bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2025–01–26
29 papers selected by
Regina F. Fernández, Johns Hopkins University



  1. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251314601
      The composition of eukaryotic membranes reflects a varied but precise amalgam of lipids. The genetic underpinning of how such diversity is achieved or maintained is surprisingly obscure, despite its clear metabolic and pathophysiological impact. The Arv1 protein is represented in all eukaryotes and was initially identified in the model eukaryote Sacccharomyces cerevisiae as a candidate transporter of lipids from the endoplasmic reticulum. Human Arv1 has been shown to directly bind cholesterol and fatty acid affinity probes. Murine in vivo studies point to a role for ARV1 in regulating obesity, glucose tolerance, insulin sensitivity and brain function. Multiple human ARV1 variants have been associated with epileptic encephalopathy, cerebellar ataxia, and severe intellectual deficits. We hypothesize that Arv1 acts as an energy independent, lipid scramblase at the endoplasmic reticulum thereby modulating membrane lipid asymmetry and thus the trafficking of sterols and the substituents of glycosyl-phosphatidylinositol and sphingolipid biosynthesis.
    Keywords:  cholesterol; encephalopathy; glycosyl-phosphatidylinositol; lipid flippase; sphingolipids
    DOI:  https://doi.org/10.1177/25152564251314601
  2. Proc Natl Acad Sci U S A. 2025 Jan 28. 122(4): e2421178122
      To regulate brain function, peripheral compounds must traverse the blood-brain barrier (BBB), an interface between the brain and the circulatory system. To determine whether specific transport mechanisms are relevant for sleep, we conducted a BBB-specific inducible RNAi knockdown (iKD) screen for genes affecting sleep in Drosophila. We observed reduced sleep with knockdown of solute carrier CG6126, a carnitine transporter, as determined by isotope flux. Our findings suggest that CG6126 regulation of sleep is through the role of the carnitine shuttle in regulating fatty acid metabolism as lipid droplets accumulate in the brains of CG6126 BBB iKD flies. Knocking down mitochondrial carnitine transferases in non-BBB glial cells mimicked the reduced sleep of the CG6126 BBB iKD flies, while bypassing the necessity of carnitine transport with dietary medium-chain fatty acids or palmitoylcarnitine rescued sleep. We propose that carnitine transport via CG6126 promotes brain fatty acid metabolism necessary for maintaining sleep.
    Keywords:  blood-brain barrier; carnitine transport; fatty acids; lipid metabolism; sleep regulation
    DOI:  https://doi.org/10.1073/pnas.2421178122
  3. Brain Imaging Behav. 2025 Jan 24.
      COVID-19 disease, caused by the SARS-CoV-2 virus, has significantly altered modern society and lifestyles. We investigated its impact on brain glucose metabolism by meta-analyzing existing studies that utilized 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans of the brain. We conducted a systematic search of MEDLINE and EMBASE databases from inception to August 2024 for English-language publications using the keywords "positron emission tomography", and "COVID-19". We included original research articles that reported changes in brain glucose metabolism following COVID-19 disease. ALE values from these studies were aggregated and tested against a null hypothesis that anticipated a random distribution of ALE values, which proved to be significantly higher than chance. We identified nine papers that met our inclusion criteria. Significant increases in brain glucose metabolism were noted in the left anterior cingulate gyrus, right thalamus, and brainstem. In children with COVID-19 disease, decreased glucose metabolism was observed in the right and left cerebellum, left amygdala/hippocampus, left anterior cingulate gyrus, and right amygdala. In adults with COVID-19 disease, decreased metabolism was seen in the right temporal lobe, brainstem (acute phase), left occipital lobe, left and right temporal lobe (chronic phase). In conclusion, COVID-19 disease impacts brain glucose metabolism, typically manifesting as areas of decreased metabolism in 18F-FDG PET scans, though increases are also observed. These changes in metabolism vary with the patient's age and the time elapsed between the diagnosis of COVID-19 disease and the PET scan.
    Keywords:   18F-fluorodeoxyglucose; Brain; COVID-19 disease; Positron emission tomography
    DOI:  https://doi.org/10.1007/s11682-025-00966-2
  4. JIMD Rep. 2025 Jan;66(1): e12461
       Background: Deficiency of the Glut1 transporter due to mono-allelic variants in SLC2A1 causes hypoglycorrhachia, resulting in a neurological spectrum from neonatal epilepsy to adult-onset paroxysmal movement disorders (PMD). The brain utilises ketone bodies as an alternative energy source to glucose. Thus, early initiation of the ketogenic diet (KD) is standard care for Glut1 deficiency syndrome (Glut1DS). Commencement and adherence in older Glut1DS patients is difficult to achieve, leaving few treatment options. Oral D,L-3-hydroxybutyrate (D,L-3-HB) crosses the blood-brain barrier, making it a potential treatment for Glut1DS.
    Methods: A retrospective case review of patients with Glut1DS under the Adult and Paediatric National Metabolic Service (APNMS) of New Zealand, treated with D,L-3-HB between 2012 and 2023 was performed. Clinical notes, standardised, neuropsychological assessments and subjective data on and off D,L-3-HB were obtained. The best on and off D,L-3-HB measures of working memory (WMI) and processing speed (PSI) were compared to assess the efficacy.
    Results: D,L-3-HB was offered to 12 patients with Glut1DS (age 10-52 years). Compliance-dependent improvements in subjective, cognitive and adaptive function were reported by those who were reassessed on-treatment (9/12). Four reported improved PMD. Objective improvements were found in WM (9/9) and PS (6/9). Subjective improvements were reported in patients' health, wellbeing and independence.
    Conclusions: KD remains standard of care for Glut1DS, but effective alternatives are lacking for those who do not tolerate this. D,L-3-HB was associated with improved WM, PS and perceived life quality in this small group of patients with Glut1DS, thus providing a potential treatment for this distinct group.
    Keywords:  D,L‐3‐HB; D,L‐3‐hydroxybutyrate; Glut1; cognitive impairment; glut1ds; ketogenic; ketones
    DOI:  https://doi.org/10.1002/jmd2.12461
  5. Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(24)00077-4. [Epub ahead of print]143 387-409
      Lipids play an essential role in synaptic function, significantly impacting synaptic physiology through their dynamic nature and signaling capabilities. Membrane lipids, including cholesterol, phospholipids, and gangliosides, are crucial for synaptic organization and function. They act as structural integrators and signaling molecules, guiding vesicle intracellular movement and regulating enzyme activity to support neuronal activity. The lipid compositions of pre-synaptic and post-synaptic membranes influence vesicle generation and receptor mobility, highlighting their active involvement in synaptic processes. Astrocytes also contribute to synaptic health by upholding the blood-brain barrier, regulating ion levels, and providing metabolic support. Lipid-mediated processes control synaptic plasticity and development, with astrocytes playing a crucial role in glutamate homeostasis. Amyloid-beta and Tau proteins are key in Alzheimer's disease (AD), where synaptic disruption leads to cognitive deficits. Clathrin-mediated endocytosis (CME) and caveolin-mediated endocytosis are critical pathways for lipid-mediated synaptic function, with disruptions in these pathways contributing to AD pathogenesis.
    Keywords:  Alzheimer’s disease; Amyloid beta; Endocytosis; Lipid metabolism; Microglial activation; Synaptic dysfunction; Tau protein
    DOI:  https://doi.org/10.1016/bs.apcsb.2024.08.002
  6. Front Neurol. 2024 ;15 1499876
      Mitochondria is the cell's powerhouse. Mitochondrial disease refers to a group of clinically heterogeneous disorders caused by dysfunction in the mitochondrial respiratory chain, often due to mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that encodes mitochondrial proteins. This dysfunction can lead to a variety of clinical phenotypes, particularly affecting organs with high energy demands, such as the brain and muscles. Epilepsy is a prevalent neurological disorder in children and is also a frequent manifestation of mitochondrial disease. The exact mechanisms underlying epilepsy in mitochondrial disease remain unclear and are thought to involve multiple contributing factors. This review explores common mitochondrial diseases associated with epilepsy, focusing on their prevalence, seizure types, EEG features, therapeutic strategies, and outcomes. It also summarizes the relationship between the molecular genetics of mitochondrial respiratory chain components and the development of epilepsy.
    Keywords:  coenzyme Q; cytochrome C; epilepsy; genes; mitochondrial complex
    DOI:  https://doi.org/10.3389/fneur.2024.1499876
  7. Pharmacol Res. 2025 Jan 20. pii: S1043-6618(25)00040-4. [Epub ahead of print] 107615
      In recent years, increasing evidence has supported that high-fat diet (HFD) can induce the chronic, low-grade neuroinflammation in the brain, which is closely associated with the impairment of cognitive function. As the key organelles responsible for energy metabolism in the cell, mitochondria are believed to involved in the pathogenesis of a variety of neurological disorders. This review summarizes the current progress in the field of the relationship between HFD exposure and neurodegenerative diseases, and outline the major routines of HFD induced neuroinflammation and its pathological significance in the pathogenesis of neurodegenerative diseases. Furthermore, the article highlights the pivotal role of mitochondrial dysfunction in driving the neuroinflammation in the setting of HFD. Danger-associated molecular patterns (DAMPs) from damaged mitochondria can activate innate immune signaling pathways, while mitochondrial dysfunction itself can lead to metabolic remodeling of inflammatory cells, thus inducing neuroinflammation. More importantly, mitochondrial damage, neuroinflammation, and insulin resistance caused by HFD form a mutually reinforcing vicious cycle, ultimately leading to the death of neurons and promoting the progression of neurodegenerative diseases. Thus, in-depth elucidation of the role and underlying mechanisms of mitochondrial dysfunction in HFD-induced metabolic disorders may not only expand our understanding of the mechanistic linkages between HFD and etiology of neurodegenerative diseases, but also help develop the specific strategies for the prevention and treatment of neurodegenerative diseases.
    Keywords:  High-fat diet (HFD); mitochondrial dysfunction; neurodegenerative diseases; neuroinflammation; obesity; oxidative stress
    DOI:  https://doi.org/10.1016/j.phrs.2025.107615
  8. Metabolites. 2025 Jan 08. pii: 29. [Epub ahead of print]15(1):
      Background: Polyunsaturated fatty acids in particular omega-3 fatty acids, such as docosahexaenoic acid (DHA), are essential nutrients and components of the plasma membrane. They are involved in various processes, including synaptic development, functionality, integrity, and plasticity, and are therefore thought to have general neuroprotective properties. Considerable research evidence further supports the beneficial effects of omega-3 fatty acids, specifically on mitochondria, through their antioxidant and anti-apoptotic properties, making them an attractive addition in treatment options for neurodegenerative disorders in which mitochondrial alterations are commonly observed. However, precise information on the underlying protective mechanisms is still lacking. Methods: We utilized the most common neuronal cell line (SH-SY5Y) and induced mitochondrial oxidative stress through the addition of rotenone. To study the potential protective effect of DHA, the cells were additionally pre-treated with DHA prior to rotenone administration. By combining SILAC labeling, mitochondria enrichment, and subsequent proteomic analyses, we aimed to determine the capacity of DHA to alleviate mitochondrial oxidative stress in vitro and further shed light on the molecular mechanisms contributing to the proposed neuroprotective effect. Results: We confirmed a reduced cell viability and an increased abundance of reactive oxygen species upon rotenone treatment, DHA pre-treatment was shown to decrease said species. Additionally proteomic analysis revealed an increased expression of mitochondrial proteins in DHA pre-treated cells. Conclusions: With our study, we were able to define a potential compensatory mechanism by which the inhibition of complex I is overcome by an increased activity of the fatty acid beta oxidation in response to DHA.
    Keywords:  SH-SY5Y; docosahexaenoic acid; mitochondria; proteomics; rotenone
    DOI:  https://doi.org/10.3390/metabo15010029
  9. J Magn Reson Imaging. 2025 Jan 21.
      The biochemical composition and structure of the brain are in a rapid change during the exuberant stage of fetal and neonatal development. 1H-MRS is a noninvasive tool that can evaluate brain metabolites in healthy fetuses and infants as well as those with neurological diseases. This review aims to provide readers with an understanding of 1) the basic principles and technical considerations relevant to 1H-MRS in the fetal-neonatal brain and 2) the role of 1H-MRS in early fetal-neonatal development brain research. We performed a PubMed search to identify original studies using 1H-MRS in neonates and fetuses to establish the clinical applications of 1H-MRS. The eligible studies for this review included original research with 1H-MRS applications to the fetal-neonatal brain in healthy and high-risk conditions. We ran our search between 2000 and 2023, then added in several high-impact landmark publications from the 1990s. A total of 366 results appeared. After, we excluded original studies that did not include fetuses or neonates, non-proton MRS and non-neurological studies. Eventually, 110 studies were included in this literature review. Overall, the function of 1H-MRS in healthy fetal-neonatal brain studies focuses on measuring the change of metabolite concentrations during neurodevelopment and the physical properties of the metabolites such as T1/T2 relaxation times. For high-risk neonates, studies in very low birth weight preterm infants and full-term neonates with hypoxic-ischemic encephalopathy, along with examining the associations between brain biochemistry and cognitive neurodevelopment are most common. Additional high-risk conditions included infants with congenital heart disease or metabolic diseases, as well as fetuses of pregnant women with hypertensive disorders were of specific interest to researchers using 1H-MRS. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.
    Keywords:  brain; fetuses; metabolites; neonates; proton magnetic resonance spectroscopy
    DOI:  https://doi.org/10.1002/jmri.29709
  10. Front Pharmacol. 2024 ;15 1531524
       Background: Lipids are vital biomolecules involved in the formation of various biofilms. Seizures can cause changes in lipid metabolism in the brain. In-depth studies at multiple levels are urgently needed to elucidate lipid composition, distribution, and metabolic pathways in the brain after seizure.
    Methods: In this research, a cutting-edge targeted quantitative lipidomics study was conducted on the hippocampal tissues of six rats with temporal lobe epilepsy and six normal rats. Accurate lipid quantification based on linear equations was calculated using an internal standard. The lipids were quantitatively and qualitatively analyzed by ultra-high performance liquid chromatography (UPLC) and mass spectrometry (MS).
    Results: A total of 21 lipid classes were identified. Among them, the most abundant were triacylglycerol (TG), phosphatidyl ethanolamine (PE-P), and fatty acids (FA). Cholesteryl ester (ChE) exhibits the most considerable difference between the normal and epileptic samples. ChE was found to be the most significantly upregulated lipid, while FA was observed to be the most significantly downregulated lipid.
    Conclusion: Based on the absolute quantitative analysis of lipids in rat hippocampal specimens, the contents and change trends of different lipids were observed. Upregulation of ChE and dihydroceramide (DHCer) was observed, and an analysis of the distribution changes elucidated the causes and possible molecular mechanisms of lipid accumulation in temporal lobe epilepsy. The results and methods described provide a comprehensive analysis of lipid metabolism in temporal lobe epilepsy and a new therapeutic target for the treatment of epilepsy.
    Keywords:  epilepsy; molecular mechanism; targeted lipidomics analysis; temporal lobe epilepsy; therapeutic target
    DOI:  https://doi.org/10.3389/fphar.2024.1531524
  11. Purinergic Signal. 2025 Jan 21.
      The two main glial cell types of the central nervous system (CNS), astrocytes and microglia, are responsible for neuroimmune homeostasis. Recent evidence indicates astrocytes can participate in removal of pathological structures by becoming phagocytic under conditions of neurodegenerative disease when microglia, the professional phagocytes, are impaired. We hypothesized that adenosine triphosphate (ATP), which acts as damage-associated molecular pattern (DAMP), when released at high concentrations into extracellular space, upregulates phagocytic activity of human astrocytes. This study is the first to measure changes in phagocytic activity and mitochondrial respiration of human astrocytic cells in response to extracellular ATP. We demonstrate that ATP-induced phagocytic activity of U118 MG astrocytic cells is accompanied by upregulated mitochondrial oxidative phosphorylation, which likely supports this energy-dependent process. Application of a selective antagonist A438079 provides evidence identifying astrocytic purinergic P2X7 receptor (P2X7R) as the potential regulator of their phagocytic function. We also report a rapid ATP-induced increase in intracellular calcium ([Ca2+]i), which could serve as regulator of both the phagocytic activity and mitochondrial metabolism, but this hypothesis will need to be tested in future studies. Since ATP upregulates interleukin (IL)-8 secretion by astrocytes but has no effect on their cytotoxicity towards neuronal cells, we conclude that extracellular ATP affects only specific functions of astrocytes. The selectivity of P2X7R-dependent regulation of astrocyte functions by extracellular ATP could allow targeting this receptor-ligand interaction to upregulate their phagocytic function. This could have beneficial outcomes in neurodegenerative disorders, such as Alzheimer's disease, that are characterized by reactive astrocytes and defective phagocytic processes.
    Keywords:  Astrocytes; Damage-associated molecular pattern (DAMP); Extracellular adenosine triphosphate (ATP); Oxidative phosphorylation; Phagocytosis; Purinergic receptor P2X7
    DOI:  https://doi.org/10.1007/s11302-025-10066-x
  12. Acta Paediatr. 2025 Jan 21.
       AIM: To investigate fasting metabolism in children with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and medium-chain acyl-CoA dehydrogenase deficiency (MCADD) using microdialysis technique.
    METHODS: Twelve patients (7 with VLCADD, 5 with MCADD, mean age 4.9 years, 10/12 diagnosed via newborn screening) were recruited for investigation in connection to clinical fasting examinations at the Karolinska University Hospital (between 2015 and 2024). Patients were subjected to a 9-h night fast after a standard late evening meal. Analysis of glucose, glycerol, lactate, and pyruvate was conducted by continuous microdialysis. Fasting hormones and acylcarnitines were analysed in blood samples at 1-h intervals in patients with VLCADD.
    RESULTS: Children with VLCADD showed signs of lipolysis after a median fasting time of 4.5 h, whereas patients with MCADD showed no significant increase in lipolysis during the fast. A shorter time to initiation of lipolysis tended to correlate with a lower residual enzyme activity in patients with VLCADD. All patients maintained euglycemia during fasting.
    CONCLUSION: Children with VLCADD had a shorter time to initiation of lipolysis during fasting than children with MCADD. Clinical evaluation of fasting metabolism in beta-oxidation disorders should include assessment of lipolysis as an early and important determinant.
    Keywords:  Beta‐oxidation disorders; MCADD; VLCADD; fasting intolerance; microdialysis
    DOI:  https://doi.org/10.1111/apa.17591
  13. Nucl Med Commun. 2025 Jan 20.
       OBJECTIVES: Parkinson's disease (PD) is a neurodegenerative disorder with distinct metabolic alterations in the brain, which are detectable via 18F-FDG PET. This study aims to delineate glucose metabolism patterns and network topology changes across early- and mid-stage PD patients.
    METHODS: A total of 80 PD patients (Hoehn-Yahr stages 1-3) were retrospectively analyzed, including 40 early-stage and 40 mid-stage cases, along with 40 age-matched healthy controls. All participants underwent 18F-FDG PET imaging. The brain metabolic activity was quantified, and network topology was assessed using graph theory metrics. Statistical comparisons between PD stages and control groups were performed to identify significant differences in metabolic patterns and network alterations.
    RESULTS: Early-stage PD patients exhibited hypermetabolism in regions such as the pons and thalamus, with significant differences in metabolic activity compared with controls. Mid-stage PD patients showed more extensive hypermetabolism in the pons, right cerebellum, and putamen, alongside hypometabolism in the cuneus and calcarine regions. Hub node connectivity analysis revealed decreased connectivity in temporal and occipital lobes for both stages, while the limbic and frontal lobes showed enhanced connectivity. Compared with early-stage PD, mid-stage PD had reduced connectivity in the limbic system but increased in the frontal and occipital lobes.
    CONCLUSIONS: 18F-FDG PET imaging reveals progressive metabolic disruptions and network changes in PD, offering potential biomarkers for disease staging and therapeutic targeting, while also aiding in the understanding of disease progression and guiding therapeutic interventions.
    DOI:  https://doi.org/10.1097/MNM.0000000000001951
  14. Nat Commun. 2025 Jan 22. 16(1): 917
      The multi-enzyme pyruvate dehydrogenase complex (PDHc) links glycolysis to the citric acid cycle and plays vital roles in metabolism, energy production, and cellular signaling. Although all components have been individually characterized, the intact PDHc structure remains unclear, hampering our understanding of its composition and dynamical catalytic mechanisms. Here, we report the in-situ architecture of intact mammalian PDHc by cryo-electron tomography. The organization of peripheral E1 and E3 components varies substantially among the observed PDHcs, with an average of 21 E1 surrounding each PDHc core, and up to 12 E3 locating primarily along the pentagonal openings. In addition, we observed dynamic interactions of the substrate translocating lipoyl domains (LDs) with both E1 and E2, and the interaction interfaces were further analyzed by molecular dynamics simulations. By revealing intrinsic dynamics of PDHc peripheral compositions, our findings indicate a distinctive activity regulation mechanism, through which the number of E1, E3 and functional LDs may be coordinated to meet constantly changing demands of metabolism.
    DOI:  https://doi.org/10.1038/s41467-025-56171-8
  15. Commun Biol. 2025 Jan 21. 8(1): 105
      Metabolic and neurological disorders commonly display dysfunctional branched-chain amino acid (BCAA) metabolism, though it is poorly understood how this leads to neurological damage. We investigated this by generating Drosophila mutants lacking BCAA-catabolic activity, resulting in elevated BCAA levels and neurological dysfunction, mimicking disease-relevant symptoms. Our findings reveal a reduction in neuronal AMP-activated protein kinase (AMPK) activity, which disrupts autophagy in mutant brain tissues, linking BCAA imbalance to brain dysfunction. Mechanistically, we show that excess BCAA-induced mitochondrial reactive oxygen species (ROS) triggered the binding of protein phosphatase 2 A catalytic subunit (PP2Ac) to AMPK, suppressing AMPK activity. This initiated a dysregulated feedback loop of AMPK-mitochondrial interactions, exacerbating mitochondrial dysfunction and oxidative neuronal damage. Our study identifies BCAA imbalance as a critical driver of neuronal damage through AMPK suppression and autophagy dysfunction, offering insights into metabolic-neuronal interactions in neurological diseases and potential therapeutic targets for BCAA-related neurological conditions.
    DOI:  https://doi.org/10.1038/s42003-025-07457-6
  16. J Physiol Sci. 2024 Dec 21. pii: S1880-6546(24)00984-3. [Epub ahead of print]75(1): 100003
      Reactive oxygen species (ROS) are redox-signaling molecules involved in aging and lifestyle-related diseases. In the brain, in addition to the production of ROS as byproducts of metabolism, expression of ROS synthases has recently been demonstrated, suggesting possible involvement of ROS in various brain functions. This review highlights current knowledge on the relationship between ROS and brain functions, including their contribution to age-related decline in synaptic plasticity and cognitive function. While most studies demonstrate either the positive or negative effects of ROS on synaptic plasticity, the dual effects of ROS at individual synapses have been demonstrated recently in the mouse cerebellum. Furthermore, the cooperative interaction between these two effects determines the direction of synaptic plasticity. It is anticipated that further elucidation of both the positive and negative effects of ROS on brain function will lead to the development of more effective therapeutic strategies with fewer side effects for ROS-related brain dysfunction.
    Keywords:  Aging; Cerebellum; Long-term depression; Long-term potentiation; Reactive oxygen species; Synaptic plasticity
    DOI:  https://doi.org/10.1016/j.jphyss.2024.100003
  17. J Exp Clin Cancer Res. 2025 Jan 17. 44(1): 17
       BACKGROUND: Glioblastoma (GBM) is a lethal brain tumor characterized by the glioma stem cell (GSC) niche. The V-ATPase proton pump has been described as a crucial factor in sustaining GSC viability and tumorigenicity. Here we studied how patients-derived GSCs rely on V-ATPase activity to sustain mitochondrial bioenergetics and cell growth.
    METHODS: V-ATPase activity in GSC cultures was modulated using Bafilomycin A1 (BafA1) and cell viability and metabolic traits were analyzed using live assays. The GBM patients-derived orthotopic xenografts were used as in vivo models of disease. Cell extracts, proximity-ligation assay and advanced microscopy was used to analyze subcellular presence of proteins. A metabolomic screening was performed using Biocrates p180 kit, whereas transcriptomic analysis was performed using Nanostring panels.
    RESULTS: Perturbation of V-ATPase activity reduces GSC growth in vitro and in vivo. In GSC there is a pool of V-ATPase that localize in mitochondria. At the functional level, V-ATPase inhibition in GSC induces ROS production, mitochondrial damage, while hindering mitochondrial oxidative phosphorylation and reducing protein synthesis. This metabolic rewiring is accompanied by a higher glycolytic rate and intracellular lactate accumulation, which is not exploited by GSCs for biosynthetic or survival purposes.
    CONCLUSIONS: V-ATPase activity in GSC is critical for mitochondrial metabolism and cell growth. Targeting V-ATPase activity may be a novel potential vulnerability for glioblastoma treatment.
    Keywords:  Bafilomycin A1; Glioma; Glioma stem cell; Metabolism; V-ATPase
    DOI:  https://doi.org/10.1186/s13046-025-03280-3
  18. Nucl Med Biol. 2025 Jan 10. pii: S0969-8051(25)00002-2. [Epub ahead of print]142-143 108993
      The role of mitochondrial complex I (MC-I) dysfunction is well-documented across a range of neurodegenerative disorders. Recently, a novel positron emission tomography (PET) radioligand, [18F]CNL02, has been synthesized to target MC-I. In this paper, we provide a comprehensive characterization of [18F]CNL02, using nonhuman primate as a model system. In the brain of a rhesus macaque, [18F]CNL02 demonstrated specific binding in regions expressing MC-I. All observed brain regions showed rapid kinetic profiles. Analysis of arterial plasma indicated a swift clearance of [18F]CNL02 from the bloodstream. Metabolite analysis identified two predominant radiometabolites in the plasma. The regional brain time-activity curves (TACs) for [18F]CNL02 were effectively characterized through a two-tissue compartment model (2TCM). Furthermore, the total distribution volume was reliably estimated employing the Logan plot method. Consequently, continued development and refinement of [18F]CNL02 are imperative.
    Keywords:  Brain tissue; Mitochondrial complex I; Positron emission tomography; Radiotracers; Rhesus macaque
    DOI:  https://doi.org/10.1016/j.nucmedbio.2025.108993
  19. bioRxiv. 2025 Jan 07. pii: 2025.01.07.631801. [Epub ahead of print]
      Mitochondrial ATP production and calcium buffering are critical for metabolic regulation and neurotransmission making the formation and maintenance of the mitochondrial network a critical component of neuronal health. Cortical pyramidal neurons contain compartment-specific mitochondrial morphologies that result from distinct axonal and dendritic mitochondrial fission and fusion profiles. We previously showed that axonal mitochondria are maintained at a small size as a result of high axonal mitochondrial fission factor (Mff) activity. However, loss of Mff activity had little effect on cortical dendritic mitochondria, raising the question of how fission/fusion balance is controlled in the dendrites. Thus, we sought to investigate the role of another fission factor, fission 1 (Fis1), on mitochondrial morphology, dynamics and function in cortical neurons. We knocked down Fis1 in cortical neurons both in primary culture and in vivo , and unexpectedly found that Fis1 depletion decreased mitochondrial length in the dendrites, without affecting mitochondrial size in the axon. Further, loss of Fis1 activity resulted in both increased mitochondrial motility and dynamics in the dendrites. These results argue Fis1 exhibits dendrite selectivity and plays a more complex role in neuronal mitochondrial dynamics than previously reported. Functionally, Fis1 loss resulted in reduced mitochondrial membrane potential, increased sensitivity to complex III blockade, and decreased mitochondrial calcium uptake during neuronal activity. The altered mitochondrial network culminated in elevated resting calcium levels that increased dendritic branching but reduced spine density. We conclude that Fis1 regulates morphological and functional mitochondrial characteristics that influence dendritic tree arborization and connectivity.
    DOI:  https://doi.org/10.1101/2025.01.07.631801
  20. Autism Res. 2025 Jan 18.
      Neurodevelopmental disorders (NDDs) encompass a group of conditions that impact brain development and function, exhibiting significant genetic and clinical heterogeneity. NAA15, the auxiliary subunit of the N-terminal acetyltransferase complex, has garnered attention due to its association with NDDs. However, the precise role of NAA15 in cortical development and its contribution to NDDs remain elusive. By employing targeted sequencing on a large Chinese cohort affected by ASD and conducting an extensive literature review, we have compiled 64 distinct variants in the NAA15 gene identified among individuals with neurodevelopmental disorders. Our research demonstrates that loss of NAA15 leads to a substantial increase in neuronal count, potentially resulting in aberrant brain development and triggering repetitive as well as anxious behaviors in mice models. Furthermore, disorder-associated variants within NAA15 impair axon and synapse formation processes crucial for neural connectivity establishment. These findings shed light on the consequences of NAA15 deficiency along with its de novo mutations on brain development while unraveling the cellular mechanisms underlying NDDs.
    Keywords:  NAA15; autism spectrum disorders; brain development; de novo mutations; neurodevelopmental disorders
    DOI:  https://doi.org/10.1002/aur.3308
  21. J Physiol. 2025 Jan 19.
      The endocannabinoid system's significance in maintaining blood-brain barrier (BBB) integrity under physiological and pathological conditions is suggested by several reports, but the underlying molecular mechanisms are not well understood. In this paper, we investigated the effects of depletion of 2-arachidonoylglycerol (2-AG), one of the main endocannabinoids in the central nervous system, on BBB integrity using pharmacological tools. Female Sprague-Dawley rats were injected with the diacylglycerol lipase α (DAGLα) inhibitor LEI-106 (40 mg/kg, i.p.), followed by assessment of BBB integrity via in situ brain perfusion. Liquid chromatography-mass spectrometry, western immunoblotting, light transmittance experiments and pressure myography were also used to further examine the results of DAGLα blockade on the BBB and vascular reactivity. We found that DAGLα inhibition caused BBB opening in cortical brain areas, manifesting as increased sucrose transport measured by in situ brain perfusion. This was accompanied by reduced levels of 2-AG and decreased detection of the tight junction protein zonula occludens-1 (ZO-1). The protein level in cortical areas of neuronal PAS domain protein 4 (NPAS4), encoded by an activity-dependent immediate early gene, was increased without the presence of cortical spreading depression after LEI-106 administration. We also observed a significant increase in pressure-induced constriction within the parenchymal microcirculation after inhibition of DAGLα, possibly altering shear stress in the microcirculation. These results support the role of endogenous 2-AG in maintaining normal tight junction function. This improved understanding of the molecular mechanisms of endocannabinoid system function at the neurovascular unit can help to unlock the therapeutic potentials of cannabinoids in central nervous system disorders associated with BBB dysfunction. KEY POINTS: The administration of the diacylglycerol lipase α (DAGLα) inhibitor LEI-106 (40 mg/kg, i.p.) induced blood-brain barrier (BBB) opening of cortical brain areas in female Sprague-Dawley rats. This BBB disruption was accompanied by reduced levels of 2-arachidonoylglycerol (2-AG) and decreased detection of the tight junction protein zonula occludens-1 (ZO-1). The protein level in cortical areas of neuronal PAS domain protein 4 (NPAS4), encoded by an activity-dependent immediate early gene, was increased without the presence of cortical spreading depression after LEI-106 administration. A significant increase in pressure-induced constriction within the parenchymal microcirculation was also observed after inhibition of DAGLα, possibly altering shear stress. These results support the role of endogenous 2-AG in maintaining normal tight junction function.
    Keywords:  2‐AG; DAGLα; ZO‐1; blood–brain barrier; endocannabinoid system
    DOI:  https://doi.org/10.1113/JP287680
  22. Metab Brain Dis. 2025 Jan 18. 40(1): 108
      Phenylketonuria is a genetic disorder characterized by high phenylalanine levels, the main toxic metabolite of the disease. Hyperphenylalaninemia can cause neurological impairment. In order to avoid this symptomatology, patients typically follow a phenylalanine-free diet supplemented with a synthetic formula that provides essential amino acids, including L-carnitine. This work aims to evaluate the potential neuroprotective effects of L-carnitine treatment in the cerebral cortex of rats submitted to a chronic chemically-induced model of Hyperphenylalaninemia, evaluating brain oxidative damage and neuroinflammation. We confirm the effectiveness of the animal model, through the increase of phenylalanine and L-carnitine in blood and cerebral cortex. L-carnitine treatment was effective in significantly decreasing the generation of reactive species and attenuating the superoxide dismutase (SOD) activity. Significant negative correlations between L-carnitine and superoxide dismutase as well as L-carnitine and reactive species generation were also found, reinforcing the involvement of oxidative stress and the effect of L-carnitine. Besides, L-carnitine attenuated the decrease in IL-4 levels, demonstrating both anti-inflammatory properties and a neuroprotective effect, through the decrease in the overexpression of the glial fibrillary acidic protein (GFAP) present in the cerebral cortex of rats with Hyperphenylalaninemia. Our results highlight the neuroprotective role of L-carnitine in the treatment of Phenylketonuria, mainly against neuroinflammation and the oxidative process, contributing to better clarify the pathophysiology of the disease.
    Keywords:  Glial fibrillary acidic protein; Hyperphenylalaninemia; L-carnitine; Neuroinflammation; Oxidative stress; Phenylketonuria
    DOI:  https://doi.org/10.1007/s11011-025-01537-6
  23. Funct Integr Genomics. 2025 Jan 23. 25(1): 26
      Mitochondria, the cellular powerhouses, are pivotal to neuronal function and health, particularly through their role in regulating synaptic structure and function. Spine reprogramming, which underlies synapse development, depends heavily on mitochondrial dynamics-such as biogenesis, fission, fusion, and mitophagy as well as functions including ATP production, calcium (Ca2+) regulation, and retrograde signaling. Mitochondria supply the energy necessary for assisting synapse development and plasticity, while also regulating intracellular Ca2+ homeostasis to prevent excitotoxicity and support synaptic neurotransmission. Additionally, the dynamic processes of mitochondria ensure mitochondrial quality and adaptability, which are essential for maintaining effective synaptic activity. Emerging evidence highlights the significant role of epigenetic modifications in regulating mitochondrial dynamics and function. Epigenetic changes influence gene expression, which in turn affects mitochondrial activity, ensuring coordinated responses necessary for synapse development. Furthermore, metabolic changes within mitochondria can impact the epigenetic machinery, thereby modulating gene expression patterns that support synaptic integrity. Altered epigenetic regulation affecting mitochondrial dynamics and functions is linked to several neurological disorders, including Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases, emphasizing its crucial function. The review delves into the molecular machinery involved in mitochondrial dynamics, ATP and Ca2+ regulation, highlighting the role of key proteins that facilitate the processes. Additionally, it also shed light on the emerging epigenetic factors influencing these regulations. It provides a thorough summary on the current understanding of the role of mitochondria in synapse development and emphasizes the importance of both molecular and epigenetic mechanisms in maintaining synaptic integrity.
    DOI:  https://doi.org/10.1007/s10142-025-01530-3
  24. Prostaglandins Leukot Essent Fatty Acids. 2025 Jan 16. pii: S0952-3278(25)00001-8. [Epub ahead of print]204 102664
       BACKGROUND: The long-chain omega-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have beneficial effects in depression, and these effects may be mediated via changes in functional brain connectivity. However, little is known about these effects in those with subthreshold depression.
    METHODS: 15 Participants aged 18-29 years with Patient Health Questionnaire-8 (PHQ-8) scores ≥ 4 and Generalised Anxiety Disorder Assessment-7 (GAD-7) scores ≥ 5, underwent resting-state functional magnetic resonance imaging. Whole-brain, seed-based connectivity analyses were performed using bilateral orbitofrontal cortex (OFC) and amygdala seeds. Omega-3 and -6 PUFA status was assessed from dried bloodspot analysis of %DHA, %EPA, Omega-3 Index (calculated as the sum of DHA plus EPA expressed as a percentage of the total measured fatty acids and a correction applied as dried blood spot samples were used instead of erythrocytes) and ratio of the omega-6 PUFA arachidonic acid (ARA) to EPA (ARA/EPA).
    RESULTS: PHQ-8 scores indicated subthreshold depression (mean = 10.0; SD = 4.2) and were negatively associated with DHA levels and Omega-3 Index. Significant negative associations were also identified between connectivity of the OFC with the angular gyrus and DHA and Omega-3 Index, while weaker connectivity of these regions was associated with lower PHQ-8 and GAD-7 scores. DHA and Omega-3 Index values were significantly associated with greater connectivity of the amygdala with the posterior cingulate cortex, which was also associated with lower PHQ-8 scores.
    CONCLUSIONS: Higher omega-3 PUFA status in young adults with moderate, but mean subthreshold depression was associated with lower depression rating scores and altered functional connectivity of brain regions shown to play a role in the neurobiology of depression.
    Keywords:  Docosahexaenoic acid; Functional magnetic resonance imaging; Omega-3 polyunsaturated fatty acids; Subthreshold depression
    DOI:  https://doi.org/10.1016/j.plefa.2025.102664
  25. Metabolites. 2025 Jan 02. pii: 10. [Epub ahead of print]15(1):
       BACKGROUND: Huntington's disease (HD) is a multifaceted neurological disorder characterized by the progressive deterioration of motor, cognitive, and psychiatric functions. Despite a limited understanding of its pathogenesis, research has implicated abnormal trinucleotide cytosine-adenine-guanine CAG repeat expansion in the huntingtin gene (HTT) as a critical factor. The development of innovative strategies is imperative for the early detection of predictive biomarkers, enabling timely intervention and mitigating irreversible cellular damage. Lipidomics, a comprehensive analytical approach, has emerged as an indispensable tool for systematically characterizing lipid profiles and elucidating their role in disease pathology.
    METHOD: A MedLine search was performed to identify studies that use lipidomics for the characterization of HD. Search terms included "Huntington disease"; "lipidomics"; "biomarker discovery"; "NMR"; and "Mass spectrometry".
    RESULTS: This review highlights the significance of lipidomics in HD diagnosis and treatment, exploring changes in brain lipids and their functions. Recent breakthroughs in analytical techniques, particularly mass spectrometry and NMR spectroscopy, have revolutionized brain lipidomics research, enabling researchers to gain deeper insights into the complex lipidome of the brain.
    CONCLUSIONS: A comprehensive understanding of the broad spectrum of lipidomics alterations in HD is vital for precise diagnostic evaluation and effective disease management. The integration of lipidomics with artificial intelligence and interdisciplinary collaboration holds promise for addressing the clinical variability of HD.
    Keywords:  Huntington’s disease; NMR; biomarker discovery; lipidomics; mass spectrometry
    DOI:  https://doi.org/10.3390/metabo15010010
  26. Cell Mol Biol Lett. 2025 Jan 17. 30(1): 7
      The skin is a barrier that protects the human body against environmental factors (physical, including solar radiation, chemicals, and pathogens). The integrity and, consequently, the effective metabolic activity of skin cells is ensured by the cell membrane, the important structural and metabolic elements of which are phospholipids. Phospholipids are subject to continuous transformation, including enzymatic hydrolysis (with the participation of phospholipases A, C, and D) to free polyunsaturated fatty acids (PUFAs), which under the influence of cyclooxygenases (COX1/2), lipoxygenases (LOXs), and cytochrome P450 (CYPs P450) are metabolized to various classes of oxylipins, depending on the type of PUFA being metabolized and the enzyme acting. The most frequently analyzed oxylipins, especially in skin cells, are eicosanoids, which are derivatives of arachidonic acid (AA). Their level depends on both environmental factors and endogenous metabolic disorders. However, they play an important role in homeostasis mechanisms related to the structural and functional integrity of the skin, including maintaining redox balance, as well as regulating inflammatory processes arising in response to endogenous and exogenous factors reaching skin cells. Therefore, it is believed that dysregulation of eicosanoid levels may contribute to the development of skin diseases, such as psoriasis or atopic dermatitis, which in turn suggests that targeted control of the generation of specific eicosanoids may have diagnostic significance and beneficial therapeutic effects. This review is the first systemic and very detailed approach presenting both the causes and consequences of changes in phospholipid metabolism leading to the generation of eicosanoids, changes in the level of which result in specific metabolic disorders in skin cells leading to the development of various diseases. At the same time, existing literature data indicate that further detailed research is necessary to understand a clear relationship between changes in the level of specific eicosanoids and the pathomechanisms of specific skin diseases, as well as to develop an effective diagnostic and therapeutic approach.
    Keywords:  Cyclooxygenases; Cytochrome P450; Eicosanoids; Fatty acids; Leukotrienes; Lipoxygenases; Phospholipases; Phospholipids metabolism; Prostaglandins
    DOI:  https://doi.org/10.1186/s11658-025-00685-y
  27. Exp Neurol. 2025 Jan 18. pii: S0014-4886(25)00015-9. [Epub ahead of print] 115151
      Hypoxic-ischemic (HI) brain injury is a common neurological problem in neonates. The postsynaptic density protein-95 (PSD-95) is an excitatory synaptic scaffolding protein that regulates synaptic function, and represents a potential therapeutic target to attenuate HI brain injury. Syn3 and d-Syn3 are novel high affinity cyclic peptides that bind the PDZ3 domain of PSD-95. We investigated the neuroprotective efficacy of Syn3 and d-Syn3 after exposure to HI in neonatal rodents. Postnatal (P) day-7 rats were treated with Syn3 and d-Syn3 at zero, 24, and 48-h after carotid artery ligation and 90-min of 8 % oxygen. Hemispheric volume atrophy and Iba-1 positive microglia were quantified by cresyl violet and immunohistochemical staining. Treatment with Syn3 and d-Syn3 reduced tissue volume loss by 47.0 % and 41.0 % in the male plus female, and by 42.1 % and 65.0 % in the male groups, respectively. Syn3 reduced tissue loss by 52.3 % in females. D-Syn3 reduced Iba-1 positive microglia/DAPI ratios in the pooled group, males, and females. Syn3 effects were observed in the pooled group and females. Changes in Iba-1 positive microglia/DAPI cellular ratios correlated directly with reduced hemispheric volume loss, suggesting that Syn3 and d-Syn3 provide neuroprotection in part by their effects on Iba-1 positive microglia. The pathogenic cis phosphorylated Thr231 in Tau (cis P-tau) is a marker of neuronal injury. Cis P-tau was induced in cortical cells of the placebo-treated pooled group, males and females after HI, and reduced by treatment with d-Syn3. Therefore, treatment with these peptidomimetic agents exert neuroprotective effects after exposure of neonatal subjects to HI related brain injury.
    Keywords:  D-Syn3, hypoxic-ischemic brain injury; Neuroprotection; Newborn; Syn3
    DOI:  https://doi.org/10.1016/j.expneurol.2025.115151
  28. Adv Sci (Weinh). 2025 Jan 24. e2414141
      Recipients often suffer from hyperlactatemia during liver transplantation (LT), but whether hyperlactatemia exacerbates hepatic ischemia-reperfusion injury (IRI) after donor liver implantation remains unclear. Here, the role of hyperlactatemia in hepatic IRI is explored. In this work, hyperlactatemia is found to exacerbate ferroptosis during hepatic IRI. Lactate-primed lysine acetyltransferase 8 (KAT8) is determined to directly lactylate mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2) at Lys100 and augments PCK2 kinase activity. By using gene-edited mice, evidence indicating that PCK2 exacerbates hepatic ferroptosis during IRI is generated. Mechanistically, PCK2 lactylate at Lys100 acts as a critical inducer of ferroptosis during IRI by competitively inhibiting the Parkin-mediated polyubiquitination of 3-oxoacyl-ACP synthase (OXSM), thereby leading to metabolic remodeling of mitochondrial fatty acid synthesis (mtFAS) and the potentiation of oxidative phosphorylation and the tricarboxylic acid cycle. More importantly, targeting PCK2 is demonstrated to markedly ameliorate hyperlactatemia-mediated ferroptosis during hepatic IRI. Collectively, the findings support the use of therapeutics targeting PCK2 to suppress hepatic ferroptosis and IRI in patients with hyperlactatemia during LT.
    Keywords:  ferroptosis; hepatic ischemia‒reperfusion injury; lactate; lactylation; metabolic reprogramming; mitochondrial fatty acid synthesis; phosphoenolpyruvate carboxykinase 2
    DOI:  https://doi.org/10.1002/advs.202414141
  29. Drugs. 2025 Jan 18.
      Lysosomal storage disorders (LSDs) are rare inherited metabolic disorders characterized by defects in the function of specific enzymes responsible for breaking down substrates within cellular organelles (lysosomes) essential for the processing of macromolecules. Undigested substrate accumulates within lysosomes, leading to cellular dysfunction, tissue damage, and clinical manifestations. Clinical features vary depending on the degree and type of enzyme deficiency, the type and extent of substrate accumulated, and the tissues affected. The heterogeneous nature of LSDs results in a variety of treatment approaches, which must be tailored to patient presentation and characteristics. The treatment landscape for LSDs is rapidly evolving. An up-to-date discussion of current evidence is required to provide clinicians with an appropriate overview of treatment options. Therefore, we aimed to review current and ongoing trials pertaining to the treatment of common LSDs.
    DOI:  https://doi.org/10.1007/s40265-025-02145-5