bims-medebr 2025-09-28 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–09–28
eleven papers selected by
Regina F. Fernández, Johns Hopkins University

Elucidating reaction dynamics in a model of human brain energy metabolism.
Restoration of glucose metabolic homeostasis for treating CNS diseases: mechanistic insights and potential clinical prospect.
Individual lipid alterations at the origin of neuronal Ceramide Synthase defects.
Spatial lipidomics reveals demyelination and remyelination dynamics in the mouse brain.
The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases.
Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke.
Mitochondrial Aging in the CNS: Unravelling Implications for Neurological Health and Disease.
Adaptaquin is selectively toxic to glioma stem cells through disruption of iron and cholesterol metabolism.
Temporal Requirement for Stearoyl-CoA Desaturase 1 in Oligodendrocyte Development but Not Myelin Maintenance.
Dysregulation of Glu/GABA and reduction of triglycerides contribute to valproic acid-induced autism model in zebrafish.
Effects of sex, injury, and docosahexaenoic acid in a preclinical porcine model of pediatric traumatic brain injury using novel serial collection of CSF, urine, and serum biomarkers.

PLoS Comput Biol. 2025 Sep 24. 21(9): e1013504

Elucidating reaction dynamics in a model of human brain energy metabolism.

Dimitris G Patsatzis, Efstathios-Al Tingas, S Mani Sarathy, Dimitris A Goussis, Renaud Blaise Jolivet.

Energy metabolism is essential to brain function, but its study is experimentally challenging. Similarly, biologically accurate computational models are too complex for simple investigations. Here, we analyse an experimentally-calibrated multiscale model of human brain energy metabolism using Computational Singular Perturbation. This approach leads to the novel identification of functional periods during and after synaptic activation, and highlights the central reactions and metabolites controlling the system's behaviour within those periods. We identify a key role for both oxidative and glycolytic astrocytic metabolism in driving the brain's metabolic circuitry. We also identify phosphocreatine as the main endogenous energy supply to brain cells, and propose revising our view of brain energy metabolism accordingly. Our approach highlights the importance of glial cells in brain metabolism, and introduces a systematic and unbiased methodology to study the dynamics of complex biochemical networks that can be scaled, in principle, to metabolic networks of any size and complexity.

DOI: https://doi.org/10.1371/journal.pcbi.1013504
Free Radic Biol Med. 2025 Sep 18. pii: S0891-5849(25)00983-9. [Epub ahead of print]

Restoration of glucose metabolic homeostasis for treating CNS diseases: mechanistic insights and potential clinical prospect.

Yi-Yue Zhang, Xing-Yu Long, Bi-Feng Yao, Jing Tian, Jun Peng, Xiu-Ju Luo.

  Brain glucose metabolism orchestrates central nervous system (CNS) homeostasis via cell-type-specific metabolic networks and metabolite-mediated signaling. Recent studies have shown that dysregulated glucose metabolism can disrupt energy balance, antioxidant system stability, and neuroimmune communication, in turn exacerbating CNS diseases. Impaired neuronal oxidative phosphorylation (OXPHOS) causes energy deficits and mitochondrial dysfunction, leading to neuronal cell death. Damaged astrocyte PPP support system impairs antioxidant defenses, leading to cumulative lipid peroxidation and thus exacerbating oxidative stress. Metabolic reprogramming in microglia further links overactivation of glycolysis to neuroinflammation. Crucially, glucose-derived metabolites drive post-translational modifications (PTMs), including glycosylation, lactylation, acetylation, and succinylation, that regulate chromatin states, protein function, and pathogenic signaling pathways in CNS diseases. Therefore, therapeutic strategies targeting glucose metabolism, including targeting the glucose metabolic pathways to restore metabolic flexibility, managing the metabolism-induced PTMs, and bypassing the impaired pathways with alternative fuels, offer promising opportunities for treating CNS disorders. However, the compensatory mechanisms inherent to interconnected metabolic networks undermines single-target therapies, necessitating combination strategies to simultaneously address multiple nodes. This review provides an overview of recent advances in understanding the cell-specific glucose metabolism, glucose metabolite-driven PTMs, and their pathogenic significance in CNS diseases. We further discuss the regulators involved in different strategies to restore glucose metabolic homeostasis. Future work should integrate novel tools such as single-cell spatial metabolomics and AI-driven modelling to develop combination therapies targeting brain's constantly adjusting metabolic system, ultimately translating these discoveries into clinical treatments for metabolic dysregulation.

Keywords:  Central nervous system diseases; Glucose metabolism; Metabolic regulators; Neuroinflammation; Oxidative stress; Post-translational modifications

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.026
PLoS Genet. 2025 Sep 25. 21(9): e1011880

Individual lipid alterations at the origin of neuronal Ceramide Synthase defects.

Anna B Ziegler, Cedrik Wesselmann, Konstantin Beckschäfer, Anna-Lena Wulf, Neena Dhiman, Peter Soba, Christoph Thiele, Reinhard Bauer, Gaia Tavosanis.

The brain is highly susceptible to disturbances in lipid metabolism. Among the rare, genetically-linked epilepsies Progressive Myoclonic Epilepsy Type 8 (PME8), associated with the loss of Ceramide Synthase (CerS) activity, causes epileptic symptoms accompanied by early onset of neurodegenerative traits. The function of CerS is embedded in a complex, conserved metabolic pathway, making it difficult to identify the specific disease-relevant alterations. Here, we show that the expression of an enzymatically inactive cerS allele in Drosophila sensory neurons yielded developmental and early onset dendrite loss. Combining lipidomics and refined genetics with quantitative analysis of neuronal morphology in cerS mutants, we identified which lipids species are dysregulated and how they affect neuronal morphology. In cerS mutants, long and very-long acyl-chain C18-C24-ceramides were missing and necessary for dendrite elaboration. In addition, the substrate of CerS, (dh)S, and its metabolite (dh)S1P, increased. Especially increasing (dh)S1P strongly reduces dendritic complexity in cerS mutant neurons. Finally, we performed in vivo experiments to cell-autonomously rescue the morphological defects of cerS mutant neurons and report that a complete rescue can only be achieved if the toxic CerS substrate is converted to produce specific (C18-C24) ceramides. Thus, despite the complex metabolic alterations, our data provides essential information about the metabolic origin of PME8 and delineates a potential therapeutic avenue.

DOI: https://doi.org/10.1371/journal.pgen.1011880
J Lipid Res. 2025 Sep 23. pii: S0022-2275(25)00174-9. [Epub ahead of print] 100912

Spatial lipidomics reveals demyelination and remyelination dynamics in the mouse brain.

Mikolaj Opielka, Krzysztof Urbanowicz, Klaudia Konieczna-Wolska, Elisabeth Müller, Oliwier Krajewski, Maureen Feucherolles, Qiuqin Zhou, Michal Bienkowski, Gilles Frache, Carsten Hopf, Lucas Schirmer, Aleksandra Rutkowska, Ryszard T Smolenski.

  Myelin pathology in demyelinating diseases is accompanied by lipid remodeling that remains challenging to characterize at spatial level using traditional mass spectrometry. We developed an optimized AP-MALDI-Orbitrap MSI pipeline, incorporating sample preparation improvements and mass recalibration, to investigate lipid dynamics in the cuprizone (CPZ) mouse model of demyelination. Dual-modality, untargeted lipid profiling was performed to map spatially resolved lipid alterations during demyelination and spontaneous remyelination in two key brain areas of male mice: corpus callosum (CC) and cortex (Ctx), with lipid identifications benchmarked against 4D-LC-TIMS-MS/MS. Demyelinated regions were identified using Black Gold II staining. Using 1 ppm mass tolerance, we annotated 154 and 133 lipids at the sum-composition level in CC and Ctx, respectively, with 60% validated by LC-MS/MS. Spatial lipid profiling revealed CPZ-induced alterations in sphingolipids, sulfatides, and glycerophospholipids, supported by reanalysis of a published snRNA-seq dataset from a mouse CPZ model. Long-chain ceramides (Cer) and hexosylceramides (HexCer) were reduced in demyelinated regions, with partial, region-specific recovery during remyelination. Short-chain sulfatides (SHexCer), sphingomyelins (SM) and seminolipids transiently increased in the CC during demyelination, while long-chain sulfatides decreased in both CC and Ctx. Additionally, we observed demyelination-induced upregulation of polyunsaturated glycerophospholipids in CC and phosphatidylinositols (PI) in cortex. Lipid subclass changes emerged as reliable markers of both demyelination and remyelination in the mouse brain. Region-specific alterations in lipid metabolism provide new insights into the processes of de- and remyelination. Notably, remyelinated fibers have a distinct lipid profile compared to intact myelin, suggesting that lipid-based therapeutic strategies could improve myelin repair.

Keywords:  4D-LC-TIMS-MS; AP-MALDI-MSI; brain lipids; cuprizone model; demyelination; glycolipids; mass spectrometry imaging; remyelination; spatial lipidomics; sphingolipids

DOI:  https://doi.org/10.1016/j.jlr.2025.100912
Nat Metab. 2025 Sep 22.

The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases.

Femke M Feringa, Sascha J Koppes-den Hertog, Lian Y Wang, Rico J E Derks, Iris Kruijff, Lena Erlebach, Jorin Heijneman, Ricardo Miramontes, Nadine Pömpner, Niek Blomberg, Damien Olivier-Jimenez, Lill Eva Johansen, Alexander J Cammack, Ashling Giblin, Christina E Toomey, Indigo V L Rose, Hebao Yuan, Michael E Ward, Adrian M Isaacs, Martin Kampmann, Deborah Kronenberg-Versteeg, Tammaryn Lashley, Leslie M Thompson, Alessandro Ori, Yassene Mohammed, Martin Giera, Rik van der Kant.

Lipid alterations in the brain have been implicated in many neurodegenerative diseases. To facilitate comparative lipidomic research across brain diseases, we establish a data common named the Neurolipid Atlas that we prepopulated with isogenic induced pluripotent stem cell (iPS cell)-derived lipidomics data for different brain diseases. Additionally, the resource contains lipidomics data of human and mouse brain tissue. Leveraging multiple datasets, we demonstrate that iPS cell-derived neurons, microglia and astrocytes exhibit distinct lipid profiles that recapitulate in vivo lipotypes. Notably, the Alzheimer disease (AD) risk gene ApoE4 drives cholesterol ester (CE) accumulation specifically in human astrocytes and we also observe CE accumulation in whole-brain lipidomics from persons with AD. Multiomics interrogation of iPS cell-derived astrocytes revealed that altered cholesterol metabolism has a major role in astrocyte immune pathways such as the immunoproteasome and major histocompatibility complex class I antigen presentation. Our data commons, available online ( https://neurolipidatlas.com/ ), allows for data deposition by the community and provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases.

DOI: https://doi.org/10.1038/s42255-025-01365-z
Nat Metab. 2025 Sep 23.

Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke.

Qiang Zhao, Jiajian Li, Jingjing Feng, Xin Wang, Yueting Liu, Fei Wang, Liang Liu, Bingxue Jin, Ming Lin, Ya-Chao Wang, Xiuhua Guo, Jieli Chen, Junwei Hao.

Chronic neuroinflammation is a major obstacle to post-stroke recovery, yet the underlying mechanisms, particularly the link between prolonged microglial activation and cholesterol metabolism, are not fully known. Here we show that ischaemic injury induces persistent microglial activation that perpetuates chronic inflammation, leading to microglial cholesterol accumulation and metabolic reprogramming. Using single-cell RNA sequencing, we identified distinct stroke-associated foamy microglia clusters characterized by extensive reprogramming of cholesterol metabolism. Furthermore, direct intracerebral free cholesterol or cholesterol crystal infusion recapitulated sustained microglial activation, directly linking aberrant cholesterol metabolism to prolonged neuroinflammatory responses. Therapeutically, we demonstrate that reducing microglial cholesterol overload through genetic or pharmacological activation of CYP46A1 in male mice promotes white matter repair and functional recovery. These findings highlight microglial cholesterol metabolism as a key driver of post-stroke inflammation, offering therapeutic strategies targeting cholesterol metabolism to mitigate long-term brain damage and promote neurorestoration, potentially improving stroke-related disability outcomes.

DOI: https://doi.org/10.1038/s42255-025-01379-7
Biomolecules. 2025 Aug 29. pii: 1252. [Epub ahead of print]15(9):

Mitochondrial Aging in the CNS: Unravelling Implications for Neurological Health and Disease.

Davide Steffan, Camilla Pezzini, Martina Esposito, Anais Franco-Romero.

  Mitochondrial aging plays a central role in the functional decline of the central nervous system (CNS), with profound consequences for neurological health. As the brain is one of the most energy-demanding organs, neurons are particularly susceptible to mitochondrial dysfunction that arises with aging. Key features of mitochondrial aging include impaired mitochondrial dynamics, reduced mitophagy, increased production of reactive oxygen species (ROS), and accumulation of mitochondrial DNA (mtDNA) mutations. These alterations dramatically compromise neuronal bioenergetics, disrupt synaptic integrity, and promote oxidative stress and neuroinflammation, paving the path for the development of neurodegenerative diseases. This review also examines the complex mechanisms driving mitochondrial aging in the central nervous system (CNS), including the disruption of mitochondrial-organelle communication, and explores how mitochondrial dysfunction contributes to neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. By synthesizing current evidence and identifying key knowledge gaps, we emphasize the urgent need for targeted strategies to restore mitochondrial function, maintain cognitive health, and delay or prevent age-related neurodegeneration.

Keywords:  CNS; aging; mitophagy; neurodegenerative diseases

DOI:  https://doi.org/10.3390/biom15091252
Mol Oncol. 2025 Sep 21.

Adaptaquin is selectively toxic to glioma stem cells through disruption of iron and cholesterol metabolism.

Adrien M Vaquié, Davod R Shah, Eliane E S Brechbühl, Michael McNicholas, Zhaoyang Xu, John H Stockley, Laura Morcom, Diana Gold Diaz, Gemma C Girdler, Rachel V Seear, Gabriel Balmus, Rajiv R Ratan, Harry Bulstrode, James A Nathan, Manav Pathania, Kevin M Brindle, David H Rowitch.

  Glioma stem cells (GSCs) from this aggressive brain cancer have been subject to nononcogene addiction therapeutic strategies, in particular targeting iron and cholesterol metabolic pathways. In this study, we show the small molecule Adaptaquin (AQ) has anti-GSC effects while sparing neurons, mature oligodendrocytes and astrocytes. Transcriptomic analysis of AQ-treated GSCs showed dramatic upregulation of iron transport genes and downregulation of genes involved in cholesterol biosynthesis. Indeed, we found cytotoxic effects of AQ on GSCs were potentiated when combined with the iron chelator deferoxamine (DFO). Notably, these effects were independent of PHD2 and HIF1α regulation, indicating a distinct pathway of action. Furthermore, we observed that the heme analogue, hemin, protects GSCs from AQ-mediated cell death, suggesting the presence of a functional heme transporter in GSCs, an observation confirmed by uptake of heme analogues. Importantly, we found that AQ treatment alone or in combination with iron chelators impaired cholesterol homeostasis in GSCs, leading to mitochondrial fragmentation and cell death. These findings suggest AQ in combination with iron chelators results in lethal disruption of cholesterol metabolism in glioma stem cells.

Keywords:  Adaptaquin; cholesterol; deferoxamine; glioma stem cells; iron; nononcogene addiction

DOI:  https://doi.org/10.1002/1878-0261.70128
bioRxiv. 2025 Sep 19. pii: 2025.09.18.676928. [Epub ahead of print]

Temporal Requirement for Stearoyl-CoA Desaturase 1 in Oligodendrocyte Development but Not Myelin Maintenance.

Iris Farnum, Thaddeus J Kunkel, Manideep Chavali.

Stearoyl-CoA desaturase 1 is a rate-limiting enzyme in monounsaturated fatty acid synthesis, which is crucial for membrane biosynthesis. Here we show an early requirement for Scd1 in oligodendroglial cells during developmental myelination. Using oligodendrocyte progenitor cell (OPC) specific conditional knockout model of Scd1 , we observed a myelination delay during CNS development. Genetic ablation of OPC-specific Scd1 resulted in oligodendrocyte maturation delay and hypomyelination within forebrain white matter tracts and optic nerve. Interestingly, although expressed at high levels within the mature oligodendrocytes, Scd1 was dispensable in maintenance of oligodendrocytes and axonal myelination, as loss of mature oligodendrocyte specific Scd1 showed no effect on myelin maintenance or oligodendrocyte survival. Together, our results suggest that Scd1 function is temporally restricted to the developmental period when oligodendrocytes undergo differentiation and active myelination but becomes dispensable for maintaining established myelin.

DOI: https://doi.org/10.1101/2025.09.18.676928
J Lipid Res. 2025 Sep 23. pii: S0022-2275(25)00173-7. [Epub ahead of print] 100911

Dysregulation of Glu/GABA and reduction of triglycerides contribute to valproic acid-induced autism model in zebrafish.

Qiwen Sun, Xinyi Huang, Han Long, Jianhua Guo, Ruilin Zhang, Daru Lu, Hongyan Yao, Keji Jiang, Yan Pi.

  Autism spectrum disorders are neurodevelopmental conditions that pose substantial diagnostic and therapeutic challenges. Maternal exposure to valproic acid (VPA) during pregnancy is a well-established risk factor associated with autism-like behaviors in offspring. This study characterized the metabolic phenotypes in the brain tissue of larval zebrafish following VPA exposure. Zebrafish were exposed to 4 μM VPA from 2 hours post-fertilization (hpf) until 4.5 days post-fertilization (dpf), and locomotor activity was assessed at 14 dpf. Comprehensive metabolomic profiling via ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) identified 2,613 metabolites in brain tissue, of which 50 showed potential links to autism (CTRL_CV < 15%, VPA_CV < 20%). Significant reductions were observed in the levels of glutamine, glutamate, and triacylglycerol (TG). Nile red staining confirmed profoundly decreased TG deposition in the dorsal telencephalon (pallium), habenula, and cerebellum of VPA-exposed zebrafish. Furthermore, in vivo imaging revealed attenuated fluorescence intensity in excitatory glutamatergic and inhibitory GABAergic neurons within the habenular nucleus and optic tectum, corresponding to reduced TG levels. Conversely, the cerebellar corpus (central cerebellar body) and inferior olive nucleus exhibited an increase in excitatory glutamatergic neurons and a reduction in inhibitory GABAergic neurons, indicating an excitatory/inhibitory (E/I) imbalance. Collectively, these findings suggest that VPA may promote autism pathogenesis by disrupting the glutamine-glutamate cycle and impairing triacylglycerol metabolism in the zebrafish brain. These findings offer novel insights into metabolic dysfunction in ASD and may facilitate the identification of potential diagnostic biomarkers.

Keywords:  autism; brain; lipid; metabolites; neurotransmitter; zebrafish

DOI:  https://doi.org/10.1016/j.jlr.2025.100911
J Neurosurg Pediatr. 2025 Sep 26. 1-7

Effects of sex, injury, and docosahexaenoic acid in a preclinical porcine model of pediatric traumatic brain injury using novel serial collection of CSF, urine, and serum biomarkers.

Michelle E Schober, Cynthia R Terry, Gavin C Jones, Noah Slusher, James Patterson McAllister, John C Gensel.

   OBJECTIVE: Traumatic brain injury (TBI) is a leading cause of acquired neurological disability in children of both sexes. Therapies that improve neurological disability in animal TBI models have universally failed in humans. Successful transition to clinical application should increase if experimental TBI models use animals that are more similar to humans and collect clinically relevant biomarkers. Porcine models of human disease are strong predictors of clinical efficacy. However, studies using immature swine of both sexes and serial collection of biological samples after TBI are lacking. In the authors' rat model of pediatric TBI, docosahexaenoic acid (DHA) improved outcomes and decreased white matter injury, neuroinflammation, and oxidative stress. The authors conducted a proof-of-concept study to evaluate the feasibility of obtaining serial blood, cerebrospinal fluid (CSF), and urine samples from piglets of both sexes after TBI using fluid percussion injury (FPI), and to assess the utility of these samples for measuring clinically relevant biomarkers in a preclinical pediatric TBI model.
METHODS: After pilot testing of a CSF reservoir in cadaver piglets, the authors conducted FPI followed by reservoir placement in live 4-week-old male and female piglets.
RESULTS: The authors succeeded in obtaining all 3 types of samples and measuring biomarkers of white matter injury, neuroinflammation, and oxidative stress. When inserted to an optimal depth of 10 mm, CSF reservoir function was preserved for 3-7 days despite normal piglet activity. Surgery-related mortality (occurring within 1 hour) was 3/36 piglets. One piglet had a quickly resolved scalp infection. FPI increased serum neurofilament light (NfL), a marker of axonal injury, at postinjury day (PID) 1 and 7 in males, blunted by DHA, although the sample size was small. At PID 3, FPI increased CSF interleukin (IL)-4, -8, -12, and -18. DHA abrogated the FPI-induced increase in IL-8 in males. FPI increased IL-12 in DHA-treated females but not control (coconut oil-treated) females. Female sex was associated with increased levels of 10 of the 13 CSF cytokines even in the absence of FPI. At PID 1, the authors observed markedly decreased CSF total antioxidant capacity, a measure of oxidative stress, in all groups.
CONCLUSIONS: Modified piglet FPI allowed serial collection of CSF, urine, and blood samples during the 1st week after surgery. The authors anticipate that this model will be useful for preclinical pharmacokinetic and efficacy studies that require longer term survival and serial biofluid collection after TBI.

Keywords:  developmental; fluid percussion injury; reservoir; surgical methods; traumatic brain injury

DOI:  https://doi.org/10.3171/2025.6.PEDS2555