TCA cycle by crosslinking mass spectrometry.
  26. [ZEB2 promotes glioblastoma progression by reprogramming lipid metabolism through the CYLD/FASN axis].
  27. EXPRESS: FDG: Five Decades of Transforming Molecular Imaging and Still Illuminating the Brain.
  28. Mitochondrial DNA heteroplasmy drives cortical neuronal disturbances in human organoids harbouring the common m.3243A>G mutation.
  29. Case Report of Dual Variants in SLC1A4 and APOE: A Possible Link Between Amino Acid and Lipid Metabolism.
  30. Oral GLP-1 receptor agonist promotes astrocyte-neuron lactate and lipid transfer with neuroprotective effects.
  31. Regulation of oligodendrocyte metabolism and myelination by acetyl-L-carnitine in a mouse model of post-weaning social isolation.
  32. DRP1 mutations associated with EMPF1 encephalopathy perturb the transcriptional profile and maturation of cortical neurons.
  33. Astrocyte subtype-specific expression of the sodium-coupled citrate transporter SLC13A5 and citrate metabolism genes across Alzheimer's disease pseudoprogression: a single-nucleus RNA sequencing analysis of the human middle temporal gyrus.
  34. Sphingolipids associated research in Alzheimer's disease: an explored trends analysis.
  35. Continuous Pyruvate Supplementation Enhances Neuroprotective Resilience Against Kainate-Induced Status Epilepticus Through Metabolic Preconditioning.
  36. Statin-Induced Coenzyme Q Deficiency Induces Metabolic Reprogramming in Astrocytes.
  37. Altered brain glucose metabolism and connectivity in young adults with obstructive sleep apnea.
  38. Research Progress on Anti-Inflammatory Adipokine SFRP5-Mediated Lipid Metabolism and Its Potential Role in Neural Development.
  39. Multimodal atlas of single neuron metabolic electrophysiological coupling uncovers circadian rewiring.
  1. Int J Mol Sci. 2026 Jun 08. pii: 5190. [Epub ahead of print]27(12):
    Metabolic Brain Disorders: Prodromes, Symptoms, and Syndromes.
    Janusz Wiesław Błaszczyk.
      Life is a self-organizing and self-sustaining process that involves energy transformation, primarily regulated by the brain. The brain's main structure consists of terminally differentiated, postmitotic, non-replaceable cells, whose proper functioning and longevity depend solely on glucose-based energy metabolism. Glucose serves as the primary substrate for cellular respiration and anaerobic processes, which are essential for maintaining proper neuronal function, homeostasis, and cell repair. Research indicates that brain aging and neurodegenerative changes result from an age-related decline in glucose metabolism, largely due to a deficiency in nicotinamide adenine dinucleotide (NAD). This deficiency is particularly harmful to brain structures that contain neurons with the highest energy demands. The first signs of brain aging typically appear in the hypothalamus, as well as in the GABAergic and glutamatergic structures of the cerebral cortex and subcortical nuclei. Early symptoms of senile brain changes often manifest as systemic metabolic disorders like insulin resistance and type 2 diabetes. These are accompanied by alterations in brain energy metabolism, leading to neurological and psychiatric disorders that correspond to the affected brain regions. Over time, these changes gradually impact the brain's regions with the highest energy consumption. Current clinical studies suggest that early supplementation with NAD precursors may help slow the aging and neurodegeneration processes. However, this protective therapy appears to be less effective once the disease is fully developed.
    Keywords:  aging; brain; energy metabolism; information metabolism; neurodegenerative disorders
    DOI:  https://doi.org/10.3390/ijms27125190
  2. Biomolecules. 2026 Jun 09. pii: 842. [Epub ahead of print]16(6):
    Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.
    Giampaolo Morciano, Ruggiero Gorgoglione, Vito Porcelli, Amer Ahmed, Pasquale Scarcia, Angelo Vozza, Francesco Massimo Lasorsa, Giuseppe Fiermonte, Luigi Palmieri.
      Neurodegenerative diseases are increasingly recognized as disorders of due to disrupted cellular homeostasis, with mitochondrial dysfunction playing a central and early role in disease progression. This review explores the intricate relationship between mitochondrial function and neuronal health, emphasizing the pivotal role of the solute carrier family 25 (SLC25) transporters in maintaining mitochondrial homeostasis. We provide a comprehensive overview of mitochondrial biology in the central nervous system, including energy metabolism, calcium signaling, redox regulation, organelle interactions and mitochondrial dynamics. We delve into the SLC25 transporter family, highlighting their transport mechanisms, substrates and roles in brain metabolism and neuroprotection. SLC25 on one hand and proteins involved in the regulation of mitochondrial morphology and calcium signaling on the other hand are two sides of the same coin influencing each other. A critical analysis follows, examining how mitochondrial dysfunction contributes to mitochondrial abnormalities in a spectrum of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, ALS and rare mitochondrial encephalopathies. Finally, we assess emerging therapeutic strategies targeting mitochondrial pathways and SLC25 function, including metabolic modulation, gene therapies, antioxidants and pharmacological agents. This review underscores mitochondria and the SLC25 transporters as promising targets for disease-modifying interventions in neurodegeneration and raises key questions about the causality between mitochondrial failure and neuronal death.
    Keywords:  SLC25 carriers; metabolism; mitochondrial dynamics; neurodegeneration
    DOI:  https://doi.org/10.3390/biom16060842
  3. Int J Mol Sci. 2026 Jun 20. pii: 5580. [Epub ahead of print]27(12):
    Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration.
    Wei Shao, Kai Wang, Yongchao Liu, Haojia Zhang, Zijin Sun, Rui Zhou.
      The mammalian brain fundamentally relies on precise lipid homeostasis to maintain structural integrity and complex neural signaling. Emerging evidence positions lipid metabolism reprogramming not merely as a secondary pathological byproduct but as a core initiating driver of age-related neurodegenerative diseases. This review systematically evaluates the mechanisms of cerebral lipid dyshomeostasis during brain aging, highlighting glial cells as the central mediators of this pathological cascade. We comprehensively dissect the age-associated "lipid drift", emphasizing apolipoprotein E (APOE)-induced cholesterol transport defects and lipid raft pathology, the accumulation of lipid droplets that triggers microglial metabolic stress (LDAMs), and ceramide-driven neuronal apoptosis coupled with the exosome-mediated propagation of pathogenic proteins. Furthermore, we map these aberrant lipid networks to specific pathological signatures in Alzheimer's, Parkinson's, and demyelinating diseases. Finally, we critically evaluate promising therapeutic interventions, including nutritional strategies, LXR/RXR agonists, and nanotechnology-enabled delivery systems designed to bypass the blood-brain barrier. By integrating high-throughput lipidomics for early diagnostic biomarker discovery, we underscore the translational imperative of restoring cerebral lipid homeostasis as a disease-modifying strategy for neurodegeneration.
    Keywords:  apolipoprotein E (APOE); brain aging; cerebral lipid homeostasis; lipid metabolism reprogramming; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/ijms27125580
  4. Alzheimers Dement (N Y). 2026 Apr-Jun;12(2):12(2): e70278
    A combination of ketones and NAD+ precursor preserves white matter integrity in mild cognitive impairment.
    Maggie Roy, Mélanie Fortier, Valérie St-Pierre, Marie-Christine Morin, Arnaud Boré, Manon Edde, Camille Vandenberghe, Karine Groulx, Étienne Croteau, Gabriel Richard, Stanislas Thoumyre, Tamas Fulop, Christian Bocti, François Rheault, Bernard Cuenoud, Maxime Descoteaux, Stephen C Cunnane.
       INTRODUCTION: Brain glucose metabolism declines and myelin deteriorates as Alzheimer's disease (AD) develops. Adequate energy supply to white matter (WM) is critical to maintain myelin integrity and axonal function. An exogenous source of ketones bypasses the glucose‑specific brain energy deficit and improves cognitive outcomes in mild cognitive impairment (MCI). The BREAK-AD (BRain Energy Activation with Ketones in AD) trial tested a ketone salt and nicotinamide adenine dinucleotide (NAD+) precursor mixture to compensate for reduced brain glucose uptake in MCI.
    METHODS: Participants were randomized to a placebo (n = 15) or active supplement (β-hydroxybutyrate salts + nicotinamide riboside (NR); n = 15). Brain ketone and glucose metabolism (quantified by positron emission tomography [PET]), and cognitive performance were assessed before and at the end of the 6-month intervention. For WM analysis, seven tracts of interest were extracted using diffusion magnetic resonance imaging (MRI), and myelin density measures were derived from magnetization transfer (MT) imaging.
    RESULTS: Total gray matter ketone uptake increased by 2.4-fold (p < 0.001) in the active group, with no change in gray matter glucose uptake in either group. In WM, ketone uptake increased in the active group by 3.1-3.6-fold across all seven tracts of interest (p < 0.001). In the placebo group, myelin density declined by up to 10% in specific regions of the fornix (p = 0.027), with no change in the active group. Improved processing speed was significantly associated with post-intervention change in myelin density (r = -0.39 to -0.59; p = 0.002-0.046) and ketone uptake (r = -0.40 to -0.52; p = 0.010-0.046) in WM tracts. Ketone uptake in specific WM tracts (fornix, uncinate and arcuate fasciculi), as well as in the composite of all tracts of interest was strongly associated with myelin density.
    DISCUSSION: This study shows for the first time that improved myelin density may help explain the positive association between increased WM ketone uptake and improved processing speed in MCI after a ketone salt and NAD+ precursor supplementation.
    Keywords:  Alzheimer's disease; FDG; MTR; NAD; PET imaging; beta‐hydroxybutyrate; brain metabolism; diffusion MRI; ketogenic supplement; ketone; mild cognitive impairment; myelin; processing speed; tractography; white matter
    DOI:  https://doi.org/10.1002/trc2.70278
  5. bioRxiv. 2026 Jun 09. pii: 2026.06.04.729895. [Epub ahead of print]
    Quantitative determination of longitudinal CNS cholesterol loss during myelin damage and repair.
    Disni Dedunupitiya, Eden P Go, Travis Witte, Ashlynn Elliott, Nishama De Silva Mohotti, Jenna M Williams, Hiroko Kobayashi, Rashmi Binjawadagi, Heather Desaire, Meredith D Hartley.
      1. Cholesterol in the central nervous system (CNS) is largely unesterified (>99%) and is predominantly present in the myelin sheath (∼70% of total CNS cholesterol). Damage to the myelin sheath can result in the conversion of cholesterol to cholesterol esters, which occurs in many neurological diseases, including multiple sclerosis. In this study, we measured longitudinal CNS free cholesterol and cholesterol ester levels in a genetic mouse model during postnatal myelination, demyelination, and remyelination using gas chromatography-mass spectrometry with single ion monitoring technique (GC-MS-SIM) and liquid chromatography mass spectrometry (LC-MS). Cholesterol levels in healthy mouse brains increased up to 38 weeks. In contrast, cholesterol in the healthy spinal cord increased during postnatal timepoints, but then remained steady out to 38 weeks. Interestingly, cholesterol esters in the spinal cord were highest at P1 and drastically reduced by P42, while the brain had similar levels during all postnatal time points. During demyelination, both brain and spinal cord cholesterol levels were significantly reduced as compared to healthy mice and failed to return to normal cholesterol levels even during remyelination. Absolute quantification of cholesterol esters during peak demyelination revealed that cholesterol esters comprise 19% of the total cholesterol pool in the brain and 65% in the spinal cord. The lack of recovery in CNS cholesterol levels after demyelination suggests that healthy de novo cholesterol synthesis pathways are disrupted in this model. Absolute quantification of CNS cholesterol is critical for revealing mechanisms of cholesterol regulation during disease and identifying targets for restoring cholesterol to promote myelin repair.
    DOI:  https://doi.org/10.64898/2026.06.04.729895
  6. Acta Neuropathol Commun. 2026 Jun 25.
    Ceramide-rich extracellular vesicles as pathogenic biomarkers in traumatic brain injury.
    Zainuddin Quadri, Zhihui Zhu, Xiaojia Ren, Simone Crivelli, Liping Zhang, P D Kunjadia, Patrick G Sullivan, Bibi B Broome, Tritia R Yamasaki, Erhard Bieberich.
      Extracellular vesicles (EVs) contribute to the damage caused by traumatic brain injury (TBI) and can cross the blood-brain barrier (BBB). We analyzed plasma-derived EVs from human TBI patients to identify factors potentially contributing to TBI pathology. EVs were isolated using membrane affinity (ExoEasy) and size exclusion chromatography, both yielding CD9(+) and CD63(+) EVs with minimal contamination by serum albumin and apolipoprotein. Immunoblotting detected GFAP in TBI but not control EVs, indicating astrocyte-derived EVs crossing the BBB. Proteomic analysis and immunoblotting of EVs from TBI samples identified C-reactive protein and 14-3-3 proteins, which were not detected in control EVs, indicating inflammation associated with TBI. Lipidomic analysis showed ceramide enrichment in TBI EVs, validated by anti-ceramide immunoprecipitation. In a mouse closed head-controlled cortical impact model, brain EVs similarly showed elevated ceramide, confirming ceramide-rich EV release after TBI. Immunocytochemistry localized acid sphingomyelinase (ASM), a ceramide-generating enzyme, to ependymal cilia, suggesting these sites as a potential source of EVs. This was further supported by the detection of ASM in both brain- and plasma-derived EVs, along with the ciliary marker Arl13b in the brain. To assess function, we treated murine neuronal (N2a) cells with TBI EVs. Transcriptomics and STRING analyses revealed enrichment of mitochondrial-associated transcripts. Immunoblotting showed increased p53 and voltage-dependent anion channel 1 (VDAC1), both of which have been implicated in ceramide-induced apoptosis. Seahorse assays showed that TBI EVs suppressed glycolysis, as indicated by reduced ECAR, while mitochondrial respiration (OCR) remained unchanged. LDH assays further indicated that TBI EVs were more neurotoxic than control EVs. Together, these findings identify ceramide-rich EVs as plasma biomarkers of TBI-induced inflammation, potential mediators of neuronal mitochondrial dysfunction, and pharmacological targets to prevent TBI-induced damage.
    Keywords:  Ceramide; Extracellular vesicles; Mitochondria; Traumatic brain injury
    DOI:  https://doi.org/10.1186/s40478-026-02357-0
  7. bioRxiv. 2026 Jun 10. pii: 2026.06.09.730804. [Epub ahead of print]
    Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
    Michel Thiebaut de Schotten, Cynthia C Liu, Catherine Kelly, Ke Bo, Tor D Wager, Eugene V Mosharov, Martin Picard.
      Mitochondria support the bioenergetic processes that enable brain function and cognition, but we have lacked a label-free, non-invasive approach to explore how brain mitochondria are linked to ageing, disease, and cognition in humans. A recently introduced MitoBrainMap neuroimaging framework predicts mitochondrial features from magnetic resonance data alone, potentially bridging cellular biology with macroscale brain organization. Here, we tested whether this framework captures meaningful age- and pathology-related mitochondrial variation. Consistent with existing literature, we find that MR-predicted mitochondrial density and tissue respiratory capacity consistently declined with age, whereas mitochondrial respiratory capacity-an index of mitochondrial quality-was relatively preserved across the lifespan. Moreover, the relations among specific mitochondrial features predicted from our algorithm were consistent with their biological organization, supporting preliminary construct validity for MR-predicted mitochondrial features. In patients with rare mitochondrial diseases, predicted maps revealed region-specific alterations in mitochondrial density and respiratory chain components, particularly the expected compensatory upregulation of complex II, but not of other mitochondrial genome-encoded components. Finally, the MR-based mitochondrial features were associated with the energetic stress marker GDF15 measured in blood, as well as with cognitive performance measures, linking the novel predictions of brain mitochondria to systemic stress and behavior. These findings introduce a first-generation, label-free, neuroimaging-based mitochondrial mapping as a non-invasive window into living human brain mitochondria.
    DOI:  https://doi.org/10.64898/2026.06.09.730804
  8. Glia. 2026 Aug;74(8): e70193
    Plasma Membrane Remodeling During Microglial Activation: A Hypothesis Linking Microglial Shape and Lipid Droplet Formation.
    G William Rebeck, Giorgi Shautidze, Jordy Sepulveda, Gracie S Healey, Priyanka S Narayan.
      Microglia are dynamic cells that respond both transcriptionally and morphologically to acute brain injury as well as to chronic neurodegenerative conditions. Upon activation, they become less ramified, more rounded, and accumulate intracellular lipid droplets. In this hypothesis paper, we propose that the formation of these lipid droplets supports the redistribution of plasma membrane lipids required during morphological remodeling. We rely on original and published studies of microglial morphology under conditions of aging, acute activation, and chronic activation. In ex vivo brain slices, microglia responded to either ATP or acute Aβ injections within minutes by extending their proximal processes toward the stimulus while simultaneously retracting their distal processes into their cell bodies. Chronic exposure to Aβ in mouse models of amyloid reduced microglial branching alongside a two- to three-fold loss of surface area. Transcriptomic analyses showed that activated microglia upregulate genes involved in fatty acid synthesis and fatty acid activation, both processes that are necessary in the production of triacylglycerol. Integrating these new and published analyses of microglia, we developed a hypothesis in which plasma membrane phospholipids are redistributed during acute activation and, during chronic activation, they are metabolized to triacylglycerol into lipid droplets. Tests of this hypothesis, through various pharmacological and genetic approaches, would contribute to our understanding of lipid droplets in cells that undergo substantial morphological changes.
    Keywords:  fatty acids; lipid droplets; microglia; morphology; motility; plasma membrane; triacylglycerols
    DOI:  https://doi.org/10.1002/glia.70193
  9. Transl Neurodegener. 2026 Jun 22. pii: 28. [Epub ahead of print]15(1):
    Metabolic crosstalk in the ageing brain: astrocyte-neuron coupling as a target for homeostatic restoration and therapy.
    Lihui Qian, Yanting Deng, Meiying Song, Zhouyuan Zhang, Jiawei Cheng, Boran Zhu, Minghua Wu, Haosu Zhang, Yue Hu.
      Astrocytes, the most abundant glial cells in the central nervous system, play increasingly recognized roles in metabolic regulation beyond their classical supportive functions. This review summarizes current understanding of astrocyte morphological and molecular heterogeneity, with emphasis on regional metabolic properties across different brain areas. We discuss the primary forms and functional significance of astrocyte-neuron metabolic coupling, focusing on glucose, lipid, and glutamate metabolism, lactate shuttling, as well as the mitochondrial reactive oxygen species signaling. Furthermore, we integrate emerging evidence from animal and preclinical studies linking astrocyte-neuron metabolic coupling to ageing-related diseases. Collectively, these findings highlight how astrocyte-neuron interactions sustain physiological homeostasis and contribute to pathological manifestations, underscoring their significance in both health and ageing-related diseases.
    Keywords:  Ageing; Astrocyte-neuron; Metabolic coupling; Regional; Targeted therapies
    DOI:  https://doi.org/10.1186/s40035-026-00562-4
  10. NMR Biomed. 2026 Aug;39(8): e70343
    Metabolic Assessment in Human Pluripotent Stem Cell-Derived Cerebral Organoids Using HR-MAS NMR Spectroscopy.
    Maria Alejandra Castilla Bolanos, Vorapin Chinchalongporn, Rajshree Ghosh Biswas, Colleen Bailey, Maggie Wu, Ronald Soong, Fermisk Saleh, Andre Simpson, Carol Schuurmans, Jamie Near.
      Brain metabolism is vital to healthy brain function and is often altered in disease; yet direct investigation in patients is challenging. Although animal models are commonly used for studying brain metabolism, their use is under increasing scrutiny due to concerns of animal welfare and model validity. Human pluripotent stem cell (hPSC)-derived cerebral organoids (COs) present a unique opportunity to model human brain developmental and neuropathological processes, allowing for detailed metabolic characterization via multiple approaches. Here, we applied high-resolution magic-angle spinning (HR-MAS) proton nuclear magnetic resonance (1H-NMR) spectroscopy to analyze metabolite levels in hPSC-derived COs, establishing a pipeline to study neurometabolic pathways in these engineered human brain tissues. We identified and quantified 17 metabolites in hPSC-derived COs at different stages of maturity. The high spectral quality (linewidth < 4 Hz, SNR > 65) allowed detection of metabolite levels in 85- to 312-day-old hPSC-derived COs, which exhibited a metabolic profile similar to human fetal brain, with key distinguishing features relative to human adult brain, including: elevated lactate levels; approximately equimolar glutamate and glutamine levels; low N-acetylaspartate levels; and an abundance of hypotaurine. In summary, this study presents direct metabolic assessment in intact COs via HR-MAS 1H-NMR spectroscopy. Our approach provides a platform for investigating human brain metabolism and its alteration in human brain models of neurodegeneration.
    Keywords:  NMR spectroscopy; cerebral organoids; human brain model; human pluripotent stem cells; metabolism
    DOI:  https://doi.org/10.1002/nbm.70343
  11. Antioxidants (Basel). 2026 Jun 18. pii: 764. [Epub ahead of print]15(6):
    Mitochondrial Dysfunction in Autism and Attention-Deficit/Hyperactivity Disorder: Evidence from Genetic, Biochemical, and Neuroimaging Approaches.
    Tina R Ram, Chunlong Mu, Sarah J MacEachern, Jane Shearer.
      Mitochondrial dysfunction has been increasingly implicated in the pathobiology of neurodevelopmental conditions, particularly autism and attention-deficit/hyperactivity disorder (ADHD). Because the developing brain is critically dependent on sustained ATP production, impairments in oxidative phosphorylation, mitochondrial dynamics, and redox balance may disrupt neuronal maturation, synaptic development, and neural circuit refinement during sensitive developmental periods. This review examines evidence from postmortem neurochemistry, genomics, magnetic resonance spectroscopy, and biomarker research to characterize mitochondrial impairment across autism and ADHD. Studies in autism report an elevated burden of heteroplasmic mitochondrial DNA (mtDNA) variants, along with alterations in mtDNA copy number, respiratory chain capacity, fission-fusion dynamics, and antioxidant defenses. Postmortem data demonstrate reduced activity of electron transport chain Complexes I, III, and V in the frontal cortex, temporal lobe, and cerebellum. These bioenergetic abnormalities are accompanied by elevated oxidative stress markers alongside mitochondria-mediated immune activation. In vivo neuroimaging corroborates these findings through elevated cerebral lactate and reduced phosphocreatine-to-ATP ratios. Evidence in ADHD is limited, but similarly implicates mitochondrial dysfunction, consistent with the frequent co-occurrence of these conditions and their partially shared architecture. The available literature supports mitochondrial dysfunction as a transdiagnostic biological feature of neurodevelopmental conditions, with relevance to mechanistic biomarker identification and targeted therapeutic development.
    Keywords:  bioenergetics; electron transport chain; energy; metabolism; mitochondria; neurodevelopment; neuroinflammation; oxidative stress; phenotype
    DOI:  https://doi.org/10.3390/antiox15060764
  12. Mol Neurobiol. 2026 Jun 25. pii: 717. [Epub ahead of print]63(1):
    Influence of Ketogenic Diet Lipid Composition on Anxiety-Like Behavior and Neurometabolic Profile in Healthy Rats.
    Glaucivan Gomes Gurgel, Júlia Galbiati de Souza, Ribanna Aparecida Marques Braga, Fernanda Marques Rodrigues, Andrea Matheus Faccioli, Maria Eduarda Gonçalves Fortes, Eduardo Alves da Silva, Rosana Aparecida Manólio Soares Freitas, Ricardo Mario Arida, Carla Alessandra Scorza, Emerson Soares Bernardes, Sofia Nascimento Dos Santos, Nágila Raquel Teixeira Damasceno.
      Ketogenic diets (KDs) modulate brain function, but how their fatty acid composition impacts behavior remains poorly understood. Male Wistar rats were fed a control diet (CD, n = 6), a classic ketogenic diet (CKD, n = 6) rich in saturated fatty acids (SAFAs), or a modified ketogenic diet (MKD, n = 6) enriched with polyunsaturated fatty acids (PUFAs) and DHA. After 100 days, both KDs induced similar ketosis and increased brain glucose metabolism (1⁸F-FDG PET/CT), while reducing some cerebral pro-inflammatory cytokines (IL-1β, IL-6) and oxidized LDL. Notably, the CKD group exhibited an anxiety-like phenotype in the Elevated Plus Maze versus controls, significantly reducing open arm entries [1.58(0.60) vs. 5.08(1.03); p = 0.025], increasing closed arm time [3.33 min(0.22) vs. 1.70 min(0.19); p = 0.001], and elevating the Anxiety Index [0.92(0.04) vs. 0.70(0.07); p = 0.048], which correlated with SAFA incorporation in the frontal lobe. In contrast, the MKD group did not induce this anxiety-like effect, maintaining behavioral parameters comparable to the CD group, while showing an intense incorporation of omega-3 fatty acids and DHA in the hippocampus. These findings demonstrate that the behavioral divergence between KDs occurred despite shared reductions in the specific neuroinflammatory and oxidative markers evaluated. Overall, our results suggest that the dietary fatty acid profile, rather than the magnitude of systemic ketosis level, plays a critical role in modulating behavioral outcomes under ketogenic conditions.
    Keywords:  Anxiety-like behavior; Docosahexaenoic acid; Fatty acid composition; Hippocampus; Ketogenic diet; Neuroinflammation
    DOI:  https://doi.org/10.1007/s12035-026-06023-3
  13. bioRxiv. 2026 Jun 10. pii: 2026.06.09.731195. [Epub ahead of print]
    TOMM40 '523' genotype induces sex- and tissue- specific differences in cholesterol and triglyceride levels in an APOE-TOMM40 humanized mouse model.
    Neil V Yang, Dellila Hodgson, Timothy M Jang, Justin J Kim, William K Gottschalk, Hussein N Yassine, Ornit Chiba-Falek, Ronald M Krauss.
       Introduction: Genetic variants within the APOE-TOMM40 locus are associated with Alzheimer's disease (AD). A specific role for TOMM40 is indicated by the finding that '523' poly-T variants are associated with AD risk, but the mechanism for this effect has not been established. Our studies have shown that suppression of Tomm40 in mice increased brain cholesterol content, an AD risk factor, and thus the present study sought to assess whether major '523' poly-T variants (Short [S] and Very Long [VL]) are associated with altered lipid content of brain and other tissues.
    Methods: We utilized a mouse model containing the entire human APOE3-TOMM40 locus to quantify cholesterol and triglyceride levels in brain, liver, and white adipose tissue (WAT), as well as brain content of the AD biomarkers Aβ 42 and tau, in mice carrying two homozygous TOMM40 '523' poly-T genotypes (S/S and VL/VL).
    Results: Male mice carrying the '523'-S/S genotype, but not females, showed higher brain cholesterol and triglyceride levels than VL/VL carriers, together with greater brain Aβ 42 content. WAT showed similar lipid differences as in the brain, while hepatic lipid content was broadly similar between '523'-S/S and -VL/VL genotypes, though there was a trend for higher triglycerides in VL/VL mice in a sex- and age-dependent manner.
    Discussion: These results demonstrate that TOMM40 '523' poly-T variants drive tissue-specific, sex-, and age-dependent lipid differences in humanized APOE3-TOMM40 mice, with the S/S genotype linked to elevated brain cholesterol and Aβ 42 levels, effects that link this locus to AD pathogenesis.
    DOI:  https://doi.org/10.64898/2026.06.09.731195
  14. Mol Neurobiol. 2026 Jun 26. pii: 725. [Epub ahead of print]63(1):
    SIRT3/AARS2 regulates SOD2 lactylation to determine neuronal fate in TBI.
    Jiazhi Song, Jing Liu, Wenjun Fan, Fang Gou, Hong Yang, Ping Wang, XiaoKun Yang, Kai Tao.
      Lactate accumulation is strongly associated with poor neurological outcomes in traumatic brain injury (TBI), creating a "lactate paradox" given its role as an energy substrate in the early stages of trauma. Imbalanced reactive oxygen species (ROS) act as cell injury factors throughout the pathological progression of TBI. This study aims to elucidate the key mechanisms connecting dysregulated lactate metabolism and cellular damage. We discovered that the high-lactate environment induced by TBI drives lysine lactylation of the mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2), inhibiting its enzymatic activity and leading to mitochondrial ROS (mtROS) accumulation. Mechanistically, aminoacyl-tRNA synthetase 2 (AARS2) and NAD+-dependent deacetylase sirtuin 3 (SIRT3) coordinate SOD2 lactylation through "resident sensor-writer" and "dynamic patrol-eraser" modes, respectively. Proteomic analysis revealed that SOD2 lactylation triggers a reprogramming of its interaction network, shifting its interactome away from proteins involved in energy metabolism and toward those associated with proteostasis. In a mouse model of TBI, activating SIRT3 reversed SOD2 lactylation, restored its enzymatic function, and reduced neuronal apoptosis in the injured area. This study clarifies how AARS2/SIRT3-regulated SOD2 lactylation influences neuronal fate, providing potential targets for treating secondary injury in TBI.
    Keywords:  APEX2; Lactylation; MtROS; SOD2; TBI
    DOI:  https://doi.org/10.1007/s12035-026-05931-8
  15. J Cereb Blood Flow Metab. 2026 Jun 25. 271678X261465848
    EXPRESS: Intercellular Mitochondrial Transfer in Ischemic Stroke: Emerging Roles of Microglia.
    Hong Yang, Xinyu Sun, Jie Jiang, Jinzhou Yu.
      Mitochondrial dysfunction is a central driver of injury following cerebral ischemia-reperfusion, linking energy failure, oxidative stress, and inflammation. Intercellular mitochondrial transfer has been proposed as an adaptive mechanism to support metabolic homeostasis in the injured brain. While astrocyte-to-neuron transfer is supported by in vivo evidence, microglia-mediated transfer stays less well defined. Here, we review three proposed pathways: tunneling nanotube (TNT)-mediated transfer of intact mitochondria, extracellular vesicle (EV)-mediated transfer of mitochondrial components, and gap junction-associated signaling. TNT-mediated transfer is most closely associated with bioenergetic rescue, whereas EV-mediated processes primarily influence intercellular signaling. In parallel, mitochondrial damage-associated molecular patterns (DAMPs), including mitochondrial DNA, cardiolipin, and cytochrome c, can activate innate immune pathways and contribute to post-ischemic inflammation. The functional consequences of mitochondrial exchange vary according to donor-cell state, cargo integrity, and disease stage.
    DOI:  https://doi.org/10.1177/0271678X261465848
  16. J Lipid Res. 2026 Jun 25. pii: S0022-2275(26)00117-3. [Epub ahead of print] 101091
    Phospholipid Remodeling as a Key Regulator of Ferroptosis.
    Tomoyoshi Shingaki, Junken Aoki, Nozomu Kono.
      Ferroptosis is an iron-dependent form of regulated cell death characterized by the accumulation of lipid peroxides in cellular membranes. Cellular susceptibility to ferroptosis is strongly influenced by membrane phospholipid composition, which is dynamically regulated through phospholipid remodeling. Phospholipid remodeling, also known as the Lands' cycle, drives the replacement of fatty acyl chains in phospholipids through the coordinated actions of phospholipases A, acyl-CoA synthetases (ACSLs), and lysophospholipid acyltransferases (LPLATs). Phospholipid remodeling critically influences ferroptosis sensitivity by regulating the balance between phospholipid species containing polyunsaturated fatty acids (PUFAs), which promote lipid peroxidation, and those containing saturated/monounsaturated fatty acids, which confer resistance. Recent studies have identified key remodeling enzymes, including ACSL4 and LPLAT12, as central drivers of ferroptosis through the generation of PUFA-containing phospholipids, while other enzymes suppress ferroptosis by limiting lipid peroxidation or removing oxidized phospholipids. In parallel, specific phospholipid species-including arachidonic acid- and adrenic acid-containing phospholipids, di-PUFA phospholipids, and other oxidizable lipid classes-have emerged as critical contributors to ferroptosis. Collectively, these findings highlight phospholipid remodeling as a central determinant of ferroptosis by shaping the membrane lipid landscape.
    Keywords:  acyl-CoA synthetase; ferroptosis; lysophospholipid acyltransferase; phospholipase A; phospholipid; phospholipid remodeling
    DOI:  https://doi.org/10.1016/j.jlr.2026.101091
  17. Cells. 2026 Jun 17. pii: 1101. [Epub ahead of print]15(12):
    Compensatory Intercellular Mitochondrial Transfer Improves Bioenergetics in P301L Tau-Affected Neuronal Cells.
    Aurélien Riou, Aline Broeglin, Andreas Papassotiropoulos, Anne Eckert, Amandine Grimm.
      Tauopathies are a group of neurodegenerative diseases characterized by the accumulation of abnormal tau protein, leading to mitochondrial dysfunction. Because of neurons' high energy demands, such impairments significantly contribute to neuronal vulnerability. Recent evidence indicates that mitochondria can be transferred between cells to support energy-deficient cells through intercellular mitochondrial transfer (IMT). Given the impact of pathological tau on mitochondrial transport and cytoskeletal dynamics, we hypothesized that IMT is altered in tauopathies. We investigated IMT from astrocytes to neurons, as well as the influence of abnormal tau protein on this process, using co-cultures of SH-SY5Y cells (neuronal model) and A172 cells (astrocytic model). Key data were then confirmed in human iPSC-derived neurons and astrocytes. We show that IMT is enhanced in the presence of abnormal tau and occurs predominantly through contact-dependent mechanisms. Transferred mitochondria were either integrated into the host mitochondrial network, degraded in lysosomes, or remained isolated in the recipient cells' cytosol. This transfer improved cellular respiration and was associated with increased bioenergetics in pathological cells. Together, our results highlight IMT as a link between tau pathology and neuronal metabolic adaptation, suggesting that this process reflects an endogenous metabolic adaptation holding therapeutic potential to mitigate energy deficits in neurodegenerative diseases.
    Keywords:  astrocytes; intercellular mitochondrial transfer; mitochondria; neurons; tauopathies
    DOI:  https://doi.org/10.3390/cells15121101
  18. Biochem Pharmacol. 2026 Jun 23. pii: S0006-2952(26)00514-9. [Epub ahead of print] 118175
    Extracellular vesicles (EVs) in neurodevelopment: The emerging role of lipids.
    Lorenzo Germelli, Simona Daniele, Claudia Martini, Eleonora Da Pozzo.
      Lipid‑dependent mechanisms of exosome biogenesis are increasingly recognized as key regulators of neurodevelopment, shaping neuronal differentiation, synaptogenesis, glia-neuron communication, and myelination. In this review we summarize recent multi‑omic, cellular, organoid, and in vivo studies showing that extracellular vesicles (EVs) influence neurodevelopmental trajectories both by delivering trophic signals that promote neurite outgrowth and synapse formation and by modulating glia-neuron crosstalk controlling inflammation, myelination, and synaptic pruning. Alterations in lipid metabolism, including cholesterol, sphingomyelin, ceramides, phosphatidylserine, and related bioactive lipids, directly affect multivesicular body formation, intraluminal vesicle budding, and cargo selection, thereby reshaping EV lipidomes and signaling during critical windows of brain maturation. Across neurodevelopmental disorders (NDDs), convergent evidence shows that EV biogenesis, lipid composition, and cargo loading are disrupted. In this sense, we discuss translational opportunities: small‑molecule modulators of sphingolipid and cholesterol pathways, dietary and metabolic interventions, and engineered EVs enriched in pro‑neurogenic miRNAs as tractable strategies to restore EV cargo composition and intercellular signalling. Collectively, the review highlights as targeting lipid pathways that govern EV biogenesis and cargo loading offers promising avenues for biomarker discovery and therapeutic intervention across NDDs.
    Keywords:  Diet; EV Engineering; Extracellular Vesicles; Lipidomics; Neurodevelopmental disorders; Therapeutic cargo
    DOI:  https://doi.org/10.1016/j.bcp.2026.118175
  19. Biomolecules. 2026 Jun 08. pii: 838. [Epub ahead of print]16(6):
    A Subset of Caveolin-1 Interacts with a Fraction of Acyl-CoA:Cholesterol Acyltransferase 1 (ACAT1/SOAT1) at an Endoplasmic Reticulum Subdomain to Attenuate Cholesteryl Ester Biosynthesis.
    Catherine C Y Chang, Toyoshi Fujimoto, Yoshio Yamauchi, Yasuomi Urano, Ta Yuan Chang.
      Caveolin-1 is a scaffolding protein of caveolae, flask-shaped membrane microdomains involved in diverse cellular processes. Caveolae are primarily localized to the plasma membrane, the trans-Golgi network, and mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs). Most enzymes involved in cholesterol biosynthesis reside in the ER, and although caveolin-1 avidly binds cholesterol, its role in cholesterol trafficking remains unclear. Acyl-coenzyme A:cholesterol acyltransferases (ACAT1 and ACAT2) convert free cholesterol into cholesteryl esters for storage, with ACAT1 serving as the predominant isoenzyme in most cell types. ACAT1 is an ER-resident protein, with a fraction associated with specialized ER subdomains, including the MAM. Here, we report that a subset of caveolin-1 molecules appears to be associated with a fraction of ACAT1 in ER subdomains. Using immunoprecipitation under detergent conditions, immunoadsorption of MAM-enriched membranes under detergent-free conditions, and electron microscopy, we provide evidence consistent with an association between a subset of caveolin-1 molecules and ACAT1. Functionally, in mouse embryonic fibroblasts, we show that genetic ablation of caveolin-1 significantly increases the esterification of low-density lipoprotein-derived cholesterol, suggesting that caveolin-1 may attenuate ACAT1 activity. Collectively, these findings indicate that caveolin-1 may modulate cholesterol esterification and contribute to the regulation of cholesterol distribution among cellular membranes.
    Keywords:  acyl-CoA:cholesterol acyltransferase; caveolae; caveolin-1; cholesterol; cholesteryl oleate; endoplasmic reticulum; mitochondria-associated membranes; sterol O-acyltransferase; trans-Golgi network
    DOI:  https://doi.org/10.3390/biom16060838
  20. Proc Natl Acad Sci U S A. 2026 Jun 30. 123(26): e2531706123
    Metabolism-weighted brain connectome reveals synaptic integration and vulnerability to neurodegeneration.
    Mahnaz Ashrafi, Laura Fraticelli, Gabriel Castrillón, Valentin Riedl.
      The brain's capacity for integration arises from both its structural wiring and energetically demanding electrochemical signaling. Yet current connectome analyses treat network nodes as functionally homogeneous, ignoring that neural communication is constrained by metabolic cost. Here, we introduce a metabolism-weighted connectome, a fully weighted brain graph in which both connections and the metabolic activity of each node describe the network's capacity for integration. Using three datasets of simultaneous fMRI and [18F]Fluorodeoxyglucose positron emission tomography acquisitions, we define metabolism-weighted centrality (MwC), a biologically grounded index of each region's signaling dominance that integrates functional connectivity with local energy metabolism. MwC provides a more accurate representation of cortical activity flow than classical edge-based metrics and reveals that metabolically active hubs align with higher-order cognitive networks. Transcriptomic and synaptic imaging data demonstrate that these hubs exhibit increased synaptic energy turnover, linking activity-driven centrality to the molecular architecture of signaling. Notably, the same high-MwC regions show greater susceptibility to neurodegenerative pathology, suggesting that lifelong metabolic demand influences both integrative function and disease vulnerability. By linking neuronal metabolism to network organization, our framework bridges cellular energetics and system-level computation, opening broad avenues for interpreting brain vulnerability and performance.
    Keywords:  brain connectome; brain energy metabolism; neurodegeneration; synaptic integration
    DOI:  https://doi.org/10.1073/pnas.2531706123
  21. Neuropsychopharmacology. 2026 Jun 25.
    Norepinephrine regulates hippocampal mitochondrial biogenesis via β2-adrenergic receptor signaling and PGC-1α.
    Darshana Kapri, Amogh Bhaskaran Jayaprasad, Praachi Tiwari, Mukund Sharma, Angarika Balakrishnan, Aastha Singla, Ishanee Mazumder, Ullas Kolthur-Seetharam, Sashaina E Fanibunda, Ashok D B Vaidya, Vidita A Vaidya.
      Neuronal mitochondria are central to not only maintaining cellular bioenergetics, calcium dynamics, and serving as signaling platforms, but are also critical for specialized functions including synaptic plasticity and neurotransmission. While mitochondria are postulated to have a fundamental role in the functioning of neurons, it is only recently that upstream factors that influence mitochondria in neurons have been systematically investigated. Here, we identify the critical role of the neurotransmitter, norepinephrine (NE) in modulating mitochondria in the rodent hippocampus. NE increases the expression of key regulators of mitochondrial biogenesis (SIRT1 and PGC-1α), enhances mitochondrial DNA content and ATP levels in hippocampal neurons in culture. These effects of NE are mediated via the recruitment of a β2-adrenergic receptor-Gs-cAMP-PKA signaling cascade and are dependent on PGC-1α. We find that increasing noradrenergic signaling in vivo, either through direct administration of NE into the hippocampus via osmotic minipumps or treatment with the NE reuptake inhibitor, Atomoxetine, as well administration of the β2-adrenergic receptor agonist, Formoterol, enhances mitochondrial DNA content in the hippocampus. Furthermore, increased spatial memory recall with Atomoxetine treatment was significantly correlated with both mitochondrial DNA content and ATP levels in the hippocampus. Our findings identify a novel role for NE in impacting mitochondrial biogenesis in the hippocampus, and suggest a link between bioenergetic status and spatial memory performance.
    DOI:  https://doi.org/10.1038/s41386-026-02470-7
  22. J Biol Chem. 2026 Jun 20. pii: S0021-9258(26)02153-8. [Epub ahead of print] 113281
    1-Deoxysphingolipids Require Very-Long-Chain Ceramide Synthesis to Induce ER Stress and Cytotoxicity.
    Colleen Byrnes, Benjamin A Clarke, Hongling Zhu, Y Terry Lee, Saurav Majumder, Mari Kono, Richard L Proia.
      Sphingolipids play key roles in cellular systems both as membrane components and as signaling molecules. Their biosynthesis, which occurs in the endoplasmic reticulum (ER), begins with the condensation of an amino acid, typically serine, and a fatty acyl-CoA. Under certain pathological conditions, alanine can be substituted for serine in the condensation reaction, producing 1-deoxysphingolipids, which lack the 1-hydroxyl group on the sphingoid base. Unlike typical sphingolipids, 1-deoxysphingolipids are unable to accept a head group modification, which alters their metabolic processing and prevents their canonical degradation. The accumulation of these "headless" 1-deoxysphingolipids causes neurotoxicity in various neurological and metabolic disorders. Here, we conducted a genome-wide CRISPR-Cas9 screen to identify pathways leading to 1-deoxysphinganine-induced toxicity in SH-SY5Y cells, a model used to study neurotoxic responses. Our top genetic hits highlighted the pathway involved in synthesizing ceramides with very-long-chain fatty acids (C22-C26). Using CRISPR-Cas9-modified SH-SY5Y cells with loss-of-function (LOF) mutations in the TECR or CERS2 genes-both critical for producing very-long-chain ceramides-we validated that this pathway was essential for 1-deoxysphinganine-mediated toxicity. Furthermore, we demonstrated that the ceramide synthesis pathway is required for 1-deoxysphinganine to trigger ER stress, as evidenced by significantly increased expression of the unfolded protein response in WT, but not TECR or CERS2 LOF mutant, SH-SY5Y cells exposed to 1-deoxysphinganine. Collectively, the data support a model in which ceramide synthase-dependent conversion of 1-deoxysphinganine to very-long-chain 1-deoxyceramide species is required for full ER-stress induction and cytotoxicity. The findings highlight potential therapeutic targets for neuropathological diseases caused by 1-deoxysphingolipid accumulation.
    Keywords:  1-deoxysphingolipids; endoplasmic reticulum stress (ER stress); fatty acid; fatty acid metabolism; lipid metabolism; lipotoxicity; sphingolipid; very-long-chain ceramides
    DOI:  https://doi.org/10.1016/j.jbc.2026.113281
  23. J Neurol. 2026 Jun 24. pii: 419. [Epub ahead of print]273(7):
    Bioenergetic failure in diabetic peripheral neuropathy: from glucotoxicity to multidimensional metabolic imbalance.
    Wang Tao, Yunfeng Yu, Xuerong Wu, Jiacheng He, Xiu Liu, Juan Huang, Fan Xiao, Rong Yu.
      Diabetic peripheral neuropathy (DPN), particularly distal symmetric polyneuropathy, characterized by length‑dependent axonal damage, is a common chronic complication of type 2 diabetes mellitus. The pathogenesis of DPN is complicated, yet one thing is clear: long axons require a great deal of energy. When axonal transport is compromised by impaired energy metabolism, neuronal somata fall into an energy deficit that triggers neurodegeneration. While earlier work centered on hyperglycemia-induced cytotoxicity, recent studies have increasingly implicated dysregulation of glucose, lipid, and amino acid metabolism as key contributors to DPN. In this review, we integrate the anatomical organization of peripheral nerves, bioenergetic pathways, and axon-Schwann cell interactions to establish a framework for understanding how glucose, lipid, and amino acid dysregulation converge to induce bioenergetic failure in DPN. Based on these mechanisms, we further discuss novel strategies aimed at restoring metabolic homeostasis in neurons and Schwann cells. Importantly, correcting a single metabolic pathway is unlikely to halt or reverse DPN. Instead, restoring global energy homeostasis to rebalance axonal energy supply and demand may be essential for preserving peripheral nerve function.
    Keywords:  Amino acid metabolism; Axon-Schwann cell; Bioenergetics; Diabetic peripheral neuropathy; Glucose metabolism; Intervention strategies; Lipid metabolism; Mitochondrial
    DOI:  https://doi.org/10.1007/s00415-026-13928-5
  24. Cell Death Dis. 2026 Jun 22.
    ACLY alleviates cerebral ischemia/reperfusion injury by reducing oxidative stress and enhancing mitochondrial function via histone acetylation.
    Xiaona Sun, Rui Zhao, Qidi Zhou, Xiaorong Wang, Yuxin Li, Yongkun Yang, Zhiyuan Zhao, Yu Cui, Rui Xu.
      Cell metabolism and epigenetic regulation play crucial roles in modulating cerebral ischemia/reperfusion (I/R) injury. How cell metabolism regulates cerebral I/R injury by regulating epigenetic modifications remains unclear. In this study, we utilized an in vivo injury model of transient middle cerebral artery occlusion (tMCAO) in C57BL/6 mice. The middle cerebral artery was occluded for 90 min, followed by reperfusion at different time points. We observed that the expression of ATP-citrate lyase (ACLY), an important enzyme involved in lipid synthesis, was significantly upregulated under cerebral I/R conditions. Inhibition of ACLY markedly exacerbated cerebral I/R injury in vivo. ACLY inhibition and knockdown in vitro also reduced cell viability in cultured neurons following oxygen-glucose deprivation/reoxygenation (OGD/R). Mechanistic studies revealed that ACLY enhances histone acetylation at the promoter regions of mitochondrial respiratory chain complexes by facilitating the accumulation of acetyl-CoA, thereby improving mitochondrial function and attenuating oxidative stress. Our findings reveal a novel metabolic-epigenetic axis mediated by ACLY in the regulation of cerebral I/R injury which may serve as a potential target for therapeutic intervention in ischemic stroke.
    DOI:  https://doi.org/10.1038/s41419-026-09021-4
  25. Nat Commun. 2026 Jun 23. pii: 5563. [Epub ahead of print]17(1):
    Investigating the relationship between ATP synthase and the TCA cycle by crosslinking mass spectrometry.
    Laura Pérez Pañeda, Jelena Misic, Tereza Kadavá, Nils-Göran Larsson, Albert J R Heck.
      Mitochondrial oxidative phosphorylation (OXPHOS) comprises multi-subunit protein complexes that operate in coordination with the tricarboxylic acid (TCA) cycle to generate ATP. Although these systems are metabolically interconnected, complex II is generally regarded as the only direct structural link between OXPHOS and TCA cycle. Here, we combine in-solution crosslinking mass-spectrometry (XL-MS), quantitative proteomics, complexome profiling and blue native PAGE (BN-PAGE) to explore how ATP synthase (complex V) is positioned within the mitochondrial metabolic network under physiological and pathological conditions. We demonstrate that in murine wild-type hearts, the F₁ catalytic head of ATP synthase forms extensive contacts with TCA cycle enzymes, establishing a previously unanticipated spatial link between OXPHOS and central carbon metabolism. We further report that loss of the mitochondrial RNA-stabilizing protein LRPPRC, which disrupts mtDNA gene expression in the mouse heart, results in ATP synthase destabilization and enhanced F1-TCA cycle interactions. Moreover, ATP synthase dysfunction promotes binding of the ATPase inhibitory factor 1 (ATIF1) to the F₁ head via its N-terminal inhibitory region, shifting the ATP synthase toward an energy-preserving state. Together, our findings show that impaired mitochondrial gene expression leads to secondary ATP synthase remodeling and reshaping of its interaction landscape, revealing how mitochondria may adapt to bioenergetic stress.
    DOI:  https://doi.org/10.1038/s41467-026-74730-5
  26. Nan Fang Yi Ke Da Xue Xue Bao. 2026 Jun 20. pii: 1673-4254(2026)06-1290-11. [Epub ahead of print]46(6): 1290-1300
    [ZEB2 promotes glioblastoma progression by reprogramming lipid metabolism through the CYLD/FASN axis].
    Zhenlin Chen, Peng Chai, Yangqi Mao, Ranxin Liu, Ye Song.
       OBJECTIVES: To investigate the role of ZEB2 in lipid metabolic reprogramming of glioblastoma and its mechanism for promoting glioblastoma progression.
    METHODS: Mouse models bearing orthotopic intracranial xenografts derived from LN-229 and GBM007 cells with stable ZEB2 knockdown were used to assess tumor growth and mouse survival.. Lipid droplet accumulation, lipid composition, and membrane fluidity in the cells with ZEB2 knockdown were examined using Nile Red staining, transmission electron microscopy, untargeted lipidomics, and fluorescence recovery after photobleaching (FRAP). The candidate mediators were screened by integrating RNA sequencing, fatty acid synthase (FASN) immunoprecipitation-mass spectrometry, and BioGRID interaction data. Promoter luciferase assays, ChIP-qPCR, promoter mutagenesis, co-immunoprecipitation, protein degradation pathway inhibition, and ubiquitination assays were performed to investigate the regulatory role of the ZEB2-CYLD-FASN axis.
    RESULTS: ZEB2 knockdown significantly suppressed intracranial glioblastoma growth and prolonged mouse survival. Glioblastoma cells with ZEB2 silencing showed reduced lipid droplet accumulation, decreased saturated fatty acid-associated storage lipids, increased phospholipid species containing polyunsaturated fatty acyl chains, and enhanced membrane fluidity. Mechanistically, ZEB2 knockdown reduced FASN protein abundance, whereas FASN restoration reversed lipid droplet reduction induced by ZEB2 silencing. Multi-omics screening identified CYLD as a key intermediate. ZEB2 was capable of directly binding to and activating the CYLD promoter. CYLD knockdown decreased FASN protein levels, whereas CYLD restoration recovered FASN abundance and lipid droplet formation. CYLD was co-localized and interacted with FASN. MG132 partially restored FASN abundance under ZEB2 knockdown, and CYLD overexpression reduced FASN ubiquitination.
    CONCLUSIONS: ZEB2 promotes glioblastoma lipid metabolic reprogramming and tumor progression by transcriptionally activating CYLD, which maintains FASN protein stability at least in part through ubiquitination-associated regulation.
    Keywords:  CYLD; fatty acid synthase; glioblastoma; lipid metabolism; zinc finger E-box binding homeobox 2
    DOI:  https://doi.org/10.12122/j.issn.1673-4254.2026.06.09
  27. J Cereb Blood Flow Metab. 2026 Jun 23. 271678X261465845
    EXPRESS: FDG: Five Decades of Transforming Molecular Imaging and Still Illuminating the Brain.
    Shokouh Arjmand, Paul Cumming, Albert Gjedde.
      Over half a century after its introduction, [18F]fluorodeoxyglucose ([18F]FDG) remains a cornerstone of molecular imaging by positron emission tomography (PET). This commentary reflects on [18F]FDG-PET's transformative role in neuroscience, highlighting its fundamental contributions to understanding brain metabolism and supporting clinical diagnoses of brain disorders, and the continuing evolution and refinement of brain PET imaging.
    DOI:  https://doi.org/10.1177/0271678X261465845
  28. Nat Commun. 2026 Jun 21.
    Mitochondrial DNA heteroplasmy drives cortical neuronal disturbances in human organoids harbouring the common m.3243A>G mutation.
    Denisa Hathazi, Camilla Lyons, Daniel Lagos, Oliver Podmanicky, Mariana Zarate-Mendez, Yu Nie, Juliane S Müller, Kieren S J Allinson, Huw Naylor, Majlinda Lako, Ibrahim Elsharkawi, Irena Muffels, Eva Morava, Tamas Kozicz, Patrick Chinnery, András Lakatos, Rita Horvath.
      Mitochondrial diseases frequently affect the brain leading to severe and disabling neurological symptoms. The heteroplasmic m.3243 A > G mutation in MT-TL1, encoding mt-tRNALeu, is responsible for ~80% of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which is one of the most characteristic mitochondrial syndromes, leading to disability and early death. There are no animal models harbouring this mutation to provide precise mechanistic insights informing therapeutic interventions. Here, we generate a human iPSC-derived cerebral organoid slice model that recapitulates cortical architecture and mitochondrial pathology. Using biological assays and single-cell RNA sequencing, we uncover heteroplasmy-dependent transcriptional shifts and changes in key cellular processes in cortical neurons. Organoids with high heteroplasmy show a predominant impairment of deep-layer neurons triggered by mitochondrial stress, leading to axonal degeneration and apoptosis, similar to brain autopsy of a MELAS patient. Our findings provide insights into the vulnerability of long-range projection neurons in mitochondrial diseases, advancing our understanding of disease mechanisms with a view to potential therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-026-74103-y
  29. Clin Case Rep. 2026 Jun;14(6): e73014
    Case Report of Dual Variants in SLC1A4 and APOE: A Possible Link Between Amino Acid and Lipid Metabolism.
    Mohammed Qaisiya, Kenana Altell, Wasef Alhroub, Mahmoud Ramlawe, Elisabetta Battocchio, Fabrizia Guarnieri, Mu'taz Altamimi.
      Spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) is a rare autosomal recessive neurodevelopmental disorder linked to biallelic variants in the SLC1A4 gene, which encodes the ASCT1 amino acid transporter critical for neutral amino acid uptake in neurons. While SLC1A4 mutations are well established in SPATCCM, the potential impact of additional genetic factors on disease progression remains unexplored. We report a rare case of an 8-month-old male with severe global developmental delay and progressive microcephaly, identified with whole-exome sequencing to have a novel combination of homozygous SLC1A4 (p.Arg457Trp) and heterozygous APOE (p.Cys130Arg) mutations. Neuroimaging revealed severe hypomyelination and diffuse white matter abnormalities. This is the first reported case of SPATCCM with an APOE variant, implicating a potential interplay between amino acid transport deficiencies and lipid metabolism in brain development.
    Keywords:  APOE; L‐serine; SLC1A4; progressive microcephaly; spastic tetraplegia; thin corpus callosum
    DOI:  https://doi.org/10.1002/ccr3.73014
  30. Cell Metab. 2026 Jun 22. pii: S1550-4131(26)00224-X. [Epub ahead of print]
    Oral GLP-1 receptor agonist promotes astrocyte-neuron lactate and lipid transfer with neuroprotective effects.
    Yixuan Du, Chujun Sun, Lingxi Wu, Zhongyun Wu, Yue Tong, Hong Tian, Yang Mao, Xupeiyao Shi, Haohui Ding, Wenbin Xie, Wenbing Yao, Song Chen, Xiangdong Gao.
      Glucagon-like peptide-1 receptor (GLP-1R) activation is widely assumed to regulate the metabolic disorder in Alzheimer's disease (AD). However, direct evidence for this hypothesis is lacking, and currently, there is no oral GLP-1R agonist with effective blood-brain barrier-penetrating ability. Here, we show that a candidate peptide, OHP2, an oral GLP-1R agonist with blood-brain barrier permeability, exhibits promising therapeutic potential for AD. OHP2 primarily activates GLP-1R on astrocytes, leading to increased aerobic glycolysis and driving lactate release. Astrocyte-derived lactate is taken up by neurons and elevates histone H3 lysine 9 lactylation (H3K9la), which in turn facilitates lipid transport from neurons back to astrocytes. This astrocyte-neuron metabolic coupling sustains continuous aerobic glycolysis and offers a potential treatment strategy for AD. The H3K9la derived from OHP2 links glucose and lipid metabolic cycle and facilitates metabolic coupling between astrocytes and neurons, which leads to remission of metabolic disturbances in AD. Thus, our study provides a new candidate molecule for drug research in treating AD and illustrates that intracerebral GLP-1R activation, which facilitates astrocyte-neuron metabolic coupling, may be a potential approach for the treatment of AD.
    Keywords:  Alzheimer’s disease; GLP-1RA; H3K9la; astrocyte; lactylation; sustaining aerobic glycolysis
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.014
  31. Transl Psychiatry. 2026 Jun 22.
    Regulation of oligodendrocyte metabolism and myelination by acetyl-L-carnitine in a mouse model of post-weaning social isolation.
    Hyun-Jeong Yang, Youngja Hwang Park, Dalnim Kim, Ahreum Lee, Minkuk Park, Eugene Koh, Gakyung Lee.
      Adolescent social stress can impair myelination and increase vulnerability to psychiatric symptoms. We investigated whether acetyl-L-carnitine (ALC), a metabolite linking energy and lipid metabolism, regulates oligodendrocyte (OL) myelination and rescues behavioral deficits in a post-weaning social isolation (PWSI) mouse model. In vitro, ALC uptake and conversion through the OCTN2/CrAT axis promoted myelin sheath expansion without affecting OL precursor proliferation or early differentiation. ALC activated ERK signaling, increased histone acetylation, promoted PPARγ nuclear translocation, and selectively enhanced mitochondrial respiration in mature OLs. In vivo, oral ALC supplementation restored social preference and medial prefrontal cortex MBP expression in PWSI mice, whereas cuprizone co-administration abolished these effects, suggesting that the therapeutic effects of ALC are closely associated with its impact on myelination. Lipidomic analysis of the corpus callosum showed that ALC restored PWSI-induced changes in fatty acid chain length and unsaturation. These findings identify ALC as a metabolic regulator that restores social isolation-induced myelin deficits by coordinating myelin protein synthesis, mitochondrial function, and myelin lipid remodeling. ALC may therefore provide a metabolic strategy for targeting myelin-related neurodevelopmental and psychiatric disorders.
    DOI:  https://doi.org/10.1038/s41398-026-04214-z
  32. J Neurodev Disord. 2026 Jun 26.
    DRP1 mutations associated with EMPF1 encephalopathy perturb the transcriptional profile and maturation of cortical neurons.
    T B Baum, J Costanzo, C Bodnya, D P Boulton, M C Caino, D Mogilenko, A Zhelonkin, V Gama.
      With the advent of exome sequencing, a growing number of children are being identified with de novo loss-of-function mutations in the dynamin 1-like (DNM1L) gene, which encodes the large GTPase essential for mitochondrial fission, dynamin-related protein 1 (DRP1). Mutations in DRP1 result in severe neurodevelopmental phenotypes, such as developmental delay, optic atrophy, and epileptic encephalopathies. Though it is established that mitochondrial fission is an essential precursor to the rapidly changing metabolic needs of the developing cortex, it is not understood how identified mutations in different domains of DRP1 uniquely disrupt cortical development and synaptic maturation. We leveraged the power of human induced pluripotent stem cells (iPSCs) harboring DRP1 mutations in either the GTPase or stalk domains to model early stages of cortical development in vitro. High-resolution time-lapse imaging of transport in neuronal projections revealed mutation-specific changes in mitochondrial motility of severely hyperfused mitochondrial structures. Transcriptional profiling of mutant DRP1 cortical neurons during maturation also implicated mutation-dependent alterations in synaptic development and gene expression of calcium-regulatory genes. Disruptions in calcium dynamics were confirmed using live functional recordings of 65-200 days in vitro (DIV) mutant DRP1 cortical neurons. These findings strongly suggest that altered mitochondrial morphology in DRP1 mutant neurons leads to pathogenic dysregulation of synaptic development and activity.
    Keywords:  DRP1; Mitochondria; Mitochondrial fission; Neurons
    DOI:  https://doi.org/10.1186/s11689-026-09713-0
  33. bioRxiv. 2026 Jun 08. pii: 2026.06.05.730472. [Epub ahead of print]
    Astrocyte subtype-specific expression of the sodium-coupled citrate transporter SLC13A5 and citrate metabolism genes across Alzheimer's disease pseudoprogression: a single-nucleus RNA sequencing analysis of the human middle temporal gyrus.
    Patrícia Fernanda Schuck, Gustavo da Costa Ferreira, Hércules Rezende Freitas.
      The sodium-coupled citrate transporter NaCT (SLC13A5) imports extracellular citrate into cells. In the CNS, SLC13A5 is described to be expressed predominantly in neurons. Cytosolic citrate levels rely on citrate generated in mitochondria and imported from other CNS cells, regulating intermediary metabolism and supplying acetyl-CoA for lipid synthesis and histone acetylation. Despite evidence for NaCT's role in neurometabolic homeostasis, its transcriptional behavior across Alzheimer's disease (AD) progression and across astrocyte subtypes remains uncharacterized at single-cell resolution. We analyzed single-nucleus RNA sequencing data from 1,378,211 nuclei across 84 donors in the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) Middle Temporal Gyrus dataset to profile SLC13A5 and seven citrate metabolism genes across a continuous AD pseudoprogression score. SLC13A5 expression was restricted to astrocytes (∼20% prevalence) and concentrated in the Astro 2 supertype (24.0%), a homeostatic subtype characterized by low C3 (1.6%) and CD44 (5.5%), which expanded with pseudoprogression (Spearman rho = +0.345, FDR < 0.001). The A1-reactive Astro 3 supertype, where SLC13A5 prevalence was 0.87%, declined concordantly (rho = -0.393). Opposing compositional and transcriptional forces produced apparent stability in overall SLC13A5 prevalence. SLC13A3 and ACO1 showed progressive donor-level declines correlating with Braak stage and Thal phase (rho range: -0.307 to -0.349, FDR < 0.01). APOE4 carriers exhibited lower SLC13A5 prevalence specifically within Astro 2 nuclei (median 17.6% vs. 25.9%; Wilcoxon p = 0.025), though this association did not survive multivariate regression. No difference in Astro 2 SLC13A5 expression was detected between cognitively resilient and expected-AD donors with equivalent high Braak burden (p = 0.888). Contrary to the prevailing description of NaCT as a neuronal transporter, SLC13A5 expression in the SEA-AD MTG dataset is restricted to astrocytes, concentrated in the homeostatic Astro 2 subtype, and maintained as this subtype expands with advancing AD pathology. Supertype-resolved SLC13A5 and SLC13A3 expression provide more informative readouts of astrocytic metabolic state than bulk measurements.
    DOI:  https://doi.org/10.64898/2026.06.05.730472
  34. Front Aging Neurosci. 2026 ;18 1723883
    Sphingolipids associated research in Alzheimer's disease: an explored trends analysis.
    Ming-Rong Xie, Yan-Jun Chen, Hui Yuan.
       Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment. Numerous studies have indicated that dysregulation of sphingolipid metabolism is closely associated with the core pathology of AD and acts as a crucial driving factor. This study aims to employ bibliometric methods to comprehensively summarize the relevant research on sphingolipids in AD, identify research hotspots and emerging trends, and thereby provide objective data to guide future research directions.
    Methods: Publications were retrieved from the Web of Science and Scopus databases. Visual analyses were performed using CiteSpace, VOSviewer, and Bibliometrix.
    Results: A total of 623 publications related to sphingolipids and AD were included. The United States and China were the leading contributors in this field. Johns Hopkins University was the most prolific institution. Journal of Alzheimer's Disease was the most frequently published journal. Dr. Erhard Bieberich was the author with the highest number of publications. High-frequency keywords included AD, sphingolipids, sphingolipid metabolism, ceramide, sphingomyelin, and cholesterol. Keywords with the strongest bursts in recent years included lipidomics, metabolomics, microglia, and cognitive impairment.
    Conclusion: Research on sphingolipids in AD exhibits an overall fluctuating upward trend. Extensive collaboration among researchers from various institutions has facilitated advancements in this field. Sphingolipid metabolism represents a key focus in AD research, with ceramides and sphingomyelins identified as critical molecules. Lipidomics, metabolomics, and microglia are likely to represent future research frontiers.
    Keywords:  Alzheimer’s disease; lipidomics; metabolomics; microglia; sphingolipids
    DOI:  https://doi.org/10.3389/fnagi.2026.1723883
  35. Biomolecules. 2026 May 29. pii: 805. [Epub ahead of print]16(6):
    Continuous Pyruvate Supplementation Enhances Neuroprotective Resilience Against Kainate-Induced Status Epilepticus Through Metabolic Preconditioning.
    Yong Jae Cho, Soo Jin Lee, Yuna Kim, Yeeun Kim, Seog-Young Kim, Kyunggon Kim, Dong-Cheol Woo, Hyun Ju Yoo, Joo-Yong Lee.
      Refractory status epilepticus refers to persistent and recurrent seizures unresponsive to medication, often leading to neuronal injury and neurobehavioral deficits. Studies have demonstrated that intraperitoneal bolus administration of pyruvate attenuates neuronal damage in rodent models of chemically induced status epilepticus (SE), while the precise neuroprotective mechanism remains to be further explored. This study investigated the neuroprotective effects of long-term supplementation with exogenous pyruvate against SE. When male C57BL/6 mice received 3% sodium pyruvate (SP) in the drinking water ad libitum for 20 weeks, they exhibited elevated levels of essential neurochemicals and energy metabolites in the brain compared to the control mice that received the equimolar saline solution. Following the intraperitoneal administration of kainate (KA) to induce severe SE, the SP-fed mice showed enhanced resistance to seizure activity, reduced neuronal injury, and improved neurobehavioral performance compared to the saline-fed mice. Regarding the molecular mechanisms underlying their neuroprotective properties, the levels of pyruvate metabolism-mediating proteins, neuronal and synaptic proteins, and neuroprotective proteins remained upregulated in the brains of the SP-fed mice following KA-induced SE. Conversely, the levels of pro-apoptotic and oxidative stress markers were suppressed. Collectively, this study indicates that long-term pyruvate supplementation may sustainably augment neurochemical and energy metabolism in the normal brain, thereby eliciting intrinsic neuroprotective properties. These effects contribute to preventing or ameliorating seizure activity, neuronal damage, and neurobehavioral deficits in mice following KA-induced SE, suggesting its prophylactic or therapeutic potential against epileptic seizures and SE through metabolic preconditioning.
    Keywords:  epileptic seizures; epileptogenesis; neurobehavioral comorbidity; neurochemical or energy metabolism; prophylaxis; sodium pyruvate
    DOI:  https://doi.org/10.3390/biom16060805
  36. Antioxidants (Basel). 2026 Jun 07. pii: 725. [Epub ahead of print]15(6):
    Statin-Induced Coenzyme Q Deficiency Induces Metabolic Reprogramming in Astrocytes.
    Krzysztof Wojcicki, Lukasz Galganski, Adrianna Budzinska, Grzegorz Figura, Wieslawa Jarmuszkiewicz.
      Statins are commonly used cholesterol-lowering drugs, but their effects on astrocyte oxidative metabolism are poorly understood. To investigate this, rat astrocytes were exposed to 200 nM atorvastatin or simvastatin for 6 days and then assessed for changes in coenzyme Q (CoQ) homeostasis, mitochondrial function, and energy metabolism. Both statins comparably decreased cellular CoQ9 and CoQ10 levels (~35%), with greater losses of their reduced antioxidant forms (60-75%). Lower intracellular and mitochondrial levels of reactive oxygen species (ROS) were accompanied by the upregulation of nuclear factor erythroid 2-related factor 2 (NRF2)-dependent antioxidant pathways (superoxide dismutase 1 and glutathione reductase) and metabolic stress response factors, including hypoxia-inducible factor 1-alpha (HIF1α) and brain-derived neurotrophic factor (BDNF). Both statins promoted glycolytic reprogramming, mitochondrial fission, and biogenesis while impairing oxidative phosphorylation, as evidenced by reduced ATP-linked respiration, increased proton leak, and lower ATP levels. These findings suggest that statin-treated astrocytes adapt by prioritizing redox homeostasis over ATP production. CoQ10 supplementation increased cellular CoQ10 levels and restored ATP levels without further decreasing ROS, suggesting that its primary benefit is bioenergetic support, not additional antioxidant protection. Overall, statin-induced CoQ deficiency induces adaptive metabolic remodeling of astrocytes, while CoQ10 supplementation may help maintain energy metabolism under these conditions.
    Keywords:  CoQ deficiency; astrocytes; atorvastatin; mitochondrial function; oxidative stress; simvastatin
    DOI:  https://doi.org/10.3390/antiox15060725
  37. Alzheimers Dement. 2026 Feb;22(2): e71211
    Altered brain glucose metabolism and connectivity in young adults with obstructive sleep apnea.
    Silvia P Caminiti, Mariana Fernandes, Claudio Zaccone, Rachele Malito, Agostino Chiaravalloti, Natalia Manfredi, Riccardo Camedda, Francesca Di Giuliano, Marcello D'Amelio, Nicola B Mercuri, Daniela Perani, Claudio Liguori.
       INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is a recognized risk factor for neurodegenerative disorders. However, a causal link between OSAS and brain damage has yet to be established.
    METHODS: Thirty cognitively normal patients with moderate-to-severe OSAS, free from systemic or neurological comorbidities, were enrolled and underwent 18F-fluorodeoxyglucose positron emission tomography imaging. Their scans were compared to those of cognitively normal, OSAS-free controls from the Alzheimer's Disease Neuroimaging Initiative database. Additional analyses included commonality mapping, correlations with polysomnographic parameters, and seed-based metabolic connectivity of major resting-state networks.
    RESULTS: Group-level analyses showed fronto-parietal glucose hypometabolism and cerebellar glucose hypermetabolism in patients with OSAS compared to controls. Cerebellar glucose hypermetabolism was associated with reduced rapid eye movement sleep latency and duration. Seed-based connectivity analysis revealed alterations in attentional and limbic networks.
    DISCUSSION: Moderate-to-severe OSAS may represent a cause of brain dysfunction, highlighting the importance of its early diagnosis and appropriate treatment to prevent worsening brain damage and possible future neurodegenerative processes.
    HIGHLIGHTS: Moderate-to-severe obstructive sleep apnea syndrome (OSAS) is associated with altered brain glucose metabolism. Cerebellar glucose hypermetabolism is associated with rapid eye movement sleep impairment. Attentional and limbic networks connectivity is disrupted in moderate-to-severe OSAS. Early recognition of patients with moderate-to-severe OSAS has the potential to overcome the risk of worsening brain damage that may lead to neurodegeneration.
    Keywords:  18F fluorodeoxyglucose positron emission tomography; attentional network; cerebellum; cognition; frontal lobe; limbic network; parietal lobe; polysomnography; rapid eye movement sleep
    DOI:  https://doi.org/10.1002/alz.71211
  38. Immun Inflamm Dis. 2026 Jun;14(6): e70469
    Research Progress on Anti-Inflammatory Adipokine SFRP5-Mediated Lipid Metabolism and Its Potential Role in Neural Development.
    Qianfang Jia, Zihan Li, Tianyi Yang, Weihua Yang, Wei Chi.
       OBJECTIVE: To systematically review the structural features of secreted frizzled‑related protein 5 (SFRP5) and its dual regulation of canonical/non‑canonical Wnt signaling, analyze its association with metabolic disorders, and specifically explore the role and mechanisms of the SFRP5-lipid metabolism axis in neural and optic nerve development.
    METHODS: A systematic literature search was performed to review the molecular structure of SFRP5, its regulation of Wnt pathways, and its relationship with metabolic dysregulation. The mechanisms by which SFRP5 modulates the microglia/astrocyte‑mediated neuroimmune microenvironment, myelination, synaptic plasticity, and neuronal mitochondrial energy homeostasis were analyzed, and current therapeutic strategies targeting the SFRP5 network were summarized.
    RESULTS: SFRP5 participates in normal central nervous system development by shaping the neuroimmune microenvironment, promoting myelination, regulating synaptic plasticity, and maintaining mitochondrial energy balance. Under obese and diabetic conditions, downregulation of SFRP5 leads to overactivation of Wnt5a/JNK signaling, resulting in lipid metabolic disturbances and neuroinflammation. These changes share common pathological features with neurodevelopmental disorders such as autism spectrum disorder, intellectual disability, optic nerve hypoplasia, and retinal vascular dysplasia. The SFRP5-lipid metabolism axis plays a critical role in neural and optic nerve development, and its dysregulation underlies the neuropathology associated with metabolic diseases. Therapeutic interventions explored to date-including recombinant protein, gene therapy, small‑molecule activators, and acupuncture-have shown promising potential.
    CONCLUSION: The SFRP5-lipid metabolism axis represents a key link connecting metabolic disorders with neurodevelopmental abnormalities. Future research should focus on spatiotemporal specificity at single‑cell resolution, elucidation of gene-environment interactions, and the development of efficient central nervous system delivery systems, thereby providing new avenues for the prevention and treatment of neural and optic nerve developmental abnormalities.
    Keywords:  SFRP5; lipid metabolism; neural development
    DOI:  https://doi.org/10.1002/iid3.70469
  39. iScience. 2026 Jul 17. 29(7): 116337
    Multimodal atlas of single neuron metabolic electrophysiological coupling uncovers circadian rewiring.
    Man Yuan, Siyuan Ge, Wenwei Qian, Chenjian Miao, Wei Liang, Qi Chen, Hongying Zhu, Wei Xiong.
      Neuronal metabolism fundamentally modulates synaptic activity, yet how single-cell metabolic architecture aligns with electrophysiological diversity remains elusive. By integrating patch-clamp electrophysiology with single-neuron mass spectrometry (SNMS), we resolve metabolomic heterogeneity across suprachiasmatic nucleus (SCN) neurons, revealing six metabolic states with distinct synaptic dynamics, from lipid-enriched SCN1 exhibiting high-frequency presynaptic activity to quiescent SCN6. Pathway analysis linked metabolic state-specific signatures to sulfur metabolism, glutathione regulation, and citrate cycle dynamics. Machine learning and correlation networks mapped metabolites to functional parameters: histidine, carnitine, and creatinine regulated neuronal activity, validated by intracellular metabolite delivery experiments. Strikingly, light-dark cycles dynamically reconfigured most of the metabolite-postsynaptic current correlations, including light-induced taurine coupling to synaptic transmission. This multimodal platform establishes cellular metabolism as a tunable factor associated with neuronal heterogeneity and circadian plasticity, suggesting potential therapeutic avenues for circadian disorders.
    Keywords:  cellular physiology; metabolomics; neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2026.116337
This page is being maintained by Thomas Krichel. It was last updated on 2026‒06‒29 at 11:21.