bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2025–09–07
forty-two papers selected by
Regina F. Fernández, Johns Hopkins University
  1. TDP-43 dysregulation impairs cholesterol metabolism linked with myelination defects.
  2. Defining metabolic abnormalities in acute human traumatic brain injury with cerebral microdialysis and multimodality monitoring.
  3. Systematic characterization of cell type-specific master metabolic regulators in Alzheimer's disease.
  4. Editorial: Imaging brain network and brain energy metabolism impairments in brain disorders.
  5. Ketogenic Diet Modulates Gut Microbiota-Brain Metabolite Axis in a Sex- and Genotype-Specific Manner in APOE4 Mice.
  6. Targeting glucose transporters in parkinson's disease: a novel metabolic approach for disease modification.
  7. Lactate lactylation in neural pathophysiology: Bridging metabolism and neurodegeneration.
  8. Preliminary observations of glucose metabolism dysregulation in pediatric Huntington's disease.
  9. Association Between Plasma Metabolomic Profile and Machine Learning-Based Brain Age.
  10. NRF2 deficiency is associated with synaptic alterations and ether-linked phospholipid imbalance in the hippocampus.
  11. Hippocampal dysmetabolism contributes to cognitive loss in autoimmune encephalitis and focal temporal epilepsy.
  12. Underestimation of mitochondrial respiratory capacity in gray matter voxels of the human brain map due to limited OXPHOS and TCA cycle in astrocytes.
  13. Spatially Resolved Lipid Composition of the Human Brain Cortical Layers.
  14. Lipid-laden endothelial cells exhibit a transcriptomic signature linked to blood-brain barrier dysfunction, metabolic reprogramming and increased inflammation in the aging brain.
  15. Multi-omics reveals changes in astrocyte fatty acid metabolism during early stages of Alzheimer's disease.
  16. APOE genotypes differentially remodel the astrocytic lipid droplet-associated proteome to shape lipid droplet dynamics.
  17. Effect of nicotine on the energy metabolism of substantia nigra cells in MPTP-induced Parkinson's disease.
  18. Mitochondria: Key Mediator for Environmental Toxicant-Induced Neurodegeneration.
  19. Fueling the Mind: Brain Metabolism in Health and Neurodevelopmental Disorders.
  20. Increased ATP production and P-glycoprotein activity underlie the marked changes in blood-brain barrier transport of drugs in a mouse model of amyotrophic lateral sclerosis.
  21. Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.
  22. Compensatory roles of STT3A and ALG5 in glucose metabolism of aged macaque hippocampus.
  23. Genetic suppression features ABHD18 as a Barth syndrome therapeutic target.
  24. Sex differences in brain glucose metabolism in alzheimer's disease: A voxel-based study.
  25. Biliverdin reductase-A is a key modulator in insulin signaling and metabolism.
  26. Neuromodulator control of energy reserves in dopaminergic neurons.
  27. Elovl1 inhibition reduced very long chain fatty acids in a mouse model of adrenoleukodystrophy.
  28. Mitochondria structurally remodel near synapses to fuel the sustained energy demands of plasticity.
  29. Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex.
  30. High-Specificity and Sensitivity Imaging of Neutral Lipids Using Salt-Enhanced MALDI TIMS.
  31. Palmatine mitigates ischemic brain injury by regulating microglial polarization and sphingolipid metabolism.
  32. Reelin Increases the Sphingomyelin Content of the Plasma Membrane and Affects the Surface Expression of GPI-Anchored Proteins in Hippocampal Neurons.
  33. Effects of aging and anti-aging dietary restriction on regulators of the [NADPH]/[NADP+] in different neural cell types and brain regions.
  34. Structural insights into the substrate uptake and inhibition of the human creatine transporter (hCRT).
  35. Generation of Astrocyte-Selective Cre Driver Lines With Distinct Onsets of Recombination Activity During Development.
  36. The Role of MRI in Debunking the Fallacy of "Mild" Traumatic Brain Injury.
  37. Regulatory Dynamics of Nrf2 With Sirtuins in the Brain: Exploring Cellular Metabolism, Synaptic Plasticity, and Defense Mechanisms.
  38. Temporal transcriptional regulation of mitochondrial morphology primes activity-dependent circuit connectivity.
  39. Hepatic Encephalopathy: Insights Into the Impact of Metabolic Precipitates.
  40. Proteo-transcriptomic reprogramming and resource reallocation define the aging mammalian brain.
  41. Impacts of mitochondrial dysfunction on axonal microtubule bundles as a potential mechanism of neurodegeneration.
  42. Unified mass imaging maps the lipidome of vertebrate development.
  1. Acta Neuropathol. 2025 Sep 04. 150(1): 23
    TDP-43 dysregulation impairs cholesterol metabolism linked with myelination defects.
    Irene García-Toledo, Juan M Godoy-Corchuelo, Luis C Fernández-Beltrán, Zeinab Ali, Ariadna Guindo-Arroyo, Irene Jiménez-Coca, Jesús Jiménez-Rodríguez, Karen Javaloyes-García, Marcos Viñuela, Ulises Gómez-Pinedo, Laura Saiz-Aúz, Alberto Rábano, Estela Área-Gómez, Thomas J Cunningham, Silvia Corrochano.
      TDP-43 is a nuclear protein encoded by the TARDBP gene, which forms pathological aggregates in various neurodegenerative diseases, collectively known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These diseases are characterized by multiple pathological mechanisms, with disruptions in lipid regulatory pathways emerging as a critical factor. However, the role of TDP-43 in the regulation of the brain lipid homeostasis and the potential connection of TDP-43 dysfunction to myelin alterations in TDP-43 proteionopathies remain poorly understood, despite the fact that lipids, particularly cholesterol, comprise nearly 70% of myelin. To investigate the causal relationship between TDP-43 dysfunction and disruptions in brain cholesterol homeostasis, we conducted multi-omics analyses (lipidomics, transcriptomics, and functional splicing) on the frontal cortex from the TardbpM323K/M323K knock-in mouse model. Lipidomic analysis revealed alterations in lipid pathways related to membrane composition and lipid droplet accumulation, particularly affecting cholesterol-related species. We found higher lipid droplet accumulation in primary fibroblasts derived from these mice, as well as in the brain of the mutant mice. Similarly, the immunohistochemical detection of a lipid droplet marker was higher in the postmortem frontal cortex, gray matter, and white matter of FTLD-TDP patients compared to non-neurological controls. Transcriptomic analyses showed that TDP-43 pathology led to transcriptional dysregulation of genes essential for myelin production and maintenance. We identified impaired cholesterol metabolism, mainly through the downregulation of endogenous cholesterol synthesis, alongside upregulated cholesterol transport pathways, which we further replicated in FTLD-TDP patients transcriptomic datasets. Collectively, our findings suggest that TDP-43 dysfunction disrupts brain cholesterol homeostasis, potentially compromising myelin integrity.
    Keywords:  Cholesterol metabolism; Lipid droplets; Lipidomics; Myelin; TDP-43 proteinopathies; Transcriptomics
    DOI:  https://doi.org/10.1007/s00401-025-02927-x
  2. PLoS One. 2025 ;20(9): e0331310
    Defining metabolic abnormalities in acute human traumatic brain injury with cerebral microdialysis and multimodality monitoring.
    Michael S Baker, Sara Venturini, Caroline Lindblad, Joshua M Heihre, Ivan Timofeev, Mathew R Guilfoyle, Peter J Hutchinson, Keri L H Carpenter, Adel Helmy.
       OBJECTIVE: We aimed to compare the prevalence and multimodal associations of mitochondrial dysfunction as defined by published cerebral-microdialysis-based criteria versus our novel multimodality-monitoring-based criteria in acute traumatic brain injury patients.
    METHODS: We retrospectively analyzed neurocritical care monitoring data from 619 acute traumatic brain injury patients. Monitoring modalities included cerebral microdialysis, intracranial pressure, brain tissue oxygenation, cerebral perfusion pressure, and the pressure reactivity index. The cerebral-microdialysis-based criteria we compared combine an elevated lactate/pyruvate ratio (25 or 30) with raised concentrations of lactate (2.5 mM) or pyruvate (70 μM or 120 μM). Our multimodality-monitoring-based criteria comprise a consistent lactate/pyruvate ratio > 25 with intracranial pressure ≤ 20 mmHg, brain tissue oxygenation ≥ 15 mmHg, a pressure reactivity index ≤ 0.3, and cerebral glucose ≥ 1.0 mM.
    RESULTS: Across 592 analyzable patients, a lactate/pyruvate ratio > 25 was common, with a median prevalence of 48.9% (41.5% with consistency) and a U-shaped, bimodal distribution. A lactate/pyruvate ratio > 25 was associated with lower glucose and higher glycerol, and when accompanied by high pyruvate (> 120 μM), this derangement was further distinguished by higher glutamate and cerebral perfusion pressure. Using multimodal criteria on a cohort of 268 patients, consistent mitochondrial dysfunction was identified in 25.7% to 41.0% of patients, often in the absence of other physiological derangements.
    CONCLUSIONS: Many acute traumatic brain injury patients constantly demonstrate neurometabolic derangements, among which clinical mitochondrial dysfunction is highly prevalent despite normal cerebral pressure, oxygenation, and perfusion. There is necessity for targeted, neurometabolic therapies in neurocritical care that address this abnormality.
    DOI:  https://doi.org/10.1371/journal.pone.0331310
  3. Res Sq. 2025 Aug 18. pii: rs.3.rs-7207381. [Epub ahead of print]
    Systematic characterization of cell type-specific master metabolic regulators in Alzheimer's disease.
    Yunguang Qiu, Yuan Hou, Liam Wetzel, Jessica Z K Caldwell, Xiongwei Zhu, Andrew A Pieper, Tian Liu, Feixiong Cheng.
      Alzheimer's disease (AD) exhibits metabolic heterogeneity; yet, the consequences on metabolic dynamics in a cell-type-specific manner and the underlying metabolite-sensor network basis remain unclear. Here, we show that neurons exhibit a striking decrease in energy and lipid-related metabolic activity, contrasted by an increase in microglial metabolism associated with neuroinflammation. To identify brain cell-type specific master metabolic regulators underlying the metabolic alterations of AD, we introduce scFUMES (single cell FUnctional MEtabolite-Sensor), an algorithm integrating single-cell RNA sequencing, interactomics (protein-protein interactions), genomics, transcriptomics, and metabolomics from large human brain biobanks. Applied to two AD-vulnerable regions (middle temporal gyrus and dorsolateral prefrontal cortex), scFUMES uncovers hundreds of AD-associated regulators, with neurons and microglia showing the most interactions. Particularly, scFUMES pinpoints genetics-informed master metabolic regulators across AD severity, sex and APOE genotype (e.g., PPARD-glycerol in microglia). Experimental testing reveals that two interaction pairs predicted by scFUMES, neuronal palmitic acid bound fatty acid binding protein 3 and gut metabolite indole-3-propionic acid binding to kynurenine aminotransferase 1, both lower pathological tau species in AD. In summary, scFUMES identifies cell type-specific master metabolic regulators, offering insights into cellular metabolic heterogeneity and metabolism-targeted therapeutic strategies for AD and neurodegenerative diseases if broadly applied.
    DOI:  https://doi.org/10.21203/rs.3.rs-7207381/v1
  4. Front Mol Neurosci. 2025 ;18 1676946
    Editorial: Imaging brain network and brain energy metabolism impairments in brain disorders.
    Yuhei Takado, Mor Mishkovsky, Tomokazu Tsurugizawa.
      
    Keywords:  astrocyte-neuron interactions; brain energy metabolism; functional connectivity; magnetic resonance spectroscopy; multimodal imaging; resting-state fMRI
    DOI:  https://doi.org/10.3389/fnmol.2025.1676946
  5. J Neurochem. 2025 Sep;169(9): e70216
    Ketogenic Diet Modulates Gut Microbiota-Brain Metabolite Axis in a Sex- and Genotype-Specific Manner in APOE4 Mice.
    Kira Ivanich, Andrew Yackzan, Abeoseh Flemister, Ya-Hsuan Chang, Xin Xing, Anna Chen, Lucille M Yanckello, McKenna Sun, Chetan Aware, Maalavika Govindarajan, Skyler Kramer, Aaron Ericsson, Ai-Ling Lin.
      The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), associated with early brain metabolic dysfunction and gut microbiome alterations. Targeting these early changes through dietary interventions may reduce AD risk in asymptomatic carriers. This study evaluated whether a ketogenic diet (KD) could reshape the gut microbiome and enhance key brain metabolite levels in young APOE4 mice, using APOE3 mice as a neutral-risk comparison. Male and female APOE3 and APOE4 mice were fed either a control diet or KD for 16 weeks, starting at 12 weeks of age. We used shotgun metagenomics and targeted brain metabolomics to identify microbe-metabolite signatures linked to neuroprotection. KD increased beneficial species such as Lactobacillus johnsonii and Lactobacillus reuteri while reducing pathogenic Bacteroides intestinalis. These microbial shifts correlated with improved brain metabolites related to mitochondrial function, neurotransmitter balance, redox homeostasis, and lipid metabolism. Notably, Lactobacillus species and B. intestinalis exhibited inverse correlations with key brain metabolite levels, suggesting their roles as both modulators and biomarkers of brain health. APOE4 females showed the greatest benefits, including restored microbiome diversity and normalization of brain metabolite levels. In contrast, APOE3 mice showed microbiome changes but limited brain metabolic responses. These findings highlight KD's potential to reprogram the gut-brain axis in a genotype- and sex-dependent manner, supporting its use as a precision nutrition strategy to reduce AD risk, particularly in asymptomatic female APOE4 carriers.
    Keywords:  Alzheimer's disease; apolipoprotein ε4; gut microbiome; ketogenic diet; key brain metabolite levels; precision nutrition
    DOI:  https://doi.org/10.1111/jnc.70216
  6. Metab Brain Dis. 2025 Aug 29. 40(7): 253
    Targeting glucose transporters in parkinson's disease: a novel metabolic approach for disease modification.
    Gursimran Singh, Shazia Ansari, Khadga Raj Aran.
      Glucose metabolism is vital for maintaining the effective functioning of the central nervous system (CNS). This energy supports synaptic activity, ion balance, and neurotransmitter synthesis, processes that depend on the GLUTs (glucose transporters), particularly GLUT1(Glucose transporter 1), GLUT2(Glucose transporter 2), and GLUT3 (Glucose transporter 3). There is growing evidence associating GLUT deficiency and metabolic disorders with neurodegenerative diseases, including Parkinson's disease (PD). PD is a progressive neurodegenerative disease linked with the degeneration of dopaminergic neurons in the SNpc, resulting in impaired motor and non-motor functions. More than 60% of patients with PD show glucose intolerance and insulin resistance, emphasizing the relation between metabolic disturbances and disease progression. The reduced expression of these GLUTs further restricts the neuronal glucose uptake, impairing ATP production and increasing liability to oxidative damage, leading to disease progression. Emerging finding suggests that targeting GLUT offers a therapeutic strategy for PD. Restoring GLUT function may help to reduce energy deficits and have neuroprotective effects. Several antidiabetic drugs have shown promise in reducing the symptoms and development of PD in both human and animal models. This narrative review addresses the current understanding of the connection between GLUT dysfunction and PD, highlighting the potential of targeting GLUT dysregulation as a novel therapeutic strategy. Additionally, repurposing antidiabetic drugs shows promise in improving insulin sensitivity and reducing neuroinflammation in PD. Addressing challenges like GLUT isoform specificity and BBB penetration provides a way for disease-modifying therapies that target GLUT dysfunction in PD, offering hope for effective management or reducing the rate of PD's progression.
    Keywords:  Insulin resistance; Neurodegeneration; Oxidative stress; Α-Synuclein aggregation
    DOI:  https://doi.org/10.1007/s11011-025-01697-5
  7. Neuroscience. 2025 Aug 27. pii: S0306-4522(25)00896-6. [Epub ahead of print]585 1-13
    Lactate lactylation in neural pathophysiology: Bridging metabolism and neurodegeneration.
    Mengran Cao, Zhaoyang Yin, Wenrui Hu, Ying Luo, Qinglu Wang, Panpan Dong.
      Lactate is the end product of anaerobic glycolysis. Its functions in the central nervous system have garnered increasing attention as new roles continue to emerge. Beyond serving as an energy source and a substrate for gluconeogenesis, lactate also functions as a signaling molecule that regulates diverse cellular activities. Recent studies have demonstrated that lactate contributes to protein lactylation-a novel posttranslational modification-and plays a crucial role in metabolic reprogramming. Additionally, lactate has been associated with neuroinflammation and multiple neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and others. This review summarizes the regulatory mechanisms of lactate metabolism and lactylation, along with findings related to lactate's involvement in the nervous system and neurodegenerative conditions. Specifically, it highlights the effects of lactate and lactylation on glial cells and neurons in the brain, and outlines how lactate levels and lactylation status influence disease progression in neurodegenerative disorders. The potential mechanisms by which lactylation contributes to neurodegenerative pathologies are also discussed. These insights may provide novel avenues for exploring the role of lactylation in neurological disease.
    Keywords:  Lactate; Lactylation; Nervous system; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.neuroscience.2025.08.048
  8. Front Neurol. 2025 ;16 1626275
    Preliminary observations of glucose metabolism dysregulation in pediatric Huntington's disease.
    Federica Graziola, Federica Rachele Danti, Martina Penzo, Antonio Spagarino, Eleonora Minacapilli, Marco Moscatelli, Federica Zibordi, Caterina Mariotti, Giovanna Zorzi.
       Background: Pediatric Huntington's disease (PHD), a rare and severe form of juvenile-onset Huntington's disease (JOHD), is associated with highly expanded CAG repeats in the HTT gene and a rapidly progressive neurodegenerative course. Recent studies have suggested that glucose metabolism may be impaired in PHD due to reduced expression of glucose transporters in the brain, resembling aspects of GLUT1 Deficiency Syndrome (GLUT1DS).
    Methods: We investigated glucose metabolism in two pediatric patients with genetically confirmed PHD (CAG repeats: 76 and 79) referred to our tertiary care center. Clinical, neuroimaging, and neuropsychological data were collected alongside metabolic assessments, including cerebrospinal fluid (CSF) and plasma glucose and lactate levels, CSF-to-serum glucose ratio, and red blood cell GLUT1 expression using the METAglut1 test. 18F-FDG PET imaging and brain MRI were performed to assess cerebral metabolism and structural changes.
    Results: Both patients exhibited progressive motor and cognitive decline with dystonia-parkinsonian features, learning disabilities, and behavioral disturbances. Brain MRI showed caudate and putaminal atrophy, while PET imaging demonstrated severely reduced glucose uptake in the basal ganglia. CSF/plasma glucose ratios were within or near the lower end of the normal range (0.51 and 0.6), and GLUT1 expression in red blood cells was within normal limits. No significant biochemical alterations consistent with GLUT1DS were detected.
    Conclusion: Our findings confirm localized cerebral hypometabolism in the basal ganglia of PHD patients, consistent with previous neuropathological reports. However, systemic biochemical indicators of glucose transport deficiency, including erythrocyte GLUT1 function and CSF glucose, were not significantly altered. While glucose dysregulation appears to be a feature of PHD brain pathology, our results do not support the use of metabolic interventions such as the ketogenic diet in the absence of confirmed GLUT1 dysfunction. Further studies in larger cohorts are warranted to better characterize the metabolic profile of PHD and guide therapeutic strategies.
    Keywords:  GLUT-1 deficiency syndrome; GLUT1; Huntington’s disease; juvenile-onset HD; pediatric Huntington’s disease
    DOI:  https://doi.org/10.3389/fneur.2025.1626275
  9. Aging Cell. 2025 Sep 01. e70208
    Association Between Plasma Metabolomic Profile and Machine Learning-Based Brain Age.
    Yang Li, Jiao Wang, Yuyang Miao, Michelle M Dunk, Yan Liu, Zhongze Fang, Qiang Zhang, Weili Xu.
      Metabolomics has been associated with cognitive decline and dementia, but the relationship between metabolites and brain aging remains unclear. We aimed to investigate the associations of metabolomics with brain age assessed by neuroimaging and to explore whether these relationships vary according to apolipoprotein E (APOE) ε4. This study included 17,770 chronic brain disorder-free participants aged 40-69 years from UK Biobank who underwent neuroimaging scans an average of 9 years after baseline. A total of 249 plasma metabolites were measured using nuclear magnetic resonance spectroscopy at baseline. Brain age was estimated using LASSO regression and 1079 brain MRI phenotypes and brain age gap (BAG; i.e., brain age minus chronological age) was calculated. Data were analyzed using linear regression. We identified 64 and 77 metabolites associated with brain age and BAG, respectively, of which 55 overlapped. Lipids (including cholesterol, cholesteryl esters, free cholesterol, phospholipids, and total lipids) in S/M-HDL, as well as phospholipids and triglycerides as a percentage of total lipids in different-density lipoproteins, were associated with larger BAG. The percentages of cholesterol, cholesteryl esters, and free cholesterol to total lipids in VLDL, LDL, and HDL of different particle sizes were associated with smaller BAG. The associations of LA/FA, omega-6/FA, SFA/FA, and phospholipids to total lipids in L-HDL with brain age were consistent across APOE ε4 carriers and non-carriers (all p for interaction > 0.05). Plasma metabolites show remarkably widespread associations with brain aging regardless of APOE ε4 genetic risk. Metabolic profiles could serve as an early indicator of accelerated brain aging.
    Keywords:  UK biobank; brain age; machine learning; magnetic resonance imaging; metabolites
    DOI:  https://doi.org/10.1111/acel.70208
  10. Redox Biol. 2025 Aug 30. pii: S2213-2317(25)00366-0. [Epub ahead of print]86 103853
    NRF2 deficiency is associated with synaptic alterations and ether-linked phospholipid imbalance in the hippocampus.
    Daniel Carnicero-Senabre, Mariana A Barata, José Jiménez-Villegas, Claudia Guimas Almeida, Antonio Cuadrado, Ana I Rojo.
      Synaptic loss is a key factor in the cognitive decline observed during aging and in neurodegenerative diseases such as dementia, where synaptopathy plays a central role in hippocampal dysfunction. In this study, we investigated the role of NRF2, a master regulator of cellular homeostasis, in maintaining synaptic integrity. We assessed synaptic contacts both in vitro and in vivo and found that NRF2 deficiency leads to a significant reduction in vGLUT1 levels, accompanied by a decrease in the number of synaptic contacts. Because synapses are subject to highly dynamic membrane remodeling processes, we analyzed the lipid composition of hippocampi and synaptosomes from NRF2-deficient and wild-type mouse littermates. Our results revealed an accumulation of ether-linked phospholipids in NRF2-deficient mice. When primary neuronal and organotypic cultures were exposed to an ether-lipid precursor, synaptic density decreased. By contrast, the NRF2 activator 6-(methylsulfinyl)hexyl isothiocyanate (6-MSITC or hexaraphane) prevented synaptic loss. Although ether lipids are abundant components of neuronal membranes, their specific role in synaptic function and in age-related loss of homeostatic balance remains poorly understood. This study is the first to demonstrate that NRF2 plays an essential role in preserving synaptic homeostasis through lipid metabolism, suggesting its relevance in the context of aging and neurodegenerative diseases.
    Keywords:  6-MSITC; Ether-lipids; Lipidomics; NRF2; Synapses
    DOI:  https://doi.org/10.1016/j.redox.2025.103853
  11. Front Neurol. 2025 ;16 1597928
    Hippocampal dysmetabolism contributes to cognitive loss in autoimmune encephalitis and focal temporal epilepsy.
    Olga Taraschenko, Lakshman Arcot Jayagopal, Audrina Mullane, Kyle Greenman, Matthew White, Hesham Ghonim, Shelley Lee, Rana Khalil Zabad, Tracy Jasinski, Mariano Uberti.
       Introduction: Autoimmune encephalitis (AE) is associated with severe cognitive disability. Brain metabolic dysfunction has been linked to encephalopathy in neurodegenerative disorders; however, its role in the development of cognitive loss in AE has not been studied. We hypothesized that cognitively impaired patients with AE will demonstrate altered brain metabolism and immune activation, and these measures will correlate with cognitive scores.
    Methods: The hippocampal and cortical metabolites related to neuronal integrity, oxidative metabolism, and glial activation were assessed using single-voxel proton magnetic resonance spectroscopy (1H-MRS) in patients with AE, non-lesional temporal lobe epilepsy (TLE) and control subjects. Metabolite levels were correlated with neuropsychological test scores.
    Results: We recruited patients with post-acute AE (n = 12), non-lesional TLE (n = 12), and control subjects (n = 11). Subjective cognitive complaints were reported by 83.3% of AE and all TLE patients. AE patients had fewer seizures and used fewer anti-seizure medications than TLE patients (p = 0.04, t-test and p = 0.03, post-hoc test). On neuropsychological testing, moderate and severe cognitive impairment was revealed in 58.3% of patients with AE and 41.6% of patients with TLE. Hippocampal myo-inositol (M-Ins) concentrations were higher in patients compared to control subjects, with a trend toward increase in AE and TLE relative to control (p = 0.046, ANOVA; p = 0.09 and p = 0.07 for AE and TLE vs. control, respectively; post-hoc tests). The concentration of creatine (tCr) and total choline (tCho) were significantly higher in patients with TLE compared to the controls (tCr: p = 0.007; tCh: p = 0.04; post-hoc tests). Elevated M-Ins in AE was associated with better attention but worse memory recognition scores (R 2 = 0.38, p = 0.04 and R 2 = 0.50, p = 0.02, respectively); higher tCr levels correlated with faster processing speed (R 2 = 0.38; p = 0.04). The higher concentrations of tCr, tCho, and M-Ins in TLE have selectively correlated with worse measures of attention, processing speed, language, and memory.
    Conclusions: Although AE and TLE patients report similar cognitive issues, their hippocampal metabolic signatures differ. The disease-specific changes in the measures of hippocampal inflammation and neuronal integrity can inform trajectories for cognitive recovery and be targeted therapeutically.
    Keywords:  autoimmune encephalitis; cerebral metabolism; cognitive loss; magnetic resonance spectroscopy; memory deficits; myo-inositol; temporal lobe epilepsy
    DOI:  https://doi.org/10.3389/fneur.2025.1597928
  12. Front Cell Neurosci. 2025 ;19 1661231
    Underestimation of mitochondrial respiratory capacity in gray matter voxels of the human brain map due to limited OXPHOS and TCA cycle in astrocytes.
    Christos Chinopoulos.
      Considering that the aerobic energetic landscape of the brain is shaped by its mitochondria, Mosharov et al. generated an atlas of mitochondrial content and enzymatic OXPHOS activities at a resolution comparable to MRI by physically voxelizing frozen human brain tissue. However, astrocytes in the adult human brain lack expression of several TCA cycle and OXPHOS enzymes. Therefore, their formula expressing mitochondrial respiratory capacity (MRC) -defined as tissue respiratory capacity normalized to mitochondrial density- underestimates actual values by a factor proportional to the square root of the fraction of respiration-capable cells (primarily neurons) in gray matter voxels.
    Keywords:  MRI; OXPHOS; astrocytes; mitochondria; neurons; respiratory capacity
    DOI:  https://doi.org/10.3389/fncel.2025.1661231
  13. Neurosci Bull. 2025 Aug 29.
    Spatially Resolved Lipid Composition of the Human Brain Cortical Layers.
    Dmitry Senko, Marina Zavolskova, Olga Efimova, Maria Osetrova, Elena Stekolshchikova, Gleb Vladimirov, Evgeny Nikolaev, Philipp Khaitovich.
      A better understanding of neocortical architecture provides a means for its functional elucidation. In this study, we focused on the analysis of the lipidome composition in two human neocortical regions using laser-capture microdissection combined with mass spectrometry and mass spectrometry imaging. Among the 312 lipids detected in tissue samples representing discrete neocortical layers (L1, L3, and L5), three-quarters showed significant differences in abundance among layers, forming distinct patterns. Lipid distribution among these patterns depended on both the lipids' biochemical class and their fatty acid residue length and unsaturation. The assignment of lipids to cell types using spatial transcriptomics data suggested biological underpinnings of these patterns. Collected mass spectrometry imaging data further allowed for the reconstruction of lipid spatial distribution patterns across neocortical layers. These results reveal a complex relationship between lipids' biochemical properties and neocortical histological features, laying a foundation for further studies on the lipidome architecture of the human brain.
    Keywords:  Cortex layers; Human brain; Lipidome; Matrix-assisted laser desorption/ionization mass spectrometry imaging; Ultra-performance liquid chromatography-mass spectrometry
    DOI:  https://doi.org/10.1007/s12264-025-01486-1
  14. bioRxiv. 2025 Aug 28. pii: 2025.08.22.671845. [Epub ahead of print]
    Lipid-laden endothelial cells exhibit a transcriptomic signature linked to blood-brain barrier dysfunction, metabolic reprogramming and increased inflammation in the aging brain.
    Sarah Otu-Boakye, Duraipandy Natarajan, Bhuvana Plakkot, Ilakiya Raghavendiran, Tamas Kiss, Madhan Subramanian, Priya Balasubramanian.
      Dysregulation in lipid metabolism is increasingly recognized as a key contributor to age-related diseases, including neurodegeneration and cerebrovascular dysfunction. While prior studies have largely focused on glial cells, the impact of lipid dysregulation on brain endothelial aging remains poorly understood. In this study, we conducted a secondary analysis of single-cell transcriptomic data from young and aged mouse brains, with a specific focus on endothelial cells (ECs). Our analyses revealed that aging promotes lipid droplet accumulation in brain ECs. These lipid-laden brain ECs exhibit a transcriptomic signature indicative of impaired blood-brain barrier function, increased cellular senescence, and inflammation in aging. Furthermore, lipid accumulation is associated with an altered metabolic phenotype characterized by increased fatty acid oxidation and decreased glycolysis, and impaired mitochondrial electron transport chain activity in the ECs of the aging brain. We have also validated lipid accumulation in aged ECs in vivo . Collectively, our findings indicate that lipid accumulation drives structural, functional, and metabolic impairments in the brain ECs, likely contributing to cerebrovascular aging. Understanding the mechanisms underlying lipid accumulation-induced endothelial dysfunction may offer novel therapeutic strategies for mitigating microvascular dysfunction and cognitive decline in aging.
    DOI:  https://doi.org/10.1101/2025.08.22.671845
  15. Neurochem Int. 2025 Aug 30. pii: S0197-0186(25)00122-6. [Epub ahead of print]190 106049
    Multi-omics reveals changes in astrocyte fatty acid metabolism during early stages of Alzheimer's disease.
    Jie Zhong, Manhui Li, Ziwei Dai, Jun Wan.
       BACKGROUND: Although astrocytes are known to contribute to Alzheimer's disease (AD) progression, their dynamic molecular alterations remain poorly characterized, particularly in early stages of the disease.
    METHODS: We performed multi-omics profiling (transcriptomics, proteomics, spatial metabolomics) of astrocytes from APP/PS1 and WT mice to characterize dynamic changes during AD progression. To assess similar changes in early human AD, we analyzed single-nucleus RNA sequencing data from human samples.
    RESULTS: Transcriptomic analysis of astrocytes from APP/PS1 and WT mice at five time points (2, 4, 6, 9, and 12 months of age) showed notable gene expression differences at 6 months, with reduced activity in fatty acid metabolism pathways (e.g., PPAR signaling, biosynthesis of unsaturated fatty acids). An astrocyte-specific metabolic model confirmed these disruptions. Proteomic analysis corroborated this by showing decreased activity in pathways like butanoate metabolism and PPAR signaling. Spatial metabolomics of brain slices from APP/PS1 and WT mice highlighted fatty acid enrichment in the hippocampus and cortex, alongside differential metabolites specific to the AD mouse model. Single-cell RNA sequencing analysis of human brain samples further showed fatty acid metabolism abnormalities in astrocytes from early AD cases versus controls, emphasizing its role in AD progression.
    CONCLUSION: Our study identified abnormal fatty acid metabolism as an early feature of astrocytes in AD, suggesting an association between dysregulated fatty acid metabolism and disease progression.
    Keywords:  Alzheimer's disease; Astrocytes; Fatty acid metabolism; Multi-omics
    DOI:  https://doi.org/10.1016/j.neuint.2025.106049
  16. bioRxiv. 2025 Aug 20. pii: 2025.08.19.669163. [Epub ahead of print]
    APOE genotypes differentially remodel the astrocytic lipid droplet-associated proteome to shape lipid droplet dynamics.
    Carla Cuní-López, Jessica T Root, Ying Hao, Isabelle Kowal, Niek Blomberg, Rodolfo Ghirlando, Linda G Yang, Sascha J Koppes-den Hertog, Mark R Cookson, Rik van der Kant, Martin Giera, Yue Andy Qi, Priyanka S Narayan.
      The lipids and proteins that comprise lipid droplets regulate several cellular functions including lipid storage, stress responses, and inflammation. Glial lipid droplets have been implicated in the pathogenesis and progression of Alzheimer's disease (AD), yet the mechanisms linking genetic risk to lipid droplet biology remain unclear. Here we examined how APOE, the strongest genetic modulator of late-onset AD, impacts lipid droplet composition and dynamics. We defined the lipid droplet-associated proteome and lipidome in human induced pluripotent stem cell-derived astrocytes harboring the three common APOE genotypes: APOE2 (protective), APOE3 (neutral), and APOE4 (risk). Each APOE variant displays distinct lipid droplet-associated proteins and lipids. These molecular changes yield differences in lipophagy; lipid droplets in APOE2 astrocytes undergo autophagic turnover, whereas those in APOE4 astrocytes are resistant to degradation. These findings suggest that impaired lipid droplet clearance, rather than accumulation, distinguishes APOE4-associated AD risk, and may present a new metabolic node for modulating risk.
    DOI:  https://doi.org/10.1101/2025.08.19.669163
  17. Iran J Basic Med Sci. 2025 ;28(10): 1417-1427
    Effect of nicotine on the energy metabolism of substantia nigra cells in MPTP-induced Parkinson's disease.
    Nikoloz Zhgenti, Otar Bibilashvili, Mariam Shengelia, George Burjanadze, Marine Koshoridze, Elene Davitashvili, Nana Koshoridze.
       Objectives: Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting millions globally, with no current cure despite extensive research efforts. The neurotoxin MPTP is commonly used as a PD model by inhibiting mitochondrial complex I. Nicotine, the primary alkaloid in tobacco, has shown potential neuroprotective effects against neurodegenerative diseases, including PD, although the precise mechanisms remain unclear. This study aims to investigate the effects of nicotine on the energetic metabolism of substantia nigra cells affected by MPTP.
    Materials and Methods: We examined the impact of nicotine on glycolytic, Krebs cycle, and respiratory chain enzymes in substantia nigra cells, as well as mitochondrial and cytosolic creatine kinase activities. ATP levels, mitochondrial permeability transition pore (mPTP) activity, and PI3K-AKT-mTOR signaling pathway were also assessed. The study was performed on a mouse model where PD was induced by MPTP, followed by nicotine treatment.
    Results: Nicotine administration led to improvements in mitochondrial function, with enhanced ATP production, creatine kinase activity, and overall energetic metabolism. Nicotine corrected the energetic deficiencies induced by MPTP, likely through the activation of the PI3K-AKT-mTOR pathway, which is suppressed by MPTP.
    Conclusion: Our findings suggest that nicotine may exert neuroprotective effects in Parkinson's disease by improving mitochondrial function and enhancing energetic metabolism, potentially via activation of the PI3K-AKT-mTOR pathway. This highlights nicotine's potential as a therapeutic agent in mitigating PD-induced metabolic disturbances.
    Keywords:  Energy metabolism; Mitochondrial permeability transition pore; Neurodegenerative diseases; Neuroprotective agents1; Nicotine; Parkinson’s disease
    DOI:  https://doi.org/10.22038/ijbms.2025.84754.18338
  18. Int J Toxicol. 2025 Aug 28. 10915818251369414
    Mitochondria: Key Mediator for Environmental Toxicant-Induced Neurodegeneration.
    Nishi Shah, Bhagawati Saxena, Richa Gupta.
      Compiling evidence strongly suggests the involvement of environmental toxicants, including heavy metals (aluminum, arsenic, lead, copper, cadmium, mercury, and manganese), pesticides, and solvents, as the prime culprits of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. The pathogenesis of environmental toxicant-induced neurodegenerative disease remains elusive. Studies carried out in the last decade suggest that dysfunctional mitochondria are increasingly recognized as a key factor in the progression of neurodegenerative diseases. Mitochondria, the essential organelles that regulate cellular energy production, are particularly vital in neurons, which have high energy demands and depend on proper mitochondrial function for survival. Environmental toxicants have been shown to impair mitochondrial membranes, disrupt the electron transport chain, increase oxidative stress, and damage mitochondrial DNA, leading to progressive neurodegeneration, with mitochondrial fragmentation and oxidative stress that worsens neurodegeneration. There are currently no disease-modifying treatments available for most neurodegenerative disorders, largely due to the lack of suitable molecular targets. Targeting mitochondria presents a rational strategy for neuroprotective therapy, with the potential to slow or halt disease progression. In view of this, this review highlights the central role of mitochondria in environmental toxicant-induced neurodegeneration, emphasizing how environmental exposures drive mitochondrial dysfunction and accelerate disease progression. Understanding these mechanisms is crucial for identifying environmental risk factors and developing targeted interventions. This will provide a foundation for future research targeting mitochondria and developing suitable therapeutic interventions for neurodegenerative diseases.
    Keywords:  environmental toxicants; heavy metals; mitochondrial dysfunction; neurodegenerative disorders; pesticides
    DOI:  https://doi.org/10.1177/10915818251369414
  19. Annu Rev Genet. 2025 Sep 03.
    Fueling the Mind: Brain Metabolism in Health and Neurodevelopmental Disorders.
    Domenico Marano, Vittoria Mariano, Gaia Novarino.
      The adult human brain, under resting conditions, consumes approximately 20% of total body glucose, a demand that is even higher during the first decade of life. The brain metabolic landscape is intricately regulated throughout development, and each cell type exhibits distinct metabolic signatures at each specific stage. This picture becomes even more intricate when considering that metabolism is dynamically modulated to sustain critical biological processes, such as cell proliferation and differentiation and synaptic activity-dependent processes. The orchestration between metabolic regulation and the aforementioned physiological processes often relies on metabolism-dependent changes in the epigenetic landscape, which shape gene expression patterns to trigger selected downstream biological responses. Perturbations of brain metabolic pathways are frequently the cause of severe neurodevelopmental disorders. This review explores the latest insights into the regulation of brain metabolism in health and disease.
    DOI:  https://doi.org/10.1146/annurev-genet-111523-102424
  20. Br J Pharmacol. 2025 Sep 01.
    Increased ATP production and P-glycoprotein activity underlie the marked changes in blood-brain barrier transport of drugs in a mouse model of amyotrophic lateral sclerosis.
    Yijun Pan, Alanna G Spiteri, Pranav Runwal, Jiaqi Sun, Dana S Hutchinson, Yoshiteru Kagawa, Bradley J Turner, Cheng Huang, Anup D Shah, Ralf B Schittenhelm, Joseph A Nicolazzo.
       BACKGROUND AND PURPOSE: Patients with amyotrophic lateral sclerosis (ALS) are prescribed many medications for symptomatic relief. However, how potential alterations to the blood-brain barrier (BBB) affect the brain exposure of drugs in ALS remains under-investigated.
    EXPERIMENTAL APPROACH: We used high-dimensional proteomic analysis, cellular metabolism, and mitochondrial functional assays to characterise isolated brain microvascular endothelial cells (BMECs) from wildtype and SOD1G93A transgenic mice, a mouse model of familial ALS, at a late-symptomatic age (P115-120), together with a transcardiac brain perfusion technique to assess BBB function in situ.
    KEY RESULTS: The BBB of the SOD1G93A transgenic (TG) mice was significantly altered, including a 1.3-fold decrease in apparent brain microvascular volume, and decreased BBB transport of 3H-diazepam (1.4-fold) and 3H-2-deoxy-D-glucose (1.2-fold). BMEC proteomic analysis revealed multiple changes in TG mice including altered transmembrane activity, metabolism, and mitochondrial function, as revealed by gene set enrichment analysis, alongside altered glucose transporter (Glut1) abundance. These proteomic findings supported the identified increase in mitochondrial basal/ATP-linked respiration, mitochondrial action potential, ATP production, and intracellular ATP levels in SOD1G93A mouse BMECs. The BBB transport of 3H-digoxin, a specific ATP-binding cassette efflux P-glycoprotein (P-gp) substrate, was reduced by 11.0% in SOD1G93A mice. This was confirmed by a 46.7% reduction in BMEC uptake of 3H-digoxin, an observation that was reversed by resolving the hypermetabolic state of SOD1G93A BMECs.
    CONCLUSION AND IMPLICATIONS: These findings open possible therapeutic avenues that could be exploited to overcome P-gp-mediated CNS drug resistance in ALS.
    Keywords:  P‐glycoprotein; amyotrophic lateral sclerosis; blood–brain barrier; metabolism; proteomics
    DOI:  https://doi.org/10.1111/bph.70147
  21. EMBO Rep. 2025 Aug 29.
    Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.
    Tak Shun Fung, Amrapali Ghosh, Maite R Zavala, Zuzana Nichtova, Dhavalkumar Shukal, Marco Tigano, Gyorgy Csordas, Henry N Higgs, Rajarshi Chakrabarti.
      Mitochondrial damage represents a dramatic change in cellular homeostasis, necessitating metabolic adaptation and clearance of the damaged organelle. One rapid response to mitochondrial damage is peri-mitochondrial actin polymerization within 2 min, which we term ADA (Acute Damage-induced Actin). ADA is vital for a metabolic shift from oxidative phosphorylation to glycolysis upon mitochondrial dysfunction. In the current study, we investigated the effect of ADA on Pink1/Parkin mediated mitochondrial quality control. We show that inhibition of proteins involved in the ADA pathway significantly accelerates Parkin recruitment onto depolarized mitochondria. Addressing the mechanism by which ADA resists Parkin recruitment onto depolarized mitochondria, we found that ADA disrupts ER-mitochondria contacts in an Arp2/3 complex-dependent manner. Interestingly, overexpression of ER-mitochondria tethers overrides the effect of ADA, allowing rapid recruitment of not only Parkin but also LC3 after mitochondrial depolarization. During chronic mitochondrial dysfunction, Parkin and LC3 recruitment are completely blocked, which is reversed rapidly by inhibiting ADA. Taken together we show that ADA acts as a protective mechanism, delaying mitophagy following acute damage, and blocking mitophagy during chronic mitochondrial damage.
    Keywords:  Actin; Arp2/3 Complex; ER; LC3; Parkin
    DOI:  https://doi.org/10.1038/s44319-025-00561-y
  22. Brain. 2025 Sep 05. pii: awaf282. [Epub ahead of print]
    Compensatory roles of STT3A and ALG5 in glucose metabolism of aged macaque hippocampus.
    Gao-Hong Zhu, Rui He, Zhi-Yu Yang, Ting-Ting Wang, Shi-Ci Yang, Ya-Xi Jiang, Jie Li, Yao-Hui Zhang, Fu-Xing Zhao, Yun Deng, Ting-Ting Pan, Xue-Dan Liu, Bao-Ci Shan, Xiang-Qing Zhu, Stefan H Bossmann, Xing-Hua Pan, Ting-Hua Wang.
      The hippocampus (HC), a central hub for memory and cognition, exhibits unique metabolic resilience during aging despite widespread brain glucose hypometabolism. Here, we report that aged humans and macaques paradoxically display elevated HC glucose uptake (18F-FDG PET SUVR) alongside strengthened connectivity to sensory-motor and limbic networks-an adaptive rewiring revealed by graph-theoretical metabolic network analysis. Integrated multi-omics profiling identified STT3A (oligosaccharyltransferase) and ALG5 (dolichyl-phosphate β-glucosyltransferase) as key regulators of age-related HC adaptation, with their upregulation in aged macaque hippocampi driving N-glycosylation-dependent metabolic reprogramming. Mechanistically, STT3A/ALG5 silencing in aged rats reduced insulin receptor/AKT1/AS160 phosphorylation, impairing GLUT4 membrane trafficking, while enhancing GLUT3 glycosylation and neuronal glucose uptake. This dual regulation preserved synaptic integrity and spatial memory retrieval despite reduced hippocampal FDG metabolism. Behavioral assays further demonstrated STT3A knockdown-induced motor coordination improvements through GLUT3-mediated metabolic rebalancing. Our findings establish STT3A-ALG5 as a glycosylation checkpoint that sustains HC energy homeostasis via GLUT4-to-GLUT3 substrate switching, positioning 18F-FDG PET as a dynamic biomarker for monitoring HC aging and these glycosyltransferases as therapeutic targets against cognitive decline.
    Keywords:   18F-fluoro-2-deoxyglucose; GLUTs; STT3A/ALG5; aging hippocampus; pAKT1-AS160 axis
    DOI:  https://doi.org/10.1093/brain/awaf282
  23. Nature. 2025 Sep 03.
    Genetic suppression features ABHD18 as a Barth syndrome therapeutic target.
    Sanna N Masud, Anchal Srivastava, Patricia Mero, Victoria Saba Echezarreta, Eve Anderson, Lennard van Buren, Jiarun Wei, David Thomson Taylor, Adrian Granda Farias, Nicholas Mikolajewicz, Angela Shaw, Brandon M Murareanu, Michelle Lohbihler, Olivia Sniezek Carney, Simon van Heeringen, Linda Clijsters, Olga Sizova, Jeroen van Ameijde, Freya Nye, Andrea Habsid, Lucy Nedyalkova, Laura McDonald, Craig Simpson, Leanne Wybenga-Groot, Kevin R Brown, Nhi Nho, Radu M Suciu, Katherine Chan, Amy H Y Tong, Frédéric M Vaz, Bastiaan Evers, Robert Lesurf, Tanya Papaz, Lauryl M J Nutter, Stephanie Protze, Maximilian Billmann, Michael Costanzo, Brenda J Andrews, Chad L Myers, Seema Mital, Hilary Vernon, Thijn R Brummelkamp, Charles Boone, Ian C Scott, Micah J Niphakis, Douglas Strathdee, Sebastian M B Nijman, Vincent A Blomen, Jason Moffat.
      Cardiolipin (CL) is the signature phospholipid of the inner mitochondrial membrane, where it stabilizes electron transport chain protein complexes1. The final step in CL biosynthesis relates to its remodelling: the exchange of nascent acyl chains with longer, unsaturated chains1. However, the enzyme responsible for cleaving nascent CL (nCL) has remained elusive. Here, we describe ABHD18 as a candidate deacylase in the CL biosynthesis pathway. Accordingly, ABHD18 converts CL into monolysocardiolipin (MLCL) in vitro, and its inactivation in cells and mice results in a shift to nCL in serum and tissues. Notably, ABHD18 deactivation rescues the mitochondrial defects in cells and the morbidity and mortality in mice associated with Barth syndrome. This rare genetic disease is characterized by the build-up of MLCL resulting from inactivating mutations in TAFAZZIN (TAZ), which encodes the final enzyme in the CL-remodelling cascade1. We also identified a selective, covalent, small-molecule inhibitor of ABHD18 that rescues TAZ mutant phenotypes in fibroblasts from human patients and in fish embryos. This study highlights a striking example of genetic suppression of a monogenic disease revealing a canonical enzyme in the CL biosynthesis pathway.
    DOI:  https://doi.org/10.1038/s41586-025-09373-5
  24. Geroscience. 2025 Sep 05.
    Sex differences in brain glucose metabolism in alzheimer's disease: A voxel-based study.
    Matilde Nerattini, Elisabetta Maria Abenavoli, Francesca Caramelli, Giulia Giacomucci, Benedetta Nacmias, Enrico Mossello, Valentina Bessi, Valentina Berti.
      A growing body of evidence shows significant sex differences in Alzheimer's Disease (AD) epidemiology, clinical presentation, and pathology burden; however, sex differences in neuroimaging biomarkers remain underexplored, prompting recent calls to action for more targeted research in this field. We analyzed static brain positron emission tomography (PET) imaging with 2-[18F] fluoro-2-deoxy-D-glucose (FDG) from 247 elderly individuals with AD dementia, including 151 women and 96 men. Voxel-based analysis was used to detect reductions in FDG uptake in each sex relative to a publicly shared normative database and to identify sex differences in FDG uptake within the AD cohort. Both sexes exhibited glucose hypometabolism in AD-vulnerable regions, including the parieto-temporal cortex, posterior cingulate, hippocampus, parahippocampal gyrus, and frontal lobes (PFWE ≤ 0.001 in women and ≤ 0.013 in men). Sex differences in regional FDG uptake were observed in both directions, with greater hypometabolism in limbic and frontal regions in women (PFWE ≤ 0.023) and in parietal cortices in men (PFWE ≤ 0.008). The sex-specific distribution of hypometabolism, with more pronounced anterior involvement in women and posterior involvement in men, aligns with known differences in brain reserve and hormone-sensitive regions. This pattern suggests that neurophysiological and neuroendocrine aging may contribute to AD neuropathology in a sex-dependent manner. Recognizing these variations could refine diagnostic approaches and inform the development of sex-specific therapeutic strategies.
    Keywords:  Alzheimer’s disease; FDG; Positron emission tomography; Sex; Women
    DOI:  https://doi.org/10.1007/s11357-025-01872-7
  25. Trends Endocrinol Metab. 2025 Sep 04. pii: S1043-2760(25)00176-6. [Epub ahead of print]
    Biliverdin reductase-A is a key modulator in insulin signaling and metabolism.
    Antonella Tramutola, Fabio Di Domenico, Marzia Perluigi, Eugenio Barone.
      Biliverdin reductase-A (BVRA) is a pleiotropic enzyme traditionally known for its antioxidant role in the heme degradation pathway. Recent findings have redefined BVRA as a master regulator of insulin signaling, acting as a kinase, scaffold, and redox-sensitive integrator of metabolic cues. BVRA modulates key nodes of the insulin cascade and sustains mitochondrial and synaptic function. Notably, BVRA loss precedes the accumulation of canonical markers of insulin resistance both peripherally and in the brain. Here we discuss how BVRA could represent an early cross-tissue biomarker of metabolic vulnerability. Its dysfunction contributes to mitochondrial stress, impaired proteostasis, and cognitive decline, thus linking metabolic and neurodegenerative disorders.
    Keywords:  Alzheimer’s disease; aging; biliverdin reductase-A; cell stress response; insulin signaling; mitochondrial metabolism; obesity; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1016/j.tem.2025.08.007
  26. bioRxiv. 2025 Aug 19. pii: 2025.08.19.671144. [Epub ahead of print]
    Neuromodulator control of energy reserves in dopaminergic neurons.
    Camila Pulido, Matthew S Gentry, Timothy A Ryan.
      The brain is a metabolically vulnerable organ as neurons have both high resting metabolic rates and the need for local rapid conversion of carbon sources to ATP during activity. Midbrain dopamine neurons are thought to be particularly vulnerable to metabolic perturbations, as a subset of these are the first to undergo degeneration in Parkinson's disease (PD), a neurodegenerative disorder long suspected to be in part driven by deficits in mid-brain bioenergetics (1). In skeletal muscle, energy homeostasis under varying demands is achieved in part by its ability to rely on glycogen as a fuel store, whose conversion to ATP is under hormonal regulatory control. In neurons however the absence of easily observable glycogen granules has cast doubt on whether this fuel store is operational, even though brain neurons express the key regulatory enzymes associated with building or burning glycogen (2). We show here that that in primary mid brain dopaminergic neurons, glycogen availability is under the control of dopamine auto receptors (D2R), such that dopamine itself provides a signal to store glycogen. We find that when glycogen stores are present, they provide remarkable resilience to dopamine nerve terminal function under extreme hypometabolic conditions, but loss of this dopamine derived signal, or impairment of access to glycogen, makes them hypersensitive to fuel deprivation. These data show that neurons can use an extracellular cue to regulate local metabolism and suggest that loss of dopamine secretion might make dopamine neurons particularly subject to neurodegeneration driven by metabolic stress.
    Keywords:  Biological Science; Neuroscience; dopamine; glycogen; synapse
    DOI:  https://doi.org/10.1101/2025.08.19.671144
  27. iScience. 2025 Sep 19. 28(9): 113248
    Elovl1 inhibition reduced very long chain fatty acids in a mouse model of adrenoleukodystrophy.
    Jeremy Y Huang, Brian Freed, Martin Hanus, Kelly Keefe, Ming Sum Ruby Chiang, Alexander Brezzani, Yongyi Luo, Yihang Li, Becky Lam, Stephanie Holley, Joseph Gans, Zuzana Dostalova, Buyun Tang, Clifford Phaneuf, Erin Teeple, Laura Parisi, Lilu Guo, Zhonglin Zhao, Sofia N Kinton, Jacquelyn Dwyer, Sandrine Teixeira, Hong Ma, Gary Asmussen, Rajashree McLaren, Donghui Wang, Ann Baker, Craig S Siegel, David Fink, Kristen Randall, Alexei Belenky, Suchitra Venugopal, Giorgio Gaglia, Jennifer Johnson, Dinesh S Bangari, Bailin Zhang, Alexander Michel, Jonathan D Proto, Alla Kloss, S Pablo Sardi, Tatiana Gladysheva, Can Kayatekin.
      Adrenoleukodystrophy (ALD) is a rare neurometabolic disease caused by mutations in the ABCD1 gene, which encodes for the peroxisomal very long chain fatty acid (VLCFA) transporter. It is a debilitating disorder, which has a spectrum of clinical presentations. Since the accumulation of VLCFAs are a common feature of all ALD pathologies, we developed a substrate reduction therapy for ALD in the form of an inhibitor of Elovl1, the lipid elongase responsible for the generation of VLCFAs. This inhibitor was able to successfully reduce the accumulation of VLCFA in the brain and spinal cord of Abcd1 -/y mice. Single nuclei RNA-seq analysis demonstrated that altered lipid metabolism genes and pathways were corrected, however, there were also unexpected transcriptional changes unrelated to the loss of Abcd1, including an induction of the unfolded protein response. These data suggest that Elovl1 inhibition may have broader consequences in Abcd1 -/y mice beyond correction of lipid homeostasis.
    Keywords:  Molecular interaction; Molecular mechanism of gene regulation; Molecular neuroscience; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.113248
  28. bioRxiv. 2025 Aug 27. pii: 2025.08.27.672715. [Epub ahead of print]
    Mitochondria structurally remodel near synapses to fuel the sustained energy demands of plasticity.
    Monil Shah, Ilika Ghosh, Luca Pishos, Valentina Villani, Tristano Pancani, Ryohei Yasuda, Chao Sun, Naomi Kamasawa, Vidhya Rangaraju.
      The brain is a metabolically demanding organ as it orchestrates and stabilizes neuronal network activity through plasticity. This mechanism imposes enormous and prolonged energetic demands at synapses, yet it is unclear how these needs are met in a sustained manner. Mitochondria serve as a local energy supply for dendritic spines, providing instant and sustained energy during synaptic plasticity. However, it remains unclear whether dendritic mitochondria restructure their energy production unit to meet the sustained energy demands. We developed a correlative light and electron microscopy pipeline with deep-learning-based segmentations and 3D reconstructions to quantify mitochondrial remodeling at 2 nm pixel resolution during homeostatic plasticity. Using light microscopy, we observe global increases in dendritic mitochondrial length, as well as local increases in mitochondrial area near spines. Examining the mitochondria near spines using electron microscopy, we reveal increases in mitochondrial cristae surface area, cristae curvature, endoplasmic reticulum contacts, and ribosomal cluster recruitment, accompanied by increased ATP synthase clustering within mitochondria using single-molecule localization microscopy. Using mitochondria- and spine-targeted ATP reporters, we demonstrate that the local structural remodeling of mitochondria corresponds to increased mitochondrial ATP production and spine ATP levels. These findings suggest that mitochondrial structural remodeling is a key underlying mechanism for meeting the energy requirements of synaptic and network function.
    DOI:  https://doi.org/10.1101/2025.08.27.672715
  29. J Cell Biol. 2025 Oct 06. pii: e202410130. [Epub ahead of print]224(10):
    Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex.
    Maria Pia Rodriguez Salazar, Sprihaa Kolanukuduru, Valentina Ramirez, Boyu Lyu, Gracie Manigault, Gabrielle Sejourne, Hiromi Sesaki, Guoqiang Yu, Cagla Eroglu.
      Dysfunctional mitochondrial dynamics are a hallmark of devastating neurodevelopmental disorders such as childhood refractory epilepsy. However, the role of glial mitochondria in proper brain development is not well understood. We show that astrocyte mitochondria undergo extensive fission while populating astrocyte distal branches during postnatal cortical development. Loss of mitochondrial fission regulator, dynamin-related protein 1 (Drp1), decreases mitochondrial localization to distal astrocyte processes, and this mitochondrial mislocalization reduces astrocyte morphological complexity. Functionally, astrocyte-specific conditional deletion of Drp1 induces astrocyte reactivity and disrupts astrocyte organization in the cortex. These morphological and organizational deficits are accompanied by loss of perisynaptic astrocyte process (PAP) proteins such as gap junction protein connexin 43. These findings uncover a crucial role for mitochondrial fission in coordinating astrocytic morphogenesis and organization, revealing the regulation of astrocytic mitochondrial dynamics as a critical step in neurodevelopment.
    DOI:  https://doi.org/10.1083/jcb.202410130
  30. J Am Soc Mass Spectrom. 2025 Sep 04.
    High-Specificity and Sensitivity Imaging of Neutral Lipids Using Salt-Enhanced MALDI TIMS.
    Kameron R Molloy, Martin Dufresne, Madeline E Colley, Lukasz G Migas, Raf Van de Plas, Jeffrey M Spraggins.
      Neutral lipids are vital to various cellular processes and disease pathologies. However, their characterization by matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) remains challenging due to poor ionization efficiency and difficulties distinguishing subtle structural differences among numerous isomeric and isobaric species. In this study, we enhanced neutral lipid detection by incorporating isotonic metal-cation washes into our MALDI IMS sample preparation workflow. Resulting salt adducts improved neutral lipid isobar and isomer separation by using trapped ion mobility spectrometry (TIMS). This approach increased both sensitivity and specificity for neutral lipid IMS experiments across multiple organ types, including murine brain, rabbit adrenal gland, human colon, and human kidney. Comparative analyses revealed that the most effective salt wash was tissue-dependent. However, the Na+ carbonate buffer solution (CBS) wash showed the greatest overall increase in neutral lipid detection. These findings provide a robust framework for mapping neutral lipids across multiple tissues and disease states and allow for the detailed characterization of neutral lipid isomers and isobars in complex biological tissues.
    DOI:  https://doi.org/10.1021/jasms.5c00202
  31. Int Immunopharmacol. 2025 Sep 04. pii: S1567-5769(25)01435-3. [Epub ahead of print]165 115444
    Palmatine mitigates ischemic brain injury by regulating microglial polarization and sphingolipid metabolism.
    Ningjing Wang, Xiaotong Wei, Peng Zhou, Weizhen Wu, Jiarui Liu, Huaxu Zhu, Zhishu Tang, Xin Chai, Nianyun Yang, Qingyu Zhang, Yinfeng Dong, Rui Guo, Qichun Zhang.
       BACKGROUND: To elucidate the therapeutic effects and underlying mechanisms of palmatine, a principal alkaloid derived from Coptis chinensis, on neuroinflammation in ischemic stroke rat models induced by middle cerebral artery occlusion (MCAO).
    METHODS: Initially, qPCR was employed to assess the impact of neurotrophic factors secreted by SH-SY5Y neuroblastoma cells on the phenotypes of BV2 cells. Alterations in sphingolipid profiles within neuronal supernatants were characterized using liquid chromatography-tandem mass spectrometry, and molecular docking studies were conducted to investigate the interaction of palmatine with key enzymes involved in sphingolipid metabolism. Subsequently, Rats were subjected to MCAO to mimic cerebral ischemia in vivo. Neurological function was evaluated using standardized tests, and brain pathology was assessed. LC-MS/MS was also utilized to quantify sphingolipid levels within the brain. BV2 cells and rats were subjected to TREM2 knockdown using lentiviral transfection and adeno-associated virus (AAV)-mediated delivery, respectively. The neuroprotective effects of palmatine were further delineated.
    RESULTS: In vitro, palmatine counteracted ischemia-induced microglial M1 polarization, promoting a neuroprotective M2 phenotype in BV2 cells. It modulated sphingolipid metabolism, normalizing ceramide and ceramide-1-phosphate levels in neuronal supernatants. In vivo, palmatine significantly ameliorated neurological deficits and restored sphingolipid homeostasis in MCAO-induced rats. TREM2 downregulation exacerbated ischemic injury, whereas SH-SY5Y-derived neurotrophic factors suppressed BV2 activation. Inhibition of the PI3K/AKT/mTOR/HIF-1α signaling cascade significantly attenuated palmatine's microglia-mediated neuroprotection.
    CONCLUSION: Palmatine exerts neuroprotection by reducing levels of ceramide through its conversion to ceramide-1-phosphate, a process that is mediated by TREM2 on microglia and the PI3K/AKT/mTOR/HIF-1α signaling pathway.
    Keywords:  Cerebral ischemia; Microglia; Neuroinflammation; Palmatine; Sphingolipid metabolism; TREM2
    DOI:  https://doi.org/10.1016/j.intimp.2025.115444
  32. J Neurochem. 2025 Sep;169(9): e70225
    Reelin Increases the Sphingomyelin Content of the Plasma Membrane and Affects the Surface Expression of GPI-Anchored Proteins in Hippocampal Neurons.
    Yuto Takekoshi, Hugo Ando, Takao Kohno, Hiroshi Takase, Tomohiko Taguchi, Makoto Arita, Toshihide Kobayashi, Mitsuharu Hattori.
      Sphingomyelin (SM) is primarily located in the outer leaflet of the plasma membrane. It plays a crucial role in intercellular communication and the morphology of neuronal cells by influencing the localization and function of various proteins. However, the mechanisms regulating the SM content in the neuronal plasma membrane remain largely elusive. In this study, we discovered that Reelin, an important secreted signaling protein in the central nervous system, increases the SM content of the plasma membrane of cultured hippocampal neurons by promoting SM synthesis using a SM specific probe and a fluorescently labeled SM precursor molecule. This increase in SM was associated with increased surface expression of glycosylphosphatidylinositol (GPI)-anchored proteins analyzed by immunohistochemistry or using phosphatidylinositol-specific phospholipase C, suggesting a functional link between SM levels and membrane protein trafficking. Furthermore, comparative lipidomic analysis of the postsynaptic density fraction by LC-MS/MS revealed distinct alterations in SM-related lipid species between wild-type and Reelin-deficient mice. These findings suggest that Reelin regulates the SM content in the neuronal plasma membrane, which, in turn, affects the function and morphology of the neuron by affecting the surface levels of GPI-anchored proteins. These findings identify a novel role for Reelin in modulating neuronal membrane lipid composition, which may underlie its diverse functions in neuronal development and synaptic plasticity in both the developing and adult brain.
    Keywords:  membrane; neuron; reelin; sphingomyelin
    DOI:  https://doi.org/10.1111/jnc.70225
  33. Free Radic Biol Med. 2025 Sep 02. pii: S0891-5849(25)00949-9. [Epub ahead of print]
    Effects of aging and anti-aging dietary restriction on regulators of the [NADPH]/[NADP+] in different neural cell types and brain regions.
    Leah E Jamerson, Patrick C Bradshaw.
      Dietary restriction (DR), which slows aging, increases the ratio of reduced glutathione (GSH) to oxidized glutathione disulfide (GSSG) in the brain. DR increases liver cytoplasmic [NADPH]/[NADP+] where much of the NADPH is generated by the folate cycle. This could also occur in astrocytes, the neural cell type with the highest folate cycle flux. Mice on a DR diet showed increased expression of folate cycle enzyme MTHFD1L in several brain regions and likely show increased astrocyte sarcosine catabolism increasing folate cycle cytoplasmic NADPH generation by ALDH1L1. Fasting also increases blood malate/pyruvate that increases tissue [NADPH]/[NADP+]. These events together with decreased NADPH-utilizing lipid synthesis during DR could lead to an increased brain cytoplasmic [NADPH]/[NADP+]. The more reduced NADP(H) pool, combined with the increased expression of brain glutathione disulfide reductase (GSR) and the decreased brain mitochondrial H2O2 generation, decreasing H2O2-induced oxidation of GSH, could lead to the increased brain GSH/GSSG. Aging also decreased the expression of mouse hippocampal NAD+ kinase (NADK) that was restored by DR. Studies that measure the [NADPH]/[NADP+], cysteine/cystine, and GSH/GSSG in different brain regions, subcellular compartments, and neural cell types, especially in astrocytes, during aging and DR are needed to establish effective targets and therapies for aging-related disorders.
    Keywords:  NADPH; aging; astrocyte; dietary restriction; folate cycle; pentose phosphate pathway
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.001
  34. Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2426135122
    Structural insights into the substrate uptake and inhibition of the human creatine transporter (hCRT).
    Xinyi Yuan, Jian Yin, Chang Liu, Xudong Chen, Meiying Chen, Yixue Wang, Zi Yang, Yue Wang, Li Jiang, Niyun Zhou, Xiaojuan Wang, Botong Liu, Zhaoqi Ma, Kaiyan Wang, Hongen Li, Sensen Zhang, Yongfeng Shang, Maojun Yang.
      Creatine plays a vital role in cellular energy production and adenosine triphosphate (ATP) homeostasis and has also been identified as a neurotransmitter in the mammalian brain. Creatine is transported into cells by the human creatine transporter (hCRT) (SLC6A8), an Na+/Cl--dependent symporter encoded on the X chromosome. Mutations in hCRT cause cerebral creatine deficiency syndrome 1, a neurological disorder marked by intellectual disability, speech delay, and seizures. Beyond its role in the brain and muscle, hCRT is highly expressed in metabolically active tumors. Many cancer cells, including colorectal cancer and glioblastoma, upregulate hCRT to sustain intracellular creatine levels and buffer ATP under energy stress. Pharmacological blockade of hCRT by RGX202 has been shown to impair tumor growth by disrupting energy homeostasis. Here, we report the high-resolution cryo-Electron Microscopy (cryo-EM) structures of human hCRT in three states: apo, creatine-bound, and RGX202-bound. hCRT adopts a canonical LeuT-fold with 12 transmembrane helices and two pseudosymmetric inverted repeats. Creatine is coordinated in the central substrate-binding site through interactions with transmembrane helices TM1, TM3, TM6, and TM8, while the inhibitor RGX202 occupies the same binding pocket, engaging in overlapping contacts that competitively block creatine access. Our structural and mechanistic findings clarify substrate recognition and inhibitory binding of hCRT, providing a molecular rationale for targeting hCRT in both inherited metabolic diseases and cancer therapy.
    Keywords:  competitive inhibition; human creatine transporter; substrate uptake
    DOI:  https://doi.org/10.1073/pnas.2426135122
  35. Genesis. 2025 Oct;63(5): e70025
    Generation of Astrocyte-Selective Cre Driver Lines With Distinct Onsets of Recombination Activity During Development.
    Yukina Izumi, Tomoya Nakatani, Harumi Takai, Minoru Kumai, Tsutomu Kamisako, Hiroyoshi Ishizaki, Yuichi Ono.
      Astrocytes are a major glial cell type, playing multiple roles in the development, function, and pathogenesis of the brain. Accordingly, neuronal-astrocyte communication is an important research area. However, because these cell types share the same developmental origin, selective manipulation of each cell type is needed for precise mechanistic understanding. Here, we generated two new Cre driver lines for selective gene manipulation in astrocytes: Slc7a10-IRES-Cre and Aldh1l1-IRES-Cre. An internal ribosome entry site (IRES)-Cre cassette was knocked-in to the 3'-untranslated region of the solute carrier family 7 member 10 (Slc7a10) or aldehyde dehydrogenase 1 family member L1 (Aldh1l1) locus without disrupting gene function. The Slc7a10-IRES-Cre line underwent highly selective recombination in astrocytes of the brain, apart from choroid plexus epithelial cells. The onset of recombination began after completion of differentiation in the astrocyte lineage. By contrast, the Aldh1l1-IRES-Cre line began recombination during astrocyte differentiation at early postnatal stages. Some leaky expression was observed in the oligodendrocyte lineage, probably due to early onset of Cre expression in an uncommitted glial progenitor state. Together, the combination of the two deleter lines with distinct temporal Cre expression patterns serves as valuable tools to understand the development and function of astrocytes.
    Keywords:  Cre deleter line; astrocyte; cell lineage; differentiation
    DOI:  https://doi.org/10.1002/dvg.70025
  36. J Magn Reson Imaging. 2025 Sep 05.
    The Role of MRI in Debunking the Fallacy of "Mild" Traumatic Brain Injury.
    Xingye Chen, David Wright, Sohae Chung, Yvonne Lui.
      Mild traumatic brain injury (mTBI) is a prevalent yet often overlooked public health concern due to the absence of detectable abnormalities on CT or conventional MRI scans. Approximately 18.3%-31.3% of mTBI patients experience persistent symptoms 3-6 months post-injury, despite normal imaging results, making diagnosis and treatment challenging. In recent years, advanced neuroimaging modalities have emerged with the potential to reveal subtle physiological and structural brain changes that are invisible to traditional imaging. Diffusion MRI (dMRI), for instance, is particularly valuable for detecting white matter injury; perfusion MRI assesses alterations in cerebral blood flow; sodium MRI (23Na MRI) provides insights into ionic homeostasis; and functional MRI (fMRI) detects disruptions in functional brain network connectivity. In this review, we first explore the underlying mechanisms of mTBI and then summarize current evidence supporting the use of advanced MRI techniques to detect injury signatures associated with these mechanisms. Finally, we highlight populations at heightened risk for repeated injuries-underscoring the urgent need for more sensitive diagnostic tools that can identify injury early, guide return-to-activity decisions, and prevent cumulative brain damage. EVIDENCE LEVEL: N/A. TECHNICAL EFFICACY: Stage 3.
    Keywords:  mTBI mechanisms; mild traumatic brain injury (mTBI); multimodal MRI imaging
    DOI:  https://doi.org/10.1002/jmri.70083
  37. J Neurochem. 2025 Sep;169(9): e70193
    Regulatory Dynamics of Nrf2 With Sirtuins in the Brain: Exploring Cellular Metabolism, Synaptic Plasticity, and Defense Mechanisms.
    Efrain J Perez Lao, Eric Fagerli, Fernando Ferrier, Juan I Young, Miguel A Perez-Pinzon.
      Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role as a transcription factor at the heart of cellular defense mechanisms against oxidative stress, orchestrating a suite of cytoprotective genes. This review places particular emphasis on the interplay between Nrf2 and Sirtuins-NAD+-dependent deacetylases integral to redox regulation, metabolic control, and neuroprotection. We highlight how these proteins cooperate to regulate oxidative defense and cellular metabolism, with a particular focus on brain physiology and resilience. We briefly touch on the regulatory influence of specific microRNAs (e.g., miR-126, miR-34a) as emerging modulators of this pathway. Through this review, we aim to consolidate insights into Nrf2-Sirtuin crosstalk, particularly in the context of brain health, and highlight potential therapeutic strategies including pharmacological agents, miRNA modulators, and ischemic preconditioning mimetics. This work aims to inspire further investigation and translational advances in the treatment of oxidative stress-related neurological disorders.
    Keywords:  bioenergetics; epigenetic reprogramming; metabolic plasticity; mitochondria and transcriptomic adaptation; preconditioning strategies
    DOI:  https://doi.org/10.1111/jnc.70193
  38. Nat Commun. 2025 Sep 01. 16(1): 8173
    Temporal transcriptional regulation of mitochondrial morphology primes activity-dependent circuit connectivity.
    Iryna Mohylyak, Maheva Andriatsilavo, Mercedes Bengochea, Carlos Pascual-Caro, Noemi Asfogo, Sara Fonseca-Topp, Natasha Danda, Marlene Cassar, Corentine Marie, Zeynep Kalender Atak, Maxime De Waegeneer, Stein Aerts, Olga Corti, Jaime de Juan-Sanz, Bassem A Hassan.
      Synaptic connectivity during development is known to require rapid local regulation of axonal organelles. Whether this fundamental and conserved aspect of neuronal cell biology is orchestrated by a dedicated developmental program is unknown. We hypothesized that developmental transcription factors regulate critical parameters of organelle structure and function which contribute to circuit wiring. We combined cell type-specific transcriptomics with a genetic screen to discover such factors. We identified Drosophila CG7101, which we rename mitochondrial integrity regulator of neuronal architecture (Mirana), as a temporal developmental regulator of neuronal mitochondrial quality control genes, including Pink1. Remarkably, a brief developmental downregulation of either Mirana or Pink1 suffices to cause long-lasting changes in mitochondrial morphology and abrogates neuronal connectivity which can be rescued by Pink1 expression. We show that Mirana has functional homology to the mammalian transcription factor TZAP whose loss leads to changes in mitochondrial function and reduced neurotransmitter release in hippocampal neurons. Our findings establish temporal developmental transcriptional regulation of mitochondrial morphology as a prerequisite for the priming and maintenance of activity-dependent synaptic connectivity.
    DOI:  https://doi.org/10.1038/s41467-025-62908-2
  39. Dev Neurobiol. 2025 Oct;85(4): e22999
    Hepatic Encephalopathy: Insights Into the Impact of Metabolic Precipitates.
    Udit Kumar Dash, Aparna Tripathi, Debashree Mazumdar, Dusmanta Podh, Santosh Singh.
      Hepatic failure is a severe condition marked by the progressive or sudden loss of liver function, broadly categorized into acute liver failure (ALF), which develops within days to weeks, and chronic liver failure (CLF), which evolves over months or years. Both forms can lead to serious complications such as jaundice, impaired detoxification, portal hypertension, ascites, multi-organ dysfunction, and coagulation disorders. A significant neuropsychiatric consequence of liver failure is hepatic encephalopathy (HE), a spectrum of cognitive, motor, and behavioral abnormalities. Although elevated ammonia levels have long been implicated as a central factor in the pathogenesis of HE, emerging evidence suggests that other metabolic toxins also play critical roles. These include manganese (Mn), altered glucose metabolism, short-chain fatty acids (SCFAs), mercaptans, and gamma-aminobutyric acid (GABA). This review aims to explore the multifactorial metabolic landscape contributing to HE, highlighting the potential synergistic effects and mechanistic roles of these blood-borne precipitates. Understanding these diverse metabolic contributors may pave the way for more comprehensive diagnostic and therapeutic approaches beyond the traditional focus on ammonia.
    Keywords:  ammonia; astrocyte dysfunction; hepatic encephalopathy; manganese; metabolic precipitates; neuroinflammation; oxidative stress
    DOI:  https://doi.org/10.1002/dneu.22999
  40. bioRxiv. 2025 Aug 19. pii: 2025.08.14.669896. [Epub ahead of print]
    Proteo-transcriptomic reprogramming and resource reallocation define the aging mammalian brain.
    Nisha Hemandhar-Kumar, Verena Kluever, Svenja V Kaufmann, Cornelius Bergmann, Kanaan Mousaei, Miguel Tomas, Miguel Correa Marrero, Avika Chopra, Misa Hirose, Mercè Pallas, Coral Sanfeliu, Saleh M Ibrahim, Andre Fischer, Tiago F Outeiro, Henning Urlaub, Tatjana Tchumatchenko, Carlos López Otín, Eugenio F Fornasiero.
      Brain aging is a major risk for neurodegeneration, yet the underlying molecular mechanisms remain poorly understood. Here we performed an integrative proteo-transcriptomic analysis of the aging mouse brain, uncovering molecular signatures of aging through the assessment of protein aggregation, mRNA relocalization, and comparative proteomics across eight models of premature aging and neurodegeneration. We identified dynamic changes in physiological aging highlighting differences in synaptic maintenance and energy-allocation. These were linked to changes associated with fundamental protein biochemical properties such as size and net charge. Network analysis highlighted a decrease in mitochondrial complex I proteins not compensated at the mRNA level. Aggregation of 60S ribosome subunits indicated deteriorating translation efficiency and was accompanied by mitochondrial and proteasomal imbalance. The analysis of the nine models revealed key similarities and differences between physiological aging and pathology. Overall, our study provides an extensive resource on molecular aging, and offers insights into mechanisms predisposing to neurodegeneration, easily accessible at our Brain Aging and Molecular Atlas Project (BrainAging-MAP) website.
    DOI:  https://doi.org/10.1101/2025.08.14.669896
  41. Front Neurosci. 2025 ;19 1631752
    Impacts of mitochondrial dysfunction on axonal microtubule bundles as a potential mechanism of neurodegeneration.
    Scott Murray-Cors, Milli Owens, Yu-Ting Liew, Maureece Day, William Cairns, Andreas Prokop.
      Mitochondrial dysfunction is an important cause for neurodegeneration, often associated with dyshomeostasis of reactive oxygen species, i.e., oxidative stress. However, apart from ATP production, mitochondria have many other functions the aberration of which may impact neurons in very different ways. Oxidative stress can cause the deterioration of axonal microtubule bundles, thus critically affecting the highways for life-sustaining transport and providing a potential path to neurodegeneration. We recently found that aberrant transport of mitochondria can have this effect by causing oxidative stress. We therefore asked which aberrations of mitochondrial physiology might impact microtubules, which of these might explain the observed consequences of aberrant mitochondrial transport, and whether mitochondria-induced microtubule phenotypes are always mediated by oxidative stress. Using one consistent Drosophila primary neuron system, we studied functional loss of 13 different mitochondrial factors known to be detrimental to neurons in vivo. Losses of five factors caused MT damage, namely pyruvate dehydrogenase A, succinate dehydrogenase A, adenine nucleotide translocase, frataxin and superoxide dismutase 2. All involved oxidative stress, hence supported the path from mitochondria via oxidative stress to microtubule deterioration; of these, we discuss superoxide dismutase 2 as potential candidate explaining effects of mitochondrial transport aberration. Six of the remaining factors not causing microtubule damage were important mitochondrial morphogenesis regulators, suggesting efficient protection mechanisms preventing oxidative stress upon mitochondrial contortion.
    Keywords:  Drosophila; microtubules; mitochondria; neurodegeneration; reactive oxygen species
    DOI:  https://doi.org/10.3389/fnins.2025.1631752
  42. Nat Methods. 2025 Sep 03.
    Unified mass imaging maps the lipidome of vertebrate development.
    Halima Hannah Schede, Leila Haj Abdullah Alieh, Laurel Ann Rohde, Antonio Herrera, Anjalie Schlaeppi, Guillaume Valentin, Alireza Gargoori Motlagh, Albert Dominguez Mantes, Chloe Jollivet, Jonathan Paz-Montoya, Laura Capolupo, Irina Khven, Andrew C Oates, Giovanni D'Angelo, Gioele La Manno.
      Embryo development entails the formation of anatomical structures with distinct biochemical compositions. Compared with the wealth of knowledge on gene regulation, our understanding of metabolic programs operating during embryogenesis is limited. Mass spectrometry imaging (MSI) has the potential to map the distribution of metabolites across embryo development. Here we established uMAIA, an analytical framework for the joint analysis of large MSI datasets, which enables the construction of multidimensional metabolomic atlases. Employing this framework, we mapped the four-dimensional (4D) distribution of over a hundred lipids at micrometric resolution in Danio rerio embryos. We discovered metabolic trajectories that unfold in concert with morphogenesis and revealed spatially organized biochemical coordination overlooked by bulk measurements. Interestingly, lipid mapping revealed unexpected distributions of sphingolipid and triglyceride species, suggesting their involvement in pattern establishment and organ development. Our approach empowers a new generation of whole-organism metabolomic atlases and enables the discovery of spatially organized metabolic circuits.
    DOI:  https://doi.org/10.1038/s41592-025-02771-7
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