bims-medebr 2026-08-30 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–08–30
35 papers selected by
Regina F. Fernández, Johns Hopkins University

Ketone bodies in the developing brain: Sex-specific metabolic pathways during the neonatal period.
Consumption of Fructose by Cultured Primary Rat Astrocytes.
Isomer-Resolved Mass Spectrometry Imaging Reveals Regional and Age-Dependent Glycolipid Metabolism in Rat Brain.
EXPRESS: The microdialysis-derived lactate-pyruvate gradient indicates anaerobic activity after brain injury.
Extracellular vesicles carrying the tenascin-C protein participate in glucose metabolism in neurodegenerative injury via inhibiting the AKT/GLUT1 pathway.
Glial ceramide orchestrates lipid homeostasis and age-dependent motor function.
The Microglia-Astrocyte-Neuron Lactate Shuttle model.
ABCC6 in Cellular Metabolic Homeostasis: Biochemical Links to Extracellular Nucleotide Signaling, Mitochondrial Stress, and Senescence.
Endogenous Lipid Signals in Energy Homeostasis and Fibrosis.
Polyamine Metabolism in Brain Health and Disease.
The Unsaturated/Saturated Fatty Acid Ratio: A Metabolic Hub and Therapeutic Vulnerability in Glioblastoma.
Nicotinamide Mononucleotide Adenylyltransferase 1 and NAD+ Homeostasis in Neuroprotection and Aging.
Investigating Mitochondrial Bioenergetics in Intact Heart and Brain Tissue Slices.
Lipid Metabolism in Central Nervous System Diseases: Pathological Mechanisms and Therapeutic Advances.
ODC1-associated astrocytic urea cycle dysregulation in age-related memory impairment.
Microglial Immunometabolic Remodeling After Ischemic Stroke: The Interplay Between Mitochondrial Stress and the Ischemic Microenvironment.
Anabolic androgenic steroids induce distinct monoaminergic and lipidomic alterations in the male rat brain.
Glycation at the Gate: A Brain Endothelial Glycocalyx Model and Therapeutic Roadmap for Alzheimer's Disease.
Protocol for assessing molecular signatures and metabolic function of primary murine cortical astrocytes.
Spatial Metabolomics Reveals Microregion-Specific Neurochemical Perturbations in the Brains of PCPA-Induced Insomniac Rats: Integration of MALDI-MSI and Targeted LC-MS/MS.
Truthful visualizations for mass spectrometry imaging enable high-spatial-resolution interactive m/z mapping and exploration.
Treating a Disorder Caused by an Overactive Enzyme: BCKD-Kinase Deficiency.
MALDI Mass Spectrometry Imaging in Alzheimer's Disease Lipidomics: Matrix Selection, Spatial Lipid Pathology and Emerging Analytical Strategies.
Mitochondrial Complex V Dysfunction in Neurodegeneration: Secondary Bystander or Primary Driver?
Selenoprotein I deficiency disrupts iron homeostasis in brain.
AS1411-Induced Lipidomic Alterations and Therapeutic Insights in U-87 Glioblastoma Cells.
From metabolic intermediary to neurotransmitter: purinergic signaling in neurophysiology and vulnerability of brain circuits.
Traumatic Brain Injury: Multi-Omics Insights into Brain Aging, Neurodegeneration, and Precision Therapeutics.
Decreased cerebral metabolic rate of oxygen (CMRO2) is associated with increased tau deposition in Alzheimer's disease.
Brain O-GlcNAcylation in Neurodegenerative Diseases: Context-Dependent Mechanisms and Precision Therapeutic Translation.
Ank3 loss in adult forebrain excitatory neurons disrupts behavior, neuronal activity, membrane proteome, and myelination.
Potential Role of Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) Abnormalities in Epileptogenesis: Multimodal Mechanisms and Therapeutic Targets.
Transcriptomic analysis reveals and validates lipid raft-associated biomarkers and functional networks in Alzheimer's disease.
Vitamin K in brain metabolism and cognitive function: mechanistic evidence, human associations, and unresolved questions.
Propionic Acid Remodels Mitochondrial Metabolism in SH-SY5Y Cells.

Life Sci. 2026 Aug 22. pii: S0024-3205(26)00450-9. [Epub ahead of print]404 124641

Ketone bodies in the developing brain: Sex-specific metabolic pathways during the neonatal period.

Kiara França Campos, Diorlon Nunes Machado, Adriana Fernanda Kuckartz Vizuete, Luciano Stürmer de Fraga, Carlos Alexandre Netto, Luz Elena Durán-Carabali.

  The developing central nervous system (CNS) relies on tightly regulated metabolic substrates, including glucose, lactate, and ketone bodies (KBs), to energy demands, brain maturation and neural circuit formation. Disruptions in substrate flow availability during early life can lead to long-lasting brain functional and structural impairments. Among these substrates, KBs serve as a critical alternative fuel during the neonatal period, sustaining cerebral energy demands under conditions of limited glucose availability and metabolic stress. Mounting evidence highlights pronounced sex-specific differences in brain development and vulnerability to injury, with males showing increased susceptibility to neurodevelopmental disorders, whereas females exhibit greater metabolic flexibility during hypoglycemia and oxidative stress. Despite this, most neuroscience and metabolic research remains male-focused, limiting our understanding of female-specific cerebral metabolic adaptations. This review examines KB metabolism across major neural cell types (astrocytes, neurons, oligodendrocytes and microglia) during neurodevelopment, with a particular focus on sex-specific differences in substrate utilization, metabolic signaling and cellular resilience. Understanding these distinctions is critical, as even subtle energetic impairments during early brain development may contribute to neurological disorders with sex-biased prevalence. Addressing this gap may ultimately facilitate the development of more precise, sex-specific therapeutic strategies for neurodevelopmental disorders.

Keywords:  brain metabolism; ketone bodies; neonatal period; neurodevelopment; sex differences

DOI:  https://doi.org/10.1016/j.lfs.2026.124641
Neurochem Res. 2026 Aug 27. pii: 253. [Epub ahead of print]51(5):

Consumption of Fructose by Cultured Primary Rat Astrocytes.

Mariana Mesa-Leal, Ralf Dringen.

  Fructose has recently gained substantial interest in the context of diseases that are connected with sucrose-rich diets. Several studies have shown that astrocytes are able to metabolize fructose to some extent but less efficiently than glucose. To study whether and how fructose can fuel astrocytic energy metabolism, we used cultured primary astrocytes as model. These cells consumed fructose in a time- and concentration-dependent manner that followed apparent Michaelis-Menten type kinetics with a KM value of 2.8 ± 0.9 mM and a VMax value of 325 ± 32 nmol/(mg × h). Although the specific consumption of glucose and the production of lactate from glucose were around 4 times higher than the respective values for fructose, the loss of astrocytic cellular ATP during starvation was prevented by both fructose and glucose with similar concentration dependencies. However, severe differences were observed for fructose- and glucose-fed astrocytes, if the mitochondrial oxidative phosphorylation was impaired. For fructose-treated astrocytes the application of inhibitors of mitochondrial ATP regeneration almost doubled the low basal glycolytic lactate production, but this was insufficient to prevent a rapid and severe loss in cellular ATP content and subsequent cell toxicity. In contrast, for glucose-treated cells a strong upregulation of glycolysis was connected with a slow ATP loss and a delayed onset of toxicity. Although hexokinase in astrocytic cell lysates was found to have a high KM value for fructose (4.4 ± 1.1 mM), hardly any free fructose was found in astrocytic lysates even after exposure to 10 mM fructose, suggesting that not the phosphorylation but rather the uptake of fructose limits astrocytic fructose consumption. The data presented demonstrate that millimolar concentrations of fructose are required to make this hexose a suitable extracellular substrate for astrocytic metabolism and that fructose metabolism provides energy mainly by mitochondrial respiration.

Keywords:  ATP; Astrocytes; Fructose; Glycolysis; Metabolism; Respiration

DOI:  https://doi.org/10.1007/s11064-026-04873-w
ACS Cent Sci. 2026 Aug 26. 12(8): 1146-1157

Isomer-Resolved Mass Spectrometry Imaging Reveals Regional and Age-Dependent Glycolipid Metabolism in Rat Brain.

Hsi-Chun Chao, Marisa Asadian, Stanislav S Rubakhin, Fan Lam, Jonathan V Sweedler.

Glycolipids are essential for myelin integrity, but their extensive isomeric complexity, where isomers like galactosylceramide (GalCer) and glucosylceramide (GlcCer) have unique functions, has hindered our ability to map their metabolism in the brain. Existing mass spectrometry methods fail to resolve this complexity. We fundamentally overcome this barrier with a powerful new isomer-resolved mass spectrometry imaging workflow. By coupling ion mobility and mass spectrometry imaging with targeted enzymatic pretreatment, our method provides direct visualization of distinct de novo metabolic pathways for GalCer and GlcCer in situ. When applied to rat brains across the lifespan (2, 6, and 12 months), this technology revealed a previously unrecognized age-related decline that selectively affected the GalCer pathway, while the isomeric GlcCer pathway remained comparatively stable. We confirmed these metabolic alterations colocalize with myelin-associated proteins specifically in oligodendrocyte-rich regions, providing a functional link to altered oligodendrocyte-related lipid metabolism. This integrated approach provides a new paradigm for dissecting isomer-specific glycolipid metabolism, offering insight into lipid alterations in brain aging and opening new avenues for biomarker discovery in neurodegeneration.

DOI: https://doi.org/10.1021/acscentsci.6c00340
J Cereb Blood Flow Metab. 2026 Aug 26. 271678X261485404

EXPRESS: The microdialysis-derived lactate-pyruvate gradient indicates anaerobic activity after brain injury.

Michael Steven Baker, Joshua M Heihre, Tomasz Benedykt Kuliński, Claudia Ann Smith, Berfin Barlas, Chisomo Zimphango, Ivan Timofeev, Koby Baranes, Keri L H Carpenter, Mark Kotter, Mathew R Guilfoyle, Elham Rostami, Peter Hutchinson, Adel Helmy.

BACKGROUND: Cerebral microdialysis (CMD) after traumatic brain injury (TBI) has focused on lactate/pyruvate ratio (LPR), overlooking lactate-pyruvate gradient (LPG, the linear regression slope within a time segment of CMD datapoints) as a proxy for anaerobic activity.
METHODS: We retrospectively applied changepoint detection to the linear lactate-pyruvate relationship (L = mP + b) over time within patients from two independent CMD-monitored TBI cohorts (Cambridge, n = 510; Uppsala, n = 81), estimating per-segment LPG (m) and intercept (b, capturing metabolic variance). In vitro, we tested whether rotenone-induced mitochondrial dysfunction increases LPG in hiPSC-derived neurons, as expected if LPG tracks anaerobic activity.
RESULTS: In the Cambridge cohort, a median of two linear segments were identified per patient (median LPG = 19.83; median b = 0.54 mM). Between segments, LPR tracked LPG with heavy attenuation (β = 0.255). LPG was negatively associated with cerebral microdialysate glucose (p < 0.001) and 6-month GOSE (p = 0.039). Uppsala data confirmed pipeline robustness and replicated the LPG-glucose association (p = 0.022). LPG was higher in rotenone-treated neurons than controls (32.9 vs. 14.2, p < 0.001).
CONCLUSION: LPG calculated per time segment provides a more accurate, outcome-associated proxy for anaerobic activity than datapoint-level LPR.

DOI: https://doi.org/10.1177/0271678X261485404
Chem Biol Interact. 2026 Aug 28. pii: S0009-2797(26)00426-6. [Epub ahead of print] 112318

Extracellular vesicles carrying the tenascin-C protein participate in glucose metabolism in neurodegenerative injury via inhibiting the AKT/GLUT1 pathway.

Xu Liu, Lingfan Chen, Xuedong Zhu, Qingqing Wu, Caiting Bu, Fuli Zheng, Guangxia Yu, Hong Hu, Zhenkun Guo, Jinfu Zhou, Siying Wu, Huangyuan Li, Wenya Shao.

  Extracellular vesicles (EVs) serve as key mediators of intercellular communication within the nervous system. An adequate glucose supply is essential for normal brain function; however, cerebral glucose metabolism is progressively impaired in Parkinson's disease (PD). Here, we show that EVs released by microglia exposed to 40 μM paraquat (PQ) are internalized by dopaminergic neurons, where they impair glucose metabolism and induce neurodegenerative injury through the intercellular transfer of tenascin-C (TNC). TNC, which has been proposed as a potential indicator of disease severity, is upregulated following neurological injury and has been implicated in neuronal apoptosis and neuroinflammation. EVs released by microglia exposed to 40 μM PQ reduced neuronal glucose uptake, disrupted glucose metabolism, and exacerbated mitochondrial dysfunction. Proteomic analysis revealed that EVs derived from PQ-exposed microglia were enriched in TNC. Co-immunoprecipitation analysis further demonstrated an interaction between EV-transferred TNC and protein kinase B (AKT) in recipient neurons. Both depletion of TNC from EVs and pharmacological activation of AKT restored glucose uptake in recipient neurons. Collectively, these findings demonstrate that, under PQ exposure, activated microglia impair neuronal glucose metabolism by releasing TNC-enriched EVs. The EV-mediated TNC-AKT/ glucose transporter 1 (GLUT1) axis may therefore contribute to PQ-induced dopaminergic neurotoxicity and represent a potential therapeutic target for PD.

Keywords:  Extracellular vesicles; Glucose metabolism; Paraquat; Parkinson’s disease; Tenascin-C

DOI:  https://doi.org/10.1016/j.cbi.2026.112318
Dis Model Mech. 2026 Aug 24. pii: dmm.052840. [Epub ahead of print]

Glial ceramide orchestrates lipid homeostasis and age-dependent motor function.

Lovleen Garg, Karthik H, Aakash Chandramouli, Senthilkumar D, Siddhesh Kamat, Anuradha Ratnaparkhi, Girish Ratnaparkhi.

  Glial cells have emerged as equal partners to neurons in the development and maintenance of the nervous system. In this study, we examine the consequences of modulating glial ceramide metabolism on adult motor function. Glial reduction of ER-localised ceramide synthesis, as exemplified by knockdown (KD) of schlank or ifc or lace, leads to age-dependent motor defects, as does KD of ceramide transfer protein (CERT). Motor defects in CERT-null animals can be significantly rescued by glial CERT expression, further highlighting the importance of glial ceramide homeostasis. Expectedly, glial schlank KD and CERT KD lead to lipid modulation in the brain, characterised by decreased ceramide phosphoethanolamine, increased ceramide phosphates and triacylglycerols, as measured by lipid mass spectrometry, and intriguingly, decreased Lipid Droplet (LD) size and density. Further, disruption of CERT's interaction with the ER-tethering protein VAPB also affects LD dynamics. Our research implicates the glial sphingolipid pathway as an important determinant of age-dependent adult motor function, with LDs serving as a sensitive diagnostic readout. As such, our study has implications for a host of human motor neuron diseases with late-onset motor deficits.

Keywords:  CERT; Climbing; Glia; Lipid droplets; Neurodegeneration; Sphingolipid

DOI:  https://doi.org/10.1242/dmm.052840
Trends Neurosci. 2026 Aug 27. pii: S0166-2236(26)00163-3. [Epub ahead of print]

The Microglia-Astrocyte-Neuron Lactate Shuttle model.

Eduardo R Zimmer, Anne-Karine Bouzier-Sore, Luc Pellerin.

  In a recent study, Adler and colleagues demonstrated that microglia regulate blood glucose delivery to fuel the astrocyte-neuron lactate shuttle. As neuronal protein translation supported by this mechanism is essential for motor learning, these findings reveal how coordinated interactions among microglia, astrocytes, and neurons orchestrate neuroenergetics to support cognition.

Keywords:  GLUT1; brain energetics; endothelial cell; monocarboxylate transporters; motor cortex; neuroimaging

DOI:  https://doi.org/10.1016/j.tins.2026.08.003
Cell Biochem Biophys. 2026 Aug 22.

ABCC6 in Cellular Metabolic Homeostasis: Biochemical Links to Extracellular Nucleotide Signaling, Mitochondrial Stress, and Senescence.

Lingjuan Yang, Fangsicheng Zhang, Yilu Duan, Ying Li, Jiayi Tang, Xinyuan Zhao, Xiaoke Wang.

  ABCC6 (ATP-binding cassette subfamily C member 6) was initially identified as the disease gene for pseudoxanthoma elasticum, a disorder marked by ectopic mineralization. Beyond this classical role, emerging evidence supports ABCC6 as a liver-enriched transporter with broader metabolic relevance. ABCC6 promotes hepatocyte ATP (adenosine triphosphate)/ADP (adenosine diphosphate) release and supports ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1)-dependent PPi (inorganic pyrophosphate) generation, thereby maintaining circulating anti-mineralization buffering; downstream AMP (adenosine monophosphate) metabolism may also influence adenosine-related signaling. Although its subcellular localization remains debated, evidence supports predominant basolateral plasma membrane localization, whereas one fractionation study reported enrichment at MAM (mitochondria-associated membranes) that has not been independently validated. ABCC6 deficiency has been associated with altered lipoprotein metabolism, mitochondrial bioenergetic impairment, oxidative stress, senescence-like phenotypes, and context-dependent metabolic susceptibility. These mitochondrial findings are interpreted as ABCC6 deficiency-associated downstream phenotypes rather than as evidence for stable mitochondrial or MAM residence. This review integrates established mineralization biology with emerging metabolic evidence, focusing on the extracellular nucleotide-PPi pathway, downstream adenosine-related signaling, mitochondrial stress, lipid and cholesterol handling, and vascular complications. We also discuss therapeutic strategies aimed at restoring PPi availability, limiting calcification, or recovering ABCC6 expression and function.

Keywords:  ABCC6; Adenosine-Related Signaling; Aging; Extracellular Nucleotide–PPi Pathway; Lipid Metabolism; Metabolic Diseases; Mitochondrial Function

DOI:  https://doi.org/10.1007/s12013-026-02153-6
Biomolecules. 2026 Aug 11. pii: 1170. [Epub ahead of print]16(8):

Endogenous Lipid Signals in Energy Homeostasis and Fibrosis.

Camilla Di Meo, Sakthimala Palaniappan, Cristina Urbano, Giacomo Cimino, Francesco Cestra, Noemi De Dominicis, Veronica Carnicelli, Annamaria Tisi, Mauro Maccarrone.

  Endogenous bioactive lipids are complex signaling mediators actively involved in a plethora of pathophysiological processes, including energy homeostasis and fibrosis. Energy homeostasis is a stable internal state resulting from a dynamic balance between energy expenditure and storage. Dysregulated energy balance can contribute to fibrosis, exhibiting key metabolic effects on insulin sensitivity, glucose tolerance, lipid accumulation and metabolism, as well as on energy expenditure, ultimately leading to metabolic disorders. In this context, three major classes of endogenous lipid mediators derived from polyunsaturated fatty acids (PUFAs)-eicosanoids, specialized pro-resolving mediators, and endocannabinoids-represent a key signaling network involved in the regulation of energy metabolism. Hence, alterations in their metabolism and signaling are often associated with fibrosis and other related molecular changes. Here, we provide a comprehensive overview of the role of the above-mentioned lipid classes in energy homeostasis and fibrosis by reviewing the available literature spanning nearly four decades, with a primary focus on studies published over the past 20 years.

Keywords:  bioactive lipids; eicosanoids; endocannabinoid system; energy homeostasis; fatty acid mediators; fibrosis; specialized pro-resolving mediators

DOI:  https://doi.org/10.3390/biom16081170
Neuropharmacol Ther. 2026 ;3 49-62

Polyamine Metabolism in Brain Health and Disease.

Xianzun Tao, Tracey Nassuna, R Grace Zhai.

  Polyamines, primarily spermidine and spermine, are small polycationic molecules essential for cell growth, signaling, and survival. Through electrostatic interactions with nucleic acids, lipids, and proteins, they regulate gene expression, organelle function, and adaptive responses to environmental cues. Polyamine metabolism also intersects with a myriad of other cellular pathways, including methionine, acetyl-CoA, and oxidative stress pathways, and is therefore involved in epigenetic control, cellular metabolism, and stress-response regulation. In the brain, beyond these general cellular functions, polyamines act as dynamic modulators of neurodevelopment, neural maintenance, and synaptic plasticity by influencing local proteostasis, transmitter release, and ion channel activity in both neurons and glia. Emerging evidence indicates that disruption of polyamine homeostasis contributes to neurological disorders as diverse as rare inborn errors of metabolism and common neurodegenerative diseases. Mutations in polyamine metabolic or transport genes lead to syndromes characterized by intellectual disability, hypotonia, movement disorders, and neurodegeneration; therefore, polyamine balance is critical for brain development and maintenance. In conditions such as Alzheimer's and Parkinson's diseases, dysregulated polyamine synthesis, catabolism, or lysosomal transport perturbs autophagic flux and proteostasis, thereby promoting Tau and α-synuclein aggregation, oxidative stress, and neuronal loss. Multi-omics analyses have further revealed that polyamine metabolism shapes glial inflammatory responses. Therapeutically, modulation of polyamine metabolism offers multiple intervention points. Spermidine supplementation or administration of polyamine analogues has been found to enhance autophagy and improve cognitive performance in models of aging and Alzheimer's disease. Additional strategies to reestablish metabolic equilibrium and support neuronal resilience include targeted manipulation of key enzymes, such as ornithine decarboxylase 1 (ODC1), spermidine/spermine acetyltransferase 1 (SAT1), spermine oxidase (SMOX), and spermine synthase (SMS), or restoration of lysosomal polyamine export via ATP13A2. This review synthesizes current understanding of polyamine metabolism in brain health and disease, by integrating molecular, cellular, and systems-level perspectives, and further highlights emerging therapeutic directions aimed at harnessing this pathway to mitigate neurological pathology.

Keywords:  autophagy; mitochondria; neurological disorders; neuroprotection; polyamine

DOI:  https://doi.org/10.15212/npt-2025-0028
Biomedicines. 2026 Aug 04. pii: 1757. [Epub ahead of print]14(8):

The Unsaturated/Saturated Fatty Acid Ratio: A Metabolic Hub and Therapeutic Vulnerability in Glioblastoma.

Xuhao Dai, Jialin Ku, Haixiang Li, Runxi Yan, Baofeng Wang.

  Glioblastoma (GBM) exhibits profound metabolic reprogramming, among which the balance between unsaturated and saturated fatty acids (UFA/SFA) emerges as a critical determinant of tumor behavior and treatment response. Recent studies have shown that fatty acid metabolic reprogramming is a key mechanism driving GBM progression. Abnormalities in fatty acid uptake, synthesis, desaturation, and oxidation collectively reshape the lipid composition of tumor cells, particularly by altering the unsaturated/saturated fatty acid ratio. Monounsaturated fatty acids mainly promote tumor cell proliferation and membrane biosynthesis, polyunsaturated fatty acids can induce lipid peroxidation and ferroptosis under specific stress conditions, whereas excessive saturated fatty acids can cause lipotoxicity when desaturation is limited. Key enzymes in fatty acid metabolism constitute a regulatory network and provide potential therapeutic targets for GBM. In addition, fatty acid metabolism can remodel the tumor immune microenvironment, especially by affecting the functional state of tumor-associated macrophages. Rather than targeting a single lipid species or isolated metabolic enzyme, therapeutic strategies that recalibrate the UFA/SFA ratio may provide a more integrated approach to restraining GBM progression and improving treatment sensitivity.

Keywords:  fatty acid metabolism; glioblastoma; unsaturated/saturated fatty acid ratio

DOI:  https://doi.org/10.3390/biomedicines14081757
Metabolites. 2026 Aug 21. pii: 597. [Epub ahead of print]16(8):

Nicotinamide Mononucleotide Adenylyltransferase 1 and NAD+ Homeostasis in Neuroprotection and Aging.

You Sun, Bowei Li, Zhengjiang Qian.

  Nicotinamide adenine dinucleotide (NAD+) is a fundamental metabolic cofactor and signaling molecule that supports redox reactions, DNA repair, chromatin regulation, stress adaptation, inflammation, and neuronal maintenance. Age-associated NAD+ decline has been implicated in brain aging and neurodegenerative disorders, but the causal node and limiting compartment differ across tissues and disease states. Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT-1) catalyzes the final step in NAD+ biosynthesis and represents the major nuclear isoform of the mammalian NMNAT family. Direct human genetic evidence establishes NMNAT-1 as a causal gene in inherited retinal degeneration, whereas evidence linking endogenous NMNAT-1 to broader brain aging or sporadic neurodegeneration is mainly convergent preclinical, preliminary, or indirect. Beyond NAD+ synthesis, biochemical and Drosophila studies suggest possible chaperone-like and proteostasis-supporting functions, but a separable NAD+-independent function of endogenous mammalian NMNAT-1 has not yet been established in vivo. Here, we review the molecular structure, localization, and regulation of NMNAT-1, emphasizing calibrated distinctions among catalytic nuclear NAD+ supply, engineered axonal protection, pathway-adjacent NAD+ interventions, and putative non-catalytic protection. We further discuss how NMNAT-1 dysfunction may contribute to aging-associated genomic instability, neuroinflammation, synaptic impairment, retinal degeneration, selected neurodegenerative models, and glioma biology. Finally, we evaluate therapeutic strategies targeting NMNAT-1 and NAD+ pathways, noting that no human trial has yet established efficacy for an NMNAT-1-directed neurological therapy. A compartment-aware and evidence-stratified view is therefore essential for translating NMNAT-1 biology into interventions for age-related neural disease.

Keywords:  NAD+; NMNAT-1; PARP1; SARM1; aging; axon degeneration; neuroprotection; proteostasis; retinal degeneration; sirtuins

DOI:  https://doi.org/10.3390/metabo16080597
Curr Protoc. 2026 Sep;6(9): e70451

Investigating Mitochondrial Bioenergetics in Intact Heart and Brain Tissue Slices.

Xavier R Chapa-Dubocq, Sukanya G Gakare, Walia Zahra, Meagan Donovan, Keishla M Rodriguez-Graciani, Tanner Hoole, Scott Edwards, Patricia E Molina, Michael C Salling, Janos Paloczi, Liz Simon.

  Mitochondria are essential for maintaining the high energetic demands of the heart and brain, generating ATP required for contractile function, neuronal signaling, and ionic homeostasis. In both tissues, metabolic flexibility is critical for maintaining bioenergetic efficiency, redox balance, and cellular viability. Despite their importance, existing experimental approaches to assess mitochondrial bioenergetic function present notable limitations. Isolated mitochondria and permeabilized cell assays provide precise control over substrates and respiratory states but disrupt organelle integrity and remove native cellular and extracellular context. Conversely, measurements in isolated or cultured cells preserve intact mitochondria but introduce phenotypic and metabolic artifacts. These constraints highlight the need for an intermediate platform that preserves native tissue architecture and cellular diversity while enabling quantitative assessment of mitochondrial bioenergetics. Building on prior demonstrations of respiration measurements in intact cardiac and neural tissue, we describe a tissue punch-based approach that enables region-specific analysis of mitochondrial function in small ex vivo tissue slices of intact heart and brain. This method preserves cytoarchitecture, and intercellular interactions while remaining compatible with high-resolution Seahorse respirometry analysis. Tissue punches allow multiple technical replicates from individual organs, reduce variability associated with isolation procedures, and enable assessment of regional metabolic heterogeneity, such as atrial versus ventricular myocardium or discrete brain regions. Here we present detailed and reproducible workflow protocols for brain and cardiac tissue punch preparation and extracellular flux analysis, including guidance on sample acquisition, punch sizing, normalization strategies, and data interpretation, with considerations for adapting the protocols across multiple pre-clinical models. © 2026 Wiley Periodicals LLC. Support Protocol: Preparation, Reagent Setup, and Instrumentation Basic Protocol 1: Cardiac tissue preparation Basic Protocol 2: Brain tissue preparation: rodents Basic Protocol 3: Brain tissue preparation: nonhuman primates Basic Protocol 4: Placement of tissue punches on Seahorse organoid plate Basic Protocol 5: Mitochondrial respiration measurements Basic Protocol 6: Tissue disruption for total protein quantification.

Keywords:  Seahorse XF analysis; animal models; bioenergetics; brain slices; heart slices; mitochondrial metabolism; tissue‐based respirometry

DOI:  https://doi.org/10.1002/cpz1.70451
CNS Neurosci Ther. 2026 Aug;32(8): e71109

Lipid Metabolism in Central Nervous System Diseases: Pathological Mechanisms and Therapeutic Advances.

Jiayan Yuan, Shixue Huang, Kun Jiao, Shu Yang, Xuhui Ge, Wei Liu, Wei Wang, Haoming Shu, Xuhui Zhou.

   BACKGROUND: Lipids are fundamental components of the central nervous system (CNS) structure and are essential for maintaining physiological homeostasis. Dysregulation of lipid homeostasis is a critical mechanism driving the pathogenesis and progression of classic CNS diseases, including neurodegenerative disorders, traumatic injuries, and cerebrovascular diseases. These metabolic disturbances trigger pathological processes such as abnormal protein aggregation, neuroinflammation, and lipid peroxidation, creating a vicious cycle that exacerbates disease progression. While targeting lipid metabolism offers a novel therapeutic strategy, its clinical translation faces significant hurdles.
SCOPE OF REVIEW: This review systematically summarizes the pathological roles and molecular mechanisms of lipid metabolism dysregulation across six representative CNS disorders: Alzheimer's disease (AD), Parkinson's disease (PD), spinal cord injury (SCI), traumatic brain injury (TBI), stroke, and intracerebral hemorrhage (ICH). These conditions were selected to cover a spectrum of pathologies, including protein-aggregation neurodegeneration, posttraumatic secondary injury, and cerebrovascular damage. The article outlines recent advances in therapeutic interventions targeting lipid metabolism and dissects both the shared and disease-specific regulatory mechanisms within the CNS.
KEY CHALLENGES: Despite the therapeutic potential, several challenges impede the development of effective lipid-targeting treatments. These include the incompletely defined mechanisms underlying dynamic lipid changes across different disease stages, insufficient efficiency of drug delivery across the blood-brain barrier, and the limited efficacy of single-target interventions. This review addresses these existing hurdles and proposes potential solutions to overcome them.
CONCLUSION: Targeting lipid metabolism represents a promising frontier for treating CNS diseases. By providing a comprehensive reference on the metabolic underpinnings of these disorders and addressing current research bottlenecks, this review aims to lay the groundwork for the development of precise, targeted therapeutic strategies in future clinical applications.

Keywords:  lipid metabolism; neurodegeneration; therapeutic advances; traumatic CNS injuries

DOI:  https://doi.org/10.1002/cns.71109
Biogerontology. 2026 Aug 25. pii: 145. [Epub ahead of print]27(5):

ODC1-associated astrocytic urea cycle dysregulation in age-related memory impairment.

Mengna Wu, Shengyao Zhang, Xi Zhao, Bingyu Zhang, Guoran Wan, Jie Gui, Meng Zhang, Baoxue Yang, Dilong Chen, Guoli Li, Qiu Chen, Boyue Huang, Jianhua Ran.

  Aging is an inevitable physiological process characterized by progressive functional decline and degenerative alterations across organ systems. Metabolic disturbance, particularly the disruption of substance and energy metabolism, is increasingly recognized as a central hallmark of aging. Emerging evidence suggests that dysregulation of the urea cycle (UC) contributes to aging-related pathological processes, including cognitive impairment; however, its role in astrocyte-mediated brain aging remains unclear. In this study, we used a D-galactose-induced mouse aging model to investigate the involvement of UC activation in age-related cognitive decline. Aging mice exhibited marked cognitive impairment, accompanied by an increased proportion of reactive astrocytes in the hippocampus, a key pathological feature of brain aging. Metabolic analysis and molecular validation revealed enhanced UC activity and increased urea production in aging mice. Inhibition of UC activation reduced urea production and decreased the proportion of hippocampal reactive astrocytes. Mechanistically, the expression of key UC-related enzymes, including ornithine decarboxylase 1 (ODC1) and arginase 1 (ARG1), was significantly downregulated, accompanied by improved mitochondrial dynamics, particularly the restoration of mitochondrial fusion and fission balance. Furthermore, ODC1 knockdown confirmed its critical role in mediating UC activation in astrocytes and significantly alleviated aging-like cellular phenotypes. Notably, Ganoderma lucidum polysaccharide peptides (GLPs) effectively suppressed UC activation in aging astrocytes by downregulating ODC1 and ARG1. Collectively, this study identifies dysregulated astrocytic UC activity as a novel metabolic mechanism linking astrocyte reactivity, mitochondrial dysfunction, and age-related cognitive decline, suggesting that targeting ODC1-mediated UC activation and mitochondrial dynamics may provide a promising dual strategy for combating brain aging.

Keywords:  Aging; ODC1; Reactive astrocytes; UT-B; Urea cycle

DOI:  https://doi.org/10.1007/s10522-026-10483-4
Transl Stroke Res. 2026 Aug 22. pii: 100. [Epub ahead of print]17(5):

Microglial Immunometabolic Remodeling After Ischemic Stroke: The Interplay Between Mitochondrial Stress and the Ischemic Microenvironment.

Cui Liu, Qiang Liu, Weiyao Jing, Limei Liu, Long Wei, Xing Li, Xiaozheng Du.

  Following ischemic stroke, marked alterations in the local metabolic and inflammatory milieu of the brain drive immunometabolic remodeling and mitochondrial dysfunction in microglia, thereby shaping inflammation, damage clearance, and tissue repair. Existing studies have largely focused on individual metabolic pathways, leaving the relationships among the ischemic microenvironment, mitochondrial responses, and microglial functional changes incompletely understood. Available evidence indicates that the effects of these metabolic alterations vary with stroke phase, local injury severity, and mitochondrial status. This review summarizes current evidence on glycolysis and lactate transport, the tricarboxylic acid cycle and succinate signaling, lipid handling, and danger-signal sensing, with particular emphasis on their relationships with mitochondrial redox homeostasis and quality control. We also critically evaluate divergent findings across studies. By examining the interaction between the ischemic microenvironment and mitochondrial responses, this review aims to clarify the metabolic basis of microglial functional changes and to inform the assessment of potential therapeutic targets in microglial immunometabolism.

Keywords:  Ischemic stroke; Metabolic regulation; Microglia; Mitochondria

DOI:  https://doi.org/10.1007/s12975-026-01492-z
Neuropsychopharmacology. 2026 Aug 26.

Anabolic androgenic steroids induce distinct monoaminergic and lipidomic alterations in the male rat brain.

Sofia Zelleroth, Ibrahim Kaya, Frida Stam, Johan Gising, Mats Larhed, Reza Shariatgorji, Anna Nilsson, Alfhild Grönbladh, Per E Andrén, Mathias Hallberg.

The illicit use of anabolic androgenic steroids (AAS) to enhance physical strength, performance, and appearance is associated with severe physical and psychological adverse effects. Long-term AAS use has been associated with altered behavior and cognitive impairments. Nevertheless, the neurobiological effects of AAS use remain underexplored, especially in terms of brain neurotransmitter and lipid profiles. This study applied advanced Fourier-transform ion cyclotron resonance matrix-assisted laser desorption/ionization mass spectrometry imaging (FTICR-MALDI-MSI) to investigate the effects of three AAS decanoate prodrugs, nandrolone, testosterone, and trenbolone, on brain monoamine neurotransmitter systems and lipid composition in male rats (n = 32). The AAS administration was found to alter dopamine and serotonin levels, as well as the metabolism of these molecules across multiple brain regions; significant effects on neurotransmitter levels, associated metabolites, and turnover ratios were observed. Additionally, AAS treatment affected brain lipid composition, with nandrolone and testosterone increasing the levels of phosphatidylethanolamines, ether-linked phosphatidylethanolamines, and phosphatidylserines; in contrast, trenbolone demonstrated an opposite trend. The presented findings revealed distinct, steroid-specific alterations in brain neurotransmitters and lipid profiles; these changes were particularly strong in the tail of the striatum, where lipid dysregulation was linked to neurotransmitter dynamics. The potential neurotoxic effects further highlight the importance of understanding how steroid-specific mechanisms are linked to behavioral and neurobiological changes. This study advances our knowledge of the neurobiological effects, including the potential risks, of extended AAS use.

DOI: https://doi.org/10.1038/s41386-026-02508-w
Biomedicines. 2026 Aug 10. pii: 1794. [Epub ahead of print]14(8):

Glycation at the Gate: A Brain Endothelial Glycocalyx Model and Therapeutic Roadmap for Alzheimer's Disease.

Rawan Tarawneh.

  While Alzheimer's disease (AD) is primarily considered a disorder of protein aggregation, converging evidence from clinical, neuropathological, and mechanistic studies strongly supports the notion that brain endothelial dysfunction is a primary and early event in AD pathogenesis. Brain endothelial pathways are among the most differentially expressed in human AD brains. Brain endothelial alterations precede amyloid deposition and cognitive deficits in experimental AD models and closely parallel the degree of neuronal loss in human AD brains. Despite growing evidence to support brain endothelial contributions to neurodegeneration, studies examining the potential of the brain endothelium as a druggable target in AD have been scarce. Further, there has been a relative paucity of validated fluid biomarkers that can reliably measure brain endothelial injury in AD, independently of overt vascular disease or disruption to other cerebrovascular constituents. In this perspective, we propose a brain endothelial glycocalyx-centric model of AD in which brain endothelial dysfunction, driven predominantly by non-enzymatic glycation and carbonyl stress, acts as a key upstream regulator of aberrant protein trafficking, blood-brain barrier instability, and dysregulated neuro-immune cascades. Further, recent evidence suggests the presence of direct interactions of the brain endothelium with key pathways involved in neuronal survival and synaptic signaling, highlighting potential direct contributions of brain endothelial disturbances to cognitive impairment. Within this framework, we identify several brain endothelial axes, including reduction in carbonyl stress, improved glycation-dependent signaling, attenuation of advanced glycation end-product (AGE)-mediated toxicity, and enhanced endothelial glycocalyx stability and resilience as potential therapeutic approaches in AD. Modulating brain endothelial glycation has potential as a novel therapeutic strategy in AD which may complement other disease-modifying treatments, particularly in the earliest preclinical stages. In conclusion, this framework positions the brain endothelium as a mechanistic hub linking metabolic stress to aberrant protein aggregation and neurodegeneration in AD with potential therapeutic implications in AD and other neurodegenerative disorders.

Keywords:  Alzheimer’s disease; brain endothelium; glycation; neurodegeneration

DOI:  https://doi.org/10.3390/biomedicines14081794
STAR Protoc. 2026 Aug 22. pii: S2666-1667(26)00446-6. [Epub ahead of print]7(3): 104793

Protocol for assessing molecular signatures and metabolic function of primary murine cortical astrocytes.

Nicole Blakeley, Baptiste Lacoste.

  Astrocytes are the most numerous brain cells and are central to the regulation of brain metabolism. Here, we present a protocol for identifying molecular signatures and assessing the metabolic function of primary murine cortical astrocytes. We describe steps for extracting, isolating and culturing astrocytes, characterizing these cells with immunocytochemistry, and extracting their metabolites. We then detail procedures for assessing mitochondrial function with challenges, RNA extraction for bulk sequencing, and DNA extraction for sequencing and epigenetics.

Keywords:  Cell Biology; Cell culture; Cell isolation; Cell-based Assays; Metabolomics

DOI:  https://doi.org/10.1016/j.xpro.2026.104793
Metabolites. 2026 Jul 31. pii: 543. [Epub ahead of print]16(8):

Spatial Metabolomics Reveals Microregion-Specific Neurochemical Perturbations in the Brains of PCPA-Induced Insomniac Rats: Integration of MALDI-MSI and Targeted LC-MS/MS.

Yan Yan, Jiaying Liu, Yingjian Deng, Yu Tao, Xinxin Li, Chenhui Du, Kun Yang, Ruiping Zhang.

  Objectives: Insomnia is a highly prevalent sleep disorder involving complex neurochem-ical dysregulation; however, the spatial distribution of neurotransmitters and small-molecule metabolites across distinct brain microregions in the insomniac state re-mains poorly characterized. This study aimed to map region-specific metabolic perturba-tions in situ in a p-chlorophenylalanine (PCPA)-induced insomnia rat model using opti-mized matrix-assisted laser desorption/ionization mass spectrometry imaging (MAL-DI-MSI) integrated with targeted metabolomics validation. Methods: On-tissue chemical derivatization MALDI-MSI was optimized using α-cyano-4-hydroxycinnamic acid (CHCA) as the matrix on a Bruker tims TOF flex mass spectrometer. The rats received PCPA (400 mg/kg, intraperitoneal) for three days to establish the insomnia model. Metabolite identifi-cation was conducted using MetaboScape® software (2020b) and the Human Metabolome Database. Ultra-performance liquid chromatography-tandem mass spectrometry was em-ployed to quantify nine key neurotransmitters and metabolites across six brain microre-gions. Key synthetic enzyme expression was evaluated by immunofluorescence and West-ern blotting analyses. Results: TMP-TFB-derived brain slices clearly showed the distribu-tion of neurotransmitters in brain microregions. MALDI-MSI demonstrated that the spatial distribution and abundance of eight neurotransmitters were disturbed in brains of PCPA-induced insomniac rats. A total of 346 metabolites were characterized across six brain microregions (cerebellum, cortex, hippocampus, brainstem, hypothalamus, and stri-atum), with principal coordinate analysis revealing clear metabolic separation between control and insomniac rats. PCPA treatment markedly disrupted tryptophan and tyrosine metabolism, evidenced by decreased 5-HT, 5-HTP, and 5-HIAA, alongside region-specific alterations in DA, NE, HVA, and Ach. Additionally, GABA levels decreased in the hippo-campus, striatum, and hypothalamus, whereas glutamate increased throughout the brain. Targeted metabolomics validated the MSI findings, and Bland-Altman analysis confirmed good consistency between the two analytical platforms. PCPA further disturbed the meta-bolic enzymes MAOA, DDC, and TPH2 within the Trp-5-HTP-5-HT-5-HIAA metabolic pathway in the brainstem and TYH and DBA within the tyrosine-DA-NE metabolic pathway in the striatum. Conclusions: This study demonstrates that region-specific altera-tions in tryptophan and tyrosine metabolism pathways provide mechanistic insights into insomnia pathogenesis and potential therapeutic targets.

Keywords:  LC-MS/MS; derivatization; insomnia; mass spectrometry imaging; spatial metabolomics

DOI:  https://doi.org/10.3390/metabo16080543
Sci Adv. 2026 Aug 28. 12(35): eaed3650

Truthful visualizations for mass spectrometry imaging enable high-spatial-resolution interactive m/z mapping and exploration.

Jacob Gildenblat, Jens Pahnke.

Mass spectrometry imaging (MSI) produces high-dimensional molecular data, but practical interpretation remains limited by visualizations that incompletely preserve global structure. We present MSI-VISUAL, an open-source framework for interactive MSI analysis that integrates truthful dimensionality reduction visualizations with region-of-interest selection, statistical comparison, and direct mass/charge ratio (m/z) mapping. MSI-VISUAL introduces four visualization strategies: SALO and SPEAR (optimization-based methods designed to improve global structure preservation across distance metrics) and TOP3 and PR3D (lightweight approaches for memory-efficient, rapid visualization of large datasets). Across benchmarks and lipidomics case studies, including mouse brain and kidney pathology examples, the proposed methods outperform commonly used alternatives in our benchmarks, improve detection of subtle tissue differences, and reveal fine molecular-anatomical patterns that support biological insights. These results establish MSI-VISUAL as a scalable framework for discovery-oriented and diagnostic MSI workflows.

DOI: https://doi.org/10.1126/sciadv.aed3650
J Inherit Metab Dis. 2026 Sep;49(5): e70242

Treating a Disorder Caused by an Overactive Enzyme: BCKD-Kinase Deficiency.

Juliana Ribeiro-Constante, Trine Tangeraas, Angeles García-Cazorla.

  Branched-chain ketoacid dehydrogenase kinase (BCKDK) deficiency is a rare autosomal recessive disorder. Loss of this kinase leaves the branched-chain α-ketoacid dehydrogenase complex constitutively active, leading to depletion of branched-chain amino acids (BCAAs) rather than their accumulation. To date, 31 patients from 20 families have been reported. In the largest systematic series, global developmental delay and intellectual disability are universal, autism spectrum disorder occurs in 71%, epilepsy in 43%, and progressive postnatal microcephaly. Mean age at diagnosis is close to 6 years, partly because the clinical picture resembles many forms of idiopathic neurodevelopmental disability. Treatment with a high-protein diet (≥ 2 g/kg/day) and BCAA supplementation (100-250 mg/kg/day) can normalize plasma BCAA levels and appears to stabilize motor function and head circumference. In the limited data available, three patients who started treatment before age 2 did not develop autism, and the earliest-treated patient (8 months) was developing normally at 3 years of follow-up. However, current therapy has clear limitations. Tracer studies in Bckdk knockout mice show reduced incorporation of BCAA-derived nitrogen into brain glutamate even with dietary intervention, pointing to a gap between peripheral biochemical correction and what the brain actually receives. Emerging strategies include partial pharmacological suppression of BCKDH activity, stabilization of residual mutant BCKDK protein, and gene therapy. Newborn screening, feasible with existing technology, deserves consideration given the contrast in outcomes between early and late treatment. This review examines what current treatment achieves, where it falls short, and what additional strategies may be needed.

Keywords:  BCKDK deficiency; autism spectrum disorder; branched‐chain amino acids; metabolic encephalopathy; newborn screening; treatable neurodevelopmental disorder

DOI:  https://doi.org/10.1002/jimd.70242
Int J Mol Sci. 2026 Aug 07. pii: 7074. [Epub ahead of print]27(16):

MALDI Mass Spectrometry Imaging in Alzheimer's Disease Lipidomics: Matrix Selection, Spatial Lipid Pathology and Emerging Analytical Strategies.

David Aebisher, Anna Krzysztofińska, Barbara Smolak, Patrycja Bernat, Wiktoria Czajka, Magdalena Kowal, Sylwia Krasoń, Klaudia Dynarowicz, Wiesław Guz, Dorota Bartusik-Aebisher.

  Alzheimer's disease (AD) involves not only amyloid-β and tau pathology but also extensive disturbances in lipid metabolism, membrane organization, neuroinflammatory signaling, and tissue homeostasis. Conventional lipidomics has identified changes in phospholipids, sphingolipids, sulfatides, ceramides, gangliosides, and cholesterol-related pathways, but tissue homogenization removes their anatomical context. The aim of this review is to critically assess how matrix selection, sample preparation, ionization polarity, and emerging analytical strategies influence the detection and interpretation of spatial lipid alterations specifically associated with AD neuropathology. Current evidence shows that AD-related lipid remodeling is region- and lesion-specific, with recurrent findings including ganglioside accumulation, sulfatide depletion, ceramide-related alterations, phospholipid remodeling, lysosomal lipid changes, and disturbed cholesterol homeostasis within or around amyloid plaques. Matrix chemistry strongly influences lipid-class coverage, ionization efficiency, spectral background, adduct formation, spatial resolution, and biological interpretation. Matrix-Assisted Laser Desorption/Ionization with Laser-Induced Post-Ionization (MALDI-2), ion mobility, reactive matrices, on-tissue derivatization, structural lipidomics, single-cell imaging, and spatial multiomics are expanding molecular coverage and annotation confidence. However, broader translation requires standardized workflows, structurally validated assignments, quantitative quality control, larger human cohorts, and improved interlaboratory reproducibility. Collectively, the available evidence indicates that the principal value of Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI) in AD lies not merely in detecting altered lipid abundance, but in resolving lesion-specific lipid microenvironments whose interpretation depends directly on matrix chemistry, spatial resolution, and structural validation.

Keywords:  Alzheimer’s disease; MALDI mass spectrometry imaging; amyloid plaques; gangliosides; ion mobility; matrix selection; molecular neuropathology; on-tissue derivatization; spatial lipidomics; sulfatides

DOI:  https://doi.org/10.3390/ijms27167074
Brain Sci. 2026 Aug 20. pii: 890. [Epub ahead of print]16(8):

Mitochondrial Complex V Dysfunction in Neurodegeneration: Secondary Bystander or Primary Driver?

Kate Erin Harris, Gerassimos Lascaratos, Kai-Yin Chau.

   BACKGROUND/OBJECTIVES: Mitochondrial Complex V (Complex V [CX-V], or ATP synthase) is the terminal enzyme of oxidative phosphorylation and is responsible for the majority of cellular ATP production. An increasing body of evidence suggests that CX-V dysfunction may contribute to mitochondrial impairment observed in neurodegenerative disease. This review evaluated current research on the structure, regulation, and function of CX-V, examined the consequences of CX-V dysfunction, and assessed its proposed role in neurodegenerative disorders.
METHODS: A comprehensive review of the published literature was carried out, with emphasis on primary research investigating CX-V structure and function, inherited CX-V disorders, and experimental evidence linking CX-V dysfunction to neurodegenerative disease. The reviewed studies used a range of experimental approaches, including structural biology, biochemical studies, patient-derived cellular models, animal models and post-mortem human tissue.
RESULTS: Current evidence demonstrates that disruption of CX-V impairs ATP production, alters mitochondrial membrane potential, and oxidative phosphorylation, and that pathogenic variants cause primary mitochondrial disease. Across Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis/frontotemporal dementia, glaucoma and inherited optic neuropathies, alterations in CX-V activity, regulation and structural integrity are consistently associated with mitochondrial dysfunction. Direct evidence supporting CX-V as a primary driver of neurodegeneration remains very limited, with many observations originating from broader studies of general mitochondrial dysfunction.
CONCLUSIONS: CX-V dysfunction represents a recurring feature of mitochondrial impairment across a variety of neurodegenerative disorders and may exacerbate neuronal vulnerability by disrupting cellular bioenergetics. Current evidence indicates that CX-V may serve as a common downstream target of multiple pathological pathways rather than acting as a primary pathological factor. Future studies require direct assessment of CX-V activity in clinically relevant human models and patient tissues to determine its contribution to disease progression and examine its potential as a therapeutic target.

Keywords:  ATP hydrolysis; ATP synthase; ATP synthesis; Complex V; bioenergetics; mitochondria; neurodegeneration

DOI:  https://doi.org/10.3390/brainsci16080890
Neurobiol Dis. 2026 Aug 28. pii: S0969-9961(26)00333-5. [Epub ahead of print] 107588

Selenoprotein I deficiency disrupts iron homeostasis in brain.

Karlin Wurlitzer, Chi Ma, Lance G A Nunes, Marissa Watanabe, Cole Griffin, Vedbar S Khadka, Antonio G Soares, Fukun W Hoffmann, Peter R Hoffmann, Matthew W Pitts.

  Selenoprotein I (SELENOI) is an essential enzyme for phospholipid synthesis that catalyzes the production of plasmenyl-phosphatidylethanolamine (plasmenyl-PE), a key component of myelin that protects and insulates axons. We recently generated a mouse model of central nervous system-restricted SELENOI deficiency that recapitulates features observed in humans with rare loss-of-function SELENOI gene mutations such as motor deficits, diminished plasmenyl-PE, and hypomyelination. Crucially, myelin-producing oligodendrocytes have the highest concentration of iron among cell types in brain. Iron is a vital metal cofactor due to its contribution to redox reactions, but this property also predisposes it to generating reactive oxygen species via Fenton reactions. Moreover, an excess of redox-active iron promotes lipid peroxidation and increases susceptibility to cell death via ferroptosis. In this report, we show that SELENOI deficiency in mouse brain leads to ferroptosis in white matter tracts and promotes iron accumulation. These alterations are accompanied by oligodendrocyte proliferation and elevated numbers of ferritin-positive microglia in affected regions. Overall, our findings detail an intermittent cycle of oligodendrocyte death and proliferation that occurs when SELENOI is absent from the brain, resulting in accelerated iron accrual.

Keywords:  Ether lipid; Ferroptosis; Lipid peroxidation; Oligodendrocyte; Selenoprotein; iron

DOI:  https://doi.org/10.1016/j.nbd.2026.107588
Biomolecules. 2026 Jul 25. pii: 1091. [Epub ahead of print]16(8):

AS1411-Induced Lipidomic Alterations and Therapeutic Insights in U-87 Glioblastoma Cells.

Ozan Kılıçkaya, Serap Şahin.

  Glioblastoma (GBM) is a devastating brain tumor heavily reliant on metabolic reprogramming for survival. The DNA aptamer AS1411 specifically targets cell-surface nucleolin (NCL), a protein overexpressed in GBM; however, its precise metabolic consequences remain largely unexplored. This study investigated the direct impact of AS1411-mediated NCL inhibition on the lipidomic profile of U-87 glioblastoma cells. It was demonstrated that AS1411 treatment induced acute cytotoxicity within 24 h. Subsequently, high-resolution mass spectrometry (MS) lipidomics was utilized to identify the lipidomic rewiring triggered by AS1411. Significant changes, such as the upregulation and/or exclusive emergence of specific long-chain and highly polyunsaturated diacylglycerol (DAG), triacylglycerol (TAG), and glycerophospholipid (GP) species, were determined in the species-level analyses. Additionally, our findings revealed that AS1411 treatment induced substantial alterations that profoundly affected membrane biophysics by modifying lipid saturation and acyl chain lengths. An increase in fully saturated sphingomyelin (SM) and cholesteryl ester (CE) levels was observed, leading to the formation of saturated lipid microdomains (lipid rafts) in endosomal and ER membranes, which causes membrane rigidification and decreased fluidity. Our results also demonstrate that PEs containing long-chain polyunsaturated fatty acids (PUFAs)-the primary substrates for ferroptosis-were upregulated. While AS1411 subjects cancer cells to methuotic vacuolization stress, it simultaneously reduces internal structural membrane fluidity and renders the cells metabolically vulnerable to ferroptosis. In conclusion, these detailed lipidomic results indicate that AS1411 treatment proceeds strictly through targeted remodeling and an adaptive scaffolding response.

Keywords:  aptamer AS1411; glioblastoma; lipidomics; mass spectrometry; nucleolin

DOI:  https://doi.org/10.3390/biom16081091
Biosci Rep. 2026 Sep 16. pii: BSR20250349. [Epub ahead of print]46(9):

From metabolic intermediary to neurotransmitter: purinergic signaling in neurophysiology and vulnerability of brain circuits.

Lucas Bonfim Marques, Allan de Carvalho, Raphael Luiz Lobo da Silva Souza, Fernanda Tibolla Viero, Luiz Roberto G Britto, Henning Ulrich.

  Purinergic signaling represents an ancient intercellular communication system. Operating at the interface between bioenergetic metabolism and damage detection, extracellular purines such as adenosine 5'-triphosphate (ATP) and adenosine (ADO) are recruited into the nervous system for neurotransmission and homeostatic control. Here, we discuss how purine-dependent mechanisms modulate excitation-inhibition balance, neuroplasticity, and neurodevelopment. In the hippocampus, ADO exerts inhibitory tonic functions, while ATP is released during high neuronal activity, being considered a destabilizing factor during pathological conditions. In the striatum, purinergic signaling intersects with dopaminergic and glutamatergic pathways in the fine-tuning of motor control, with ADO receptors modulating corticostriatal transmission and influencing vulnerability to excitotoxicity and neurodegeneration. Focusing on the cerebellum, we illustrate how purinergic signaling contributes to neurodevelopment and neuroplasticity, and how dysfunctions of the purinergic signaling system give rise to associated neuropathologies. In the brainstem, we demonstrate how purinergic signaling modulates autonomic and respiratory circuits to maintain cardiorespiratory homeostasis through astrocyte-neuron communication. Despite its adaptive value, purinergic signaling is optimized for transient, activity-, or damage-dependent activation. Thus, we argue that, under contemporary conditions characterized by chronic stress and extended lifespan, the purinergic signaling system may undergo a shift from predominantly acute to chronic engagement. This evolutionary mismatch may promote maladaptive purinergic activity, contributing to its involvement in synaptic dysfunction, neuroinflammation, and selective vulnerability of brain circuits. Moreover, we integrate evolutionary, neurophysiological, and neuropathological perspectives to propose purinergic signaling as a key mechanistic bridge linking neural function, bioenergetic metabolism, molecular pathways, and neurodegenerative diseases.

Keywords:  Huntington's disease; brainstem; cerebellum; epileptic seizure; hippocampus; neurodegeneration

DOI:  https://doi.org/10.1042/BSR20250349
Ageing Res Rev. 2026 Aug 27. pii: S1568-1637(26)00331-4. [Epub ahead of print] 103339

Traumatic Brain Injury: Multi-Omics Insights into Brain Aging, Neurodegeneration, and Precision Therapeutics.

Alaa Shafie, Amal Adnan Ashour, Muhanad Musaad Alhujaily, Farah Anjum, Farheen Akhtar, Md Imtaiyaz Hassan.

  Traumatic brain injury (TBI) is a major cause of mortality and persistent neurological disability and is increasingly recognized as a potential contributor to accelerated brain aging and long-term neurodegenerative processes. Beyond the immediate mechanical insult, TBI initiates dynamic secondary injury cascades involving chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, synaptic and axonal degeneration, metabolic disturbances, and blood-brain barrier disruption. The persistence and temporal evolution of these molecular alterations may interact with intrinsic aging mechanisms, contributing to progressive neuronal dysfunction and increased vulnerability to age-associated neurodegenerative disorders. The marked biological and temporal heterogeneity of TBI therefore presents major challenges for conventional diagnostic, prognostic, and therapeutic approaches. Recent advances in multi-omics technologies, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and single-cell and spatial approaches offer unprecedented opportunities to characterize the molecular trajectories linking TBI, brain aging, and neurodegeneration. Integrative multi-omics frameworks, coupled with network biology, artificial intelligence, machine learning, and causal inference, enable the identification of molecular signatures, age-related regulatory networks, clinically relevant biomarkers, and therapeutically actionable targets. This review synthesizes emerging multi-omics insights into the molecular mechanisms through which TBI may influence brain aging and neurodegenerative progression, with particular emphasis on phase-specific molecular signatures, biomarker discovery, patient stratification, therapeutic target prioritization, and precision neurotherapeutics. We further discuss longitudinal profiling, single-cell and spatial approaches, and AI-assisted modeling for patient stratification and therapeutic optimization. Integrating multi-omics with systems biology may provide a framework for studying TBI-associated brain aging and developing personalized interventions, although prospective clinical validation remains essential.

Keywords:  Traumatic brain injury; biomarkers; brain aging; multi-omics; neurodegeneration; precision medicine; systems biology

DOI:  https://doi.org/10.1016/j.arr.2026.103339
Alzheimers Dement (Amst). 2026 Jul-Sep;18(3):18(3): e70442

Decreased cerebral metabolic rate of oxygen (CMRO2) is associated with increased tau deposition in Alzheimer's disease.

Hangwei Zhuang, Liangdong Zhou, Xiuyuan Hugh Wang, Emily B Tanzi, Yi Li, Pascal Spincemaille, Ilhami Kovanlikaya, Thanh D Nguyen, Yi Wang, Gloria C Chiang.

   Introduction: Transgenic Alzheimer's (AD) mouse models and post mortem studies have shown that tau pathology disrupts the mitochondrial electron transport chain and results in mitochondrial damage and synaptic dysfunction. We assessed whether magnetic resonance imaging (MRI)-derived measures of oxygen metabolism, oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) were associated with tau deposition in vivo.
Methods: We assessed tau using 18F-MK-6240 positron emission tomography and CMRO2/OEF using multi-echo gradient-recalled echo with QQ processing, as well as pseudo-continuous arterial spin-labeling MRI in cognitively normal (CN) elderly and subjects with mild cognitive impairment/AD (N = 42). Associations among imaging measures were evaluated across cortical lobes, including comparisons between regions with and without tau deposition.
Results: Across all subjects, higher tau standardized uptake value ratio (SUVR) was associated with lower cerebral blood flow (CBF) and CMRO2. Tau SUVR was negatively associated with Montreal Cognitive Assessment scores, whereas OEF, CBF, and CMRO2 were positively associated. Within subjects, CMRO2 was lower in tau-positive temporal regions in both CN and MCI/AD subjects, and CBF was lower in tau-positive temporal regions in CN subjects.
Discussion: MRI-derived CBF and CMRO2 were associated with regional tau deposition, particularly in the temporal lobe, which suggests they have potential as non-invasive markers of metabolic alterations accompanying tau pathology.

Keywords:  Alzheimer's disease; cerebral blood flow (CBF); cerebral metabolic rate of oxygen (CMRO2); magnetic resonance imaging (MRI); oxygen extraction fraction (OEF); tau PET

DOI:  https://doi.org/10.1002/dad2.70442
Brain Sci. 2026 Aug 04. pii: 828. [Epub ahead of print]16(8):

Brain O-GlcNAcylation in Neurodegenerative Diseases: Context-Dependent Mechanisms and Precision Therapeutic Translation.

Shaoshuai Lu, Ziyang Chen, Yanyan Wang, Hongsheng Bian, Shuang Yu, Lili Huang.

  O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) is a dynamic, nutrient-sensitive post-translational modification that couples hexosamine biosynthesis pathway flux to protein function in neurons and glia. This reversible cycling, catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), integrates glucose, glutamine, acetyl-CoA, and nucleotide metabolism with synaptic activity, mitochondrial adaptation, transcriptional regulation, proteostasis, and neuroimmune signaling. Dysregulated O-GlcNAc cycling has been implicated in major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington's disease (HD), through effects on disease-related proteins, autophagy, mitochondrial function, and inflammatory networks. However, available evidence does not support a universal model in which global O-GlcNAc elevation is uniformly protective or global reduction is uniformly pathogenic. In this mechanistic narrative review, we integrate disease-specific and substrate-focused findings while distinguishing relatively mature translational evidence from model-based or hypothesis-generating observations. We propose a state-resolved framework in which disease-relevant O-GlcNAc states are interpreted across biological contexts, substrate/site specificity, and intervention dynamics. This framework helps reconcile divergent findings across experimental systems and highlights the limitations of indiscriminate global pathway modulation. Although OGA inhibitors represent the most advanced therapeutic strategy, their broad substrate effects underscore the need for pharmacodynamic biomarkers, human validation, brain-targeted delivery, and state-resolved approaches. Moving from bulk O-GlcNAc measurements toward precise correction of disease-relevant O-GlcNAc states across defined biological contexts will be essential for translating this biology into clinically meaningful interventions.

Keywords:  O-GlcNAcylation; OGA inhibitors; brain energy metabolism; neurodegenerative diseases; precision therapy; proteostasis; synaptic plasticity

DOI:  https://doi.org/10.3390/brainsci16080828
Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2606900123

Ank3 loss in adult forebrain excitatory neurons disrupts behavior, neuronal activity, membrane proteome, and myelination.

Sehyoun Yoon, Marc Dos Santos, Natalia Khalatyan, Jeffrey N Savas, Peter Penzes.

  ANK3, encoding the scaffolding protein ankyrin-G, is a major risk gene for bipolar disorder and schizophrenia, but its cellular and circuit-level mechanisms remain poorly defined. Here, we demonstrate that deletion of Ank3 in forebrain excitatory neurons-either prenatally (Ank3-/-:Emx1-Cre) or in adolescence (Ank3-/-:CaMKIIα-Cre) leads to convergent behavioral phenotypes in adulthood, including hyperactivity, reduced anxiety-like behavior, and decreased depression-like responses. Calcium imaging in cultured neurons and acute brain slices revealed that ankyrin-G loss reduces both spontaneous and evoked neuronal activity. Quantitative proteomic profiling of membrane-enriched cortical fractions uncovered widespread remodeling of the synaptic proteome, including upregulation of the kinase Taok2 and unexpected downregulation of myelin basic protein (Mbp), a structural component of oligodendrocyte-derived myelin. Importantly, chronic lithium treatment, known to reverse behavioral abnormalities in Ank3-deficient mice, also restored Mbp expression. Together, our findings identify ankyrin-G as a molecular bridge between excitatory neuronal activity, synaptic structure, and myelin-associated protein expression, revealing a pathway by which ANK3 variants may contribute to neuropsychiatric disease.

Keywords:  Ank3; Mbp; neuronal activity; neuropsychiatric disorders; proteomics

DOI:  https://doi.org/10.1073/pnas.2606900123
Mol Neurobiol. 2026 Aug 29. pii: 867. [Epub ahead of print]63(1):

Potential Role of Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) Abnormalities in Epileptogenesis: Multimodal Mechanisms and Therapeutic Targets.

Ruting Fu, Jiahao Liu, Liya Fang, Jin Guo.

  Epilepsy is a prevalent neurological disorder characterized by an incompletely understood etiology and a substantial unmet therapeutic need, particularly for drug-resistant forms. This review examines the potential role of mitochondria-associated endoplasmic reticulum membranes (MAMs) as emerging signaling hubs in epileptogenesis. We systematically analyze how MAMs regulate core cellular processes-including calcium signaling, lipid metabolism, mitochondrial dynamics, autophagy, and oxidative stress-and how dysregulation of these processes may contribute to seizure initiation and progression. Furthermore, we evaluate existing interventions, such as phytotherapeutics and the ketogenic diet, from the perspective of modulation of MAMs. The review also highlights novel strategies targeting MAMs, including small-molecule approaches, nanodelivery systems, and neuromodulation technologies, which offer promising avenues for precise therapeutic intervention. By consolidating current molecular and genetic evidence, we identify MAMs as a critical hub in epilepsy and propose that targeting their integrity and function may represent a strategy to overcome drug resistance and modify disease progression. By integrating current knowledge of MAMs biology with epilepsy pathophysiology, this work provides a mechanistic framework to guide future research. It offers insights for the development of targeted molecular therapies for epilepsy.

Keywords:  Calcium signaling regulation; Epilepsy; Epilepsy treatment strategies; Mitochondrial-associated endoplasmic reticulum membranes; Oxidative stress

DOI:  https://doi.org/10.1007/s12035-026-06141-y
IBRO Neurosci Rep. 2026 Dec;21 625-638

Transcriptomic analysis reveals and validates lipid raft-associated biomarkers and functional networks in Alzheimer's disease.

Chun-Hsien Hsu, Amadou Wurry Jallow, Fatima Saleem, Thi Minh Chau Vu, Yung-Feng Lin.

  Alzheimer's disease (AD) involves complex changes, including synaptic dysfunction, neuroinflammation, and metabolic impairment, yet the role of lipid raft-associated gene networks in these processes remains unclear. In this study, we performed an integrative transcriptomic analysis using the GSE5281 dataset and validated the findings in an independent cohort (GSE33000). By combining differential expression analysis with weighted gene co-expression network analysis, we identified 72 lipid raft-associated genes linked to mitochondrial, synaptic, and immune-related pathways. Using network analysis and machine learning approaches (LASSO and SHAP), we further identified eight key biomarkers (CBL, CD44, EZR, FAS, FYN, ITGB1, MAPK1, and TGFBR1) that showed strong diagnostic performance and consistent results across datasets. Functional analysis revealed increased inflammatory signaling, including pyroptosis and cytokine pathways, alongside reduced oxidative phosphorylation and synaptic activity. Interestingly, immune profiling showed only minor differences in immune cell infiltration, but clear activation of multiple immune pathways, such as Th2 and Treg signaling, CD8⁺ T-cell signatures, and IL-6/IL-10-mediated inflammation. These immune changes were strongly associated with lipid raft-related biomarkers. Overall, our findings suggest that lipid raft dysregulation may act as a key link between immune activation, mitochondrial dysfunction, and synaptic impairment in AD.

Keywords:  Alzheimer’s disease; Biomarkers; Lipid rafts; Neuroinflammation; Synaptic dysfunction; Transcriptomics

DOI:  https://doi.org/10.1016/j.ibneur.2026.08.013
Metab Brain Dis. 2026 Aug 24. pii: 191. [Epub ahead of print]41(1):

Vitamin K in brain metabolism and cognitive function: mechanistic evidence, human associations, and unresolved questions.

Osman Kukula.

  Vitamin K acts as a critical regulator across diverse biological systems, contributing significantly to skeletal integrity, cardiovascular functions, metabolic homeostasis, and immune defenses. Experimental studies increasingly suggest that it also plays an important role in the nervous system, supporting neuronal growth, differentiation, and survival. Its antioxidant, anti-inflammatory, and antiapoptotic effects, along with its capacity to act as an alternative electron carrier in mitochondria, further indicate potential neuroprotective properties. This narrative review synthesizes evidence from recent cell and animal studies, mechanistic research on sphingolipid metabolism, and observational data evaluating vitamin K status and cognitive outcomes. Findings from populations receiving long-term vitamin K antagonist therapy were reviewed to highlight potential clinical implications. Regulation of sphingolipid pathways by vitamin K appears to support neuronal proliferation and resilience, while adequate vitamin K levels have been associated with better cognitive performance. Conversely, prolonged exposure to vitamin K antagonists has been linked to impairments in visual memory and verbal fluency, as well as reductions in brain volume. Evidence also indicates that vitamin K is essential for the synthesis and maintenance of myelin and neuronal membrane components, and for activating vitamin K-dependent proteins that preserve neuronal integrity. Beyond its established role in coagulation, emerging preclinical and observational evidence suggests that vitamin K may possess neuroprotective potential through molecular, structural, and antioxidant mechanisms. The observed association between vitamin K antagonist therapy and cognitive decline in older adults highlights the need for comprehensive clinical studies to clarify causality, determine therapeutic relevance, and better define the role of vitamin K in brain health.

Keywords:  Cognitive function; Direct oral anticoagulants; FSP1; Ferroptosis; Menaquinone-4; Phylloquinone; Sphingolipids; UBIAD1; Vitamin K; Vitamin K antagonists

DOI:  https://doi.org/10.1007/s11011-026-01962-1
Biology (Basel). 2026 Aug 18. pii: 1424. [Epub ahead of print]15(16):

Propionic Acid Remodels Mitochondrial Metabolism in SH-SY5Y Cells.

Caitlyn Mahony, Erin Buchanan, Colleen O'Ryan.

  Mitochondrial mechanisms are increasingly implicated in complex neurological conditions, including Autism Spectrum Disorder (ASD). Propionic acid (PPA) is widely used to study mitochondrial dysfunction in preclinical models of ASD. However, the molecular mechanisms that drive PPA-induced neurotoxicity are unresolved. Here, we examined mitochondrial remodeling under PPA-induced stress in neuroblastoma SH-SY5Y cells. PPA systemically altered the transcriptional regulation of mitochondrial dynamics and disrupted canonical proteins involved in mitochondrial fusion (L-OPA1, MFN2), fission (DRP1) and quality control (LC3-II). Confocal microscopy revealed an upregulation of both fission and fusion events and impairments to mitochondrial integrity, connectivity and turnover. Live-cell respirometry demonstrated consequent deficits in both oxidative and glycolytic energy production, while respiratory chain electron flow assays illustrated a shift in TCA cycle flux driven by a remodeling of mitochondrial substrate utilization. This work describes a molecular signature of metabolic stress in the SH-SY5Y system, providing novel insights into the mechanisms and manifestations of PPA-induced neurotoxicity.

Keywords:  autism spectrum disorder; confocal microscopy; inherited metabolic diseases; mitochondrial dysfunction; propionic acidemia; respirometry

DOI:  https://doi.org/10.3390/biology15161424