bims-medebr 2025-04-13 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–04–13
thirteen papers selected by
Regina F. Fernández, Johns Hopkins University

Fatty acid synthase global inducible knockout does not alter brain fatty acid concentrations but attenuates cholesterol synthesis in the adult mouse.
Fueling Brain Inhibition: Integrating GABAergic Neurotransmission and Energy Metabolism.
Commentary to "Task activation results in regional 13C-lactate signal increase in the human brain".
Insulin acts on astrocytes to shift their substrate preference to fatty acids.
Evaluating the Protective Effects of Silymarin Along with a Cholesterol-Supplemented Diet Against Demyelination in an EAE Mouse Model of Multiple Sclerosis: Lipidomic and Inflammatory Aspects.
Neurometabolic network (NMetNet) for functional neurological disorder in children and adolescents.
Altered Mitochondrial Bioenergetics and Calcium Kinetics in Young-Onset PLA2G6 Parkinson's Disease iPSCs.
Newborn screening follow-up for very long-chain acyl-CoA dehydrogenase deficiency in Colorado: Working towards a standardized protocol.
The Duality of Astrocyte Neuromodulation: Astrocytes Sense Neuromodulators and Are Neuromodulators.
Elucidating molecular lipid perturbations in trigeminal neuralgia using cerebrospinal fluid lipidomics.
The Role of Autophagy in Excitotoxicity, Synaptic Mitochondrial Stress and Neurodegeneration.
Lipidomics and temporal-spatial distribution of organelle lipid.
Biomimetic Nanoparticles Enhance Recovery of Movement Disorders in Parkinson's Disease by Improving Microglial Mitochondrial Homeostasis and Suppressing Neuroinflammation.

Prostaglandins Leukot Essent Fatty Acids. 2025 Mar 31. pii: S0952-3278(25)00016-X. [Epub ahead of print]205 102679

Fatty acid synthase global inducible knockout does not alter brain fatty acid concentrations but attenuates cholesterol synthesis in the adult mouse.

Drew R Seeger, Peddanna Kotha, Svetlana A Golovko, Eric J Murphy, Mikhail Y Golovko.

  Fatty acid (FA) de novo synthesis, also called de novo lipogenesis (DNL), has a central role in peripheral energy storage and provides structural components for lipid membranes. However, less is known regarding its contribution to brain FA homeostasis. DNL is catalyzed by fatty acid synthase (FAS), which is a multifunctional enzyme expressed in all mammalian tissues. In the present study, we addressed, for the first time, the effect of FAS gene global conditional inducible knockout (Fasn KO) on the adult brain FA concentrations and lipid metabolism. We achieved a 67 % reduction in the brain FAS protein levels, with a significant reduction in total FA synthesis measured by 3H2O incorporation into FA, which was lethal 10 days after gene recombination induction. However, the concentrations of all 44 FA molecular species assayed by LC-MS were unchanged in the brain. We also did not detect changes in the major proteins involved in FA synthesis regulation and remodeling, including peroxisome proliferator-activated receptor α (PPARα), PPARδ, FA desaturase-1, -2, and -3, and Stearoyl-CoA desaturase 1 but did observe a decrease in PPARɣ levels. In addition, brain cholesterol synthesis was significantly reduced in the Fasn KO brains. These data indicate that DNL is not required to maintain measured FA concentrations in the brain and that dietary FA and liver-derived pools might compensate for decreased brain DNL within the duration of the study. However, our data indicate a possible role of FAS in PPARɣ regulation and cholesterol metabolism in the adult brain.

Keywords:  Brain; Cholesterol; Fatty acid; Fatty acid synthase; Knockout; PPAR; Synthesis

DOI:  https://doi.org/10.1016/j.plefa.2025.102679
Neurochem Res. 2025 Apr 07. 50(2): 136

Fueling Brain Inhibition: Integrating GABAergic Neurotransmission and Energy Metabolism.

Anne B Walls, Jens V Andersen, Helle S Waagepetersen, Lasse K Bak.

  Despite decades of research in brain energy metabolism and to what extent different cell types utilize distinct substrates for their energy metabolism, this topic remains a vibrant area of neuroscience research. In this review, we focus on the substrates utilized by the inhibitory GABAergic neurons, which has been less explored than glutamatergic neurons. First, we discuss how GABAergic neurons may utilize both glucose, lactate, or ketone bodies under different functional conditions, and provide some preliminary data suggesting that unlike glutamatergic neurons, GABAergic neurons work well when substrate supply is restricted to lactate. We end by discussing the role of GABAergic neuron energy metabolism in pathologies where failure of inhibitory function play a central role, namely epilepsy, hepatic encephalopathy, and Alzheimer's disease.

Keywords:  Alzheimer’s disease; Epilepsy; Glucose; Hepatic Encephalopathy; Ketones; Lactate

DOI:  https://doi.org/10.1007/s11064-025-04384-0
J Cereb Blood Flow Metab. 2025 Apr 11. 271678X251327935

Commentary to "Task activation results in regional 13C-lactate signal increase in the human brain".

Fahmeed Hyder.

  Metabolism is fundamental to functional brain imaging. While functional MRI (fMRI) has greatly benefited neuroscience, 13C-MRS measures coupling between neuroenergetics and neurotransmission. However, a hyperpolarized 13C-MRI study in human brain shows increased 13C-lactate (i.e., cytosolic aerobic glycolysis) with no 13C-bicarbonate change (i.e., mitochondrial oxidation) within fMRI-defined activated areas. We discuss (dis)advantages of hyperpolarized vs. non-hyperpolarized 13C experiments and metabolic implications regarding the lactate increase: Is lactate a fuel for oligodendrocytes, astrocytes, or neurons? Is lactate a neuromodulator or a vasomodulator? Is lactate a byproduct of astrocytic glycogenolysis? Caveats aside, there is great enthusiasm for hyperpolarized 13C-fMRI.

Keywords:  Calibrated fMRI; excitation; glucose; glycogen; inhibition; lactate; oxygen

DOI:  https://doi.org/10.1177/0271678X251327935
iScience. 2025 Apr 18. 28(4): 111642

Insulin acts on astrocytes to shift their substrate preference to fatty acids.

Bouchra Taib, Pragney Deme, Sujasha Gupta, Seung Wan Yoo, Saja S Khuder, Ahmet Hoke, Zhigang Li, Rexford S Ahima, Norman J Haughey.

  It is increasingly recognized that brain can β-oxidize fatty acids for use as an energy substrate. However, mechanism(s) by which neural cells switch their preference from glucose to fatty acids are not fully elucidated. Here we provide evidence that insulin acts directly on astrocytes to promote the uptake of glucose and fatty acids while modifying their substrate preference through a sequential shift in the expression of genes associated with fatty acid uptake, synthesis, transport, and metabolism. Under these conditions, fatty acids are converted into TCA cycle intermediates to satisfy astrocyte energy demands, allowing pyruvate derived from glucose to be directed toward the production of lactate; a preferred fuel for neurons. This shift in astrocyte energy substrate preference is required for insulin to enhance long-term potentiation in the Schaffer collateral. These findings establish a homeostatic mechanism where insulin promotes LTP by switching the energy substrate preference of astrocytes to fatty acids.

Keywords:  Biological sciences; Cellular neuroscience; Natural sciences; Neuroscience; Systems neuroscience

DOI:  https://doi.org/10.1016/j.isci.2024.111642
Mol Neurobiol. 2025 Apr 07.

Evaluating the Protective Effects of Silymarin Along with a Cholesterol-Supplemented Diet Against Demyelination in an EAE Mouse Model of Multiple Sclerosis: Lipidomic and Inflammatory Aspects.

Parvin Mosaddeghi, Seyed Alireza Mesbah-Namin, Mohammad Javan.

  Demyelination in multiple sclerosis (MS) is associated with chronic inflammation and dysregulation of cholesterol metabolism. In this study, we investigated the protective effects of silymarin, an herbal flavonoid, against inflammation, impairment of brain cholesterol metabolism, and demyelination in the experimental autoimmune encephalomyelitis (EAE) model of MS. Given the well-documented anti-hypercholesterolemic properties of silymarin, we sought to assess its protective effects in combination with a cholesterol-supplemented diet. Additionally, the effects of the cholesterol-supplemented diet alone were evaluated. Female C57BL/6 mice were fed either a standard chow diet or a cholesterol-supplemented standard chow for 2 weeks prior to EAE induction, continuing until day 20 post-immunization. Experimental groups received silymarin, a cholesterol-supplemented diet, or both treatments. Silymarin significantly reduced clinical symptoms and the incidence of EAE, alleviated inflammation, prevented severe demyelination, modulated the expression genes involved in brain cholesterol metabolism, and ultimately improved the serum lipid profile. The cholesterol-supplemented diet alone was partially effective. Co-administration of silymarin with the cholesterol-supplemented diet showed superior efficacy across some outcomes. String web analysis revealed the significant interaction of apolipoprotein E (ApoE), a major component of brain HDL-like particles, with other key genes. ELISA results demonstrated that silymarin alone and in combination with the cholesterol-supplemented diet restored ApoE levels in EAE-induced mice. These findings suggest that silymarin, in conjunction with a cholesterol-supplemented diet, warrants further investigation in clinical trials as a potential protective strategy for MS management.

Keywords:  ApoE; Demyelination; EAE; HDL-like particle; Multiple sclerosis; Silymarin

DOI:  https://doi.org/10.1007/s12035-025-04903-8
Neuroimage Clin. 2025 Mar 12. pii: S2213-1582(25)00037-3. [Epub ahead of print]46 103767

Neurometabolic network (NMetNet) for functional neurological disorder in children and adolescents.

Zhou Lan, Sheryl Foster, Molly Charney, Max van Grinsven, Katherine Breedlove, Kasia Kozlowska, Alexander Lin.

   OBJECTIVES: Functional neurological disorder (FND) in children and adolescents is a biopsychosocially complex condition characterized by a wide range of neurological symptoms. Using magnetic resonance spectroscopy to study neurometabolites has become an important approach to studying the mechanisms of FND. Unlike previous studies focusing on concentration-level analysis, this study examines conditional dependencies between six neurometabolites: N-acetyl aspartate, creatine, glutathione, choline, myo-inositol, and glutamate. Conditional dependence implies that two neurometabolites have joint variability that is not mediated by other neurometabolites.
METHODS: A Bayesian graphical lasso approach was used to estimate neurometabolites' conditional dependencies in three regions of interest: the anterior default mode network (aDMN), supplementary motor area (SMA), and posterior default mode network (pDMN). We introduce the term neurometabolic network (NMetNet) to describe these conditional dependencies.
RESULTS: Children and adolescents with FND (vs. healthy controls) showed a loss of conditional dependencies related to creatine and glutathione between the aDMN and SMA/pDMN. Glutathione is the primary antioxidant in the brain. Creatine plays a key role in maintaining bioenergetics and also acts as an antioxidant.
CONCLUSIONS: These findings suggest that FND is characterized by dysregulated bioenergetics and increased vulnerability to oxidative stress. Understanding NMetNet in FND offers novel insights into the disorder's neurobiology, with implications for therapeutic interventions to restore energy homeostasis and oxidative balance.

Keywords:  Bayesian graphical lasso; Bioenergetics; Brain networks; Conditional dependence; Functional neurological disorder; Functional seizures; Magnetic resonance spectroscopy; Neurometabolic network; Oxidative stress; Pediatric neurology

DOI:  https://doi.org/10.1016/j.nicl.2025.103767
J Neurochem. 2025 Apr;169(4): e70059

Altered Mitochondrial Bioenergetics and Calcium Kinetics in Young-Onset PLA2G6 Parkinson's Disease iPSCs.

Thasneem Musthafa, Syed Kavish Nizami, Ankita Mishra, Gaiti Hasan, Renjitha Gopurappilly.

  Parkinson's disease (PD) has emerged as a multisystem disorder affecting multiple cellular and organellar systems in addition to the dopaminergic neurons. Disease-specific induced pluripotent stem cells (iPSCs) model early developmental changes and cellular perturbations that are otherwise inaccessible from clinical settings. Here, we report the early changes in patient-derived iPSCs carrying a homozygous recessive mutation, R741Q, in the PLA2G6 gene. A gene-edited R747W iPSC line mirrored these phenotypes, thus validating our initial findings. Bioenergetic dysfunction and hyperpolarization of mitochondrial membrane potentials were hallmarks of the PD iPSCs. Further, a concomitant increase in glycolytic activity indicated a possible compensation for mitochondrial respiration. Elevated basal reactive oxygen species (ROS) and decreased catalase expression were also observed in the disease iPSCs. No change in autophagy was detected. These inceptive changes could be potential targets for early intervention of prodromal PD in the absence of disease-modifying therapies. However, additional investigations are crucial to delineate the cause-effect relationships of these observations.

Keywords:  PLA2G6; Parkinson's disease; disease modeling; human iPSC; mitochondrial dysfunction

DOI:  https://doi.org/10.1111/jnc.70059
Mol Genet Metab. 2025 Apr 03. pii: S1096-7192(25)00095-2. [Epub ahead of print]145(1): 109104

Newborn screening follow-up for very long-chain acyl-CoA dehydrogenase deficiency in Colorado: Working towards a standardized protocol.

M M Crenshaw, O M D'Annibale, A Schechter, M Sethuraman, C Porter, G Bonn, E Wright, T Wood, J Vockley, P L Hall, McCandless Se.

  Very long chain acyl-CoA dehydrogenase deficiency (VLCADD) is an autosomal recessive fatty acid β-oxidation disorder that has been identified by newborn screening (NBS) in most states since the early 2000s. Despite over 20 years of experience, there are aspects of VLCADD NBS that remain challenging. We conducted a retrospective chart review of abnormal NBS for VLCADD in Colorado between 2017 and 2023. We analyzed confirmatory plasma acylcarnitine profiles (P-ACP), genetic sequencing of ACADVL, Collaborative Laboratory Integrated Reports (CLIR) scores, patient enzyme analysis of VLCAD, and cell-based variant expression analysis. A real-world "Clinical Designation" was then compared to a variety of algorithms trialed on the data. Of the 67 infants with abnormal screens during this timeframe, 5 (7 %) had a Clinical Designation of affected, 4 (6 %) remained unclassified, and 58 (87 %) were discharged based on a designation of unaffected. A Kruskal-Wallis rank sum test showed the biomarker with the best discrimination between affected and unaffected individuals was C14:1/C12:1 [chi-squared 10.4 (p = 0.001)]. The highest performing algorithm was (Molecular testing + cell-based expression) + (P-ACP C14:1 OR P-ACP C14:1/C12:1). Excluding the missing data, this algorithm showed 96 % (46 of 48) agreement with the Clinical Designation. We conclude that there is not a single biomarker that can specifically discern affected from unaffected individuals who screen positive on NBS for VLCADD. Thus, we developed a standardized diagnostic approach to more accurately classify patients that starts with the molecular findings and requires at least one of the P-ACP C14:1 or P-ACP C14:1/C12:1 to agree with molecular findings. The algorithm needs to be trialed with a different data set, and will advance the conversation around maximizing benefits and minimizing harms for infants who screen positive for VLCADD.

Keywords:  Newborn screening; Very long-chain acyl-coA dehydrogenase deficiency

DOI:  https://doi.org/10.1016/j.ymgme.2025.109104
J Neurochem. 2025 Apr;169(4): e70054

The Duality of Astrocyte Neuromodulation: Astrocytes Sense Neuromodulators and Are Neuromodulators.

Justin Lines, Michelle Corkrum, Juan Aguilar, Alfonso Araque.

  Neuromodulation encompasses different processes that regulate neuronal and network function. Classical neuromodulators originating from long-range nuclei, such as acetylcholine, norepinephrine, or dopamine, act with a slower time course and wider spatial range than fast synaptic transmission and action potential firing. Accumulating evidence in vivo indicates that astrocytes, which are known to actively participate in synaptic function at tripartite synapses, are also involved in neuromodulatory processes. The present article reviews recent findings obtained in vivo indicating that astrocytes express receptors for neuromodulators that elevate their internal calcium and stimulate the release of gliotransmitters, which regulate synaptic and network function, and hence mediate, at least partially, the effects of neuromodulators. In addition, we propose that astrocytes act in local support of neuromodulators by spatially and temporally integrating neuronal and neuromodulatory signals to regulate neural network function. The presence of astrocyte-neuron hysteresis loops suggests astrocyte-neuron interaction at tripartite synapses scales up to astrocyte-neuronal networks that modulate neural network function. We finally propose that astrocytes sense the environmental conditions, including neuromodulators and network function states, and provide homeostatic control that maximizes the dynamic range of neural network activity. In summary, we propose that astrocytes are critical in mediating the effects of neuromodulators, and they also act as neuromodulators to provide neural network homeostasis thus optimizing information processing in the brain. Hence, astrocytes sense ongoing neuronal activity along with neuromodulators and, acting as neuromodulators, inform the neurons about the state of the internal system and the external world.

Keywords:  astrocyte; astrocyte‐neuron hysteresis loop; homeostasis; in vivo; neuromodulation; tripartite synapse

DOI:  https://doi.org/10.1111/jnc.70054
Sci Rep. 2025 Apr 06. 15(1): 11777

Elucidating molecular lipid perturbations in trigeminal neuralgia using cerebrospinal fluid lipidomics.

Dongyuan Xu, Xuan Dai, Qianwen He, Zhimin Mei, Yixuan Zhou, Jingwei Zhao, Nanxiang Xiong.

  Trigeminal neuralgia (TN) is a neuropathic facial pain disorder characterized by severe stabbing pain along the trigeminal nerve. While its pathogenesis remains unclear, nerve demyelination and inflammation are likely involved. Current research has primarily focused on various blood-based omics approaches, which do not fully capture the lipid alterations occurring during TN progression in brain. In contrast, our study is the first to investigate cerebrospinal fluid (CSF) lipidomic profiles in TN patients, aiming to elucidate potential disease mechanisms. CSF samples were collected from 22 TN patients and 18 healthy controls, followed by untargeted lipidomic analysis using high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. A pipeline for lipid identification and relative quantification, combined with statistical analysis, revealed 188 lipid species across 21 classes. We found significant upregulation of Cer-NPs, LPCs, PCs, TGs, and OxTGs in TN patients, while stigmasterol hexoside was downregulated. Moderate correlations were observed between lipid species and clinical parameters. These findings highlight considerable CSF lipidome alterations in TN, suggesting roles for nerve demyelination, neuroinflammation, and pain sensitization in its pathogenesis. Our study provides novel insights into lipid targets that may offer therapeutic potential for managing TN.

Keywords:  Cerebrospinal fluid; Demyelination; Lipidomics; Mass spectrometry; Neuroinflammation; Trigeminal neuralgia

DOI:  https://doi.org/10.1038/s41598-025-89755-x
Autophagy Rep. 2025 ;pii: 2464376. [Epub ahead of print]4(1):

The Role of Autophagy in Excitotoxicity, Synaptic Mitochondrial Stress and Neurodegeneration.

Charleen T Chu.

  Brain and nervous system functions depend upon maintaining the integrity of synaptic structures over the lifetime. Autophagy, a key homeostatic quality control system, plays a central role not only in neuronal development and survival/cell death, but also in regulating synaptic activity and plasticity. Glutamate is the major excitatory neurotransmitter that activates downstream targets, with a key role in learning and memory. However, an excess of glutamatergic stimulation is pathological in stroke, epilepsy and neurodegeneration, triggering excitotoxic cell death or a sublethal process of excitatory mitochondrial calcium toxicity (EMT) that triggers dendritic retraction. Markers of autophagy and mitophagy are often elevated following excitatory neuronal injuries, with the potential to influence cell death or neurodegenerative outcomes of these injuries. Interestingly, leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1), two kinases linked to autophagy, mitophagy and Parkinson disease, play important roles in regulating mitochondrial calcium handling, synaptic density and function, and maturation of dendritic spines. Mutations in LRRK2, PINK1, or proteins linked to Alzheimer's disease perturb mitochondrial calcium handling to sensitize neurons to excitatory injury. While autophagy and mitophagy can play both protective and harmful roles, studies in various excitotoxicity and stroke models often implicate autophagy in a pathogenic role. Understanding the role of autophagic degradation in regulating synaptic loss and cell death following excitatory neuronal injuries has important therapeutic implications for both acute and chronic neurological disorders.

Keywords:  Alzheimer disease; Epilepsy; Glutamate toxicity; Leucine-rich repeat kinase 2; Mitochondrial Na+/Ca2+ exchanger; Mitochondrial calcium uniporter; PTEN-induced kinase 1; Parkinson disease; hypoxia-ischemia; post-synaptic calcium

DOI:  https://doi.org/10.1080/27694127.2025.2464376
J Biol Methods. 2025 ;12(1): e99010049

Lipidomics and temporal-spatial distribution of organelle lipid.

Wenjuan Qian, Huiru Tang, Hongyan Yao.

   Background: Lipids are crucial signaling molecules or cellular membrane components orchestrating biological processes. To gain insights into lipid functions and the communication between organelles, it is essential to understand the subcellular localization of individual lipids. Advancements in lipid quantification techniques, improvements in chemical and spatial resolution for detecting various lipid species, and enhancements in organelle isolation speed have allowed for profiling of the organelle lipidome, capturing its temporal-spatial distribution.
Objective: This review examined approaches used to develop organelle lipidome and aimed to gain insights into cellular lipid homeostasis from an organelle perspective. In addition, this review discussed the advancements in lipid-mediated inter-organelle communication within complex physiological and pathological processes.
Conclusion: With the advancement of lipidomic technologies, more detailed explorations of organelle structures and the specific lipid-mediating functions they perform are feasible.

Keywords:  Cellular lipid homeostasis; Inter-organelle communication; Lipidomics; Organelle isolation; Organelle lipid distribution

DOI:  https://doi.org/10.14440/jbm.2025.0094
ACS Appl Mater Interfaces. 2025 Apr 09.

Biomimetic Nanoparticles Enhance Recovery of Movement Disorders in Parkinson's Disease by Improving Microglial Mitochondrial Homeostasis and Suppressing Neuroinflammation.

Liang Li, Chunbin Sun, Shanglin Cai, Zhongci Hang, Xiaoyu Gao, Liangxuan Hou, Luping Li, Yawen Wu, Cencan Xing, Hongwu Du.

  Neuroinflammation is a key risk factor for cognitive impairment, and microglia are the main drivers. Metformin has been shown to suppress inflammation and reduce microglial activation, protecting neurons from damage. However, its clinical efficacy is limited by low bioavailability and metabolic challenges, especially in terms of precise delivery to specific targets. To overcome this problem, we developed biomimetic microglial nanoparticles (MePN@BM) to enhance the targeted delivery and bioavailability of metformin. Through homologous targeting, the delivery efficiency of drugs in the inflammatory site of Parkinson's disease was enhanced to improve the therapeutic effect. The results showed that MePN@BM effectively delivers metformin to the brain, promotes autophagy, restores mitochondrial membrane potential, and reduces oxidative stress. In a Parkinson's disease (PD) mouse model, MePN@BM improved motor function, repaired dopaminergic neurons, and cleared α-synuclein aggregates. Notably, transcriptome analysis revealed enriched inflammation-related pathways, and immunofluorescence showed that PD mice treated with MePN@BM had higher levels of anti-inflammatory factors and lower levels of pro-inflammatory factors. Therefore, it provides a promising strategy for the treatment of inflammation-mediated motor dysfunction.

Keywords:  Parkinson’s disease; bionic nanoparticles; microglia; mitochondrial homeostasis; neuroinflammation

DOI:  https://doi.org/10.1021/acsami.4c22181