bims-medebr 2025-10-19 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–10–19
thirteen papers selected by
Regina F. Fernández, Johns Hopkins University

Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel.
Compromised lipid metabolism, mitochondria respiration and neuroprotective effects in iPSC-derived astrocytes from a Smith-Lemli-Opitz syndrome patient.
Region-Specific Quantification of 2-Hydroxyglutarate Enantiomers in Murine Brain during Mitochondrial Complex I Deficiency.
Closing the gap before using L-lactate to guide newborn care.
Postnatal Developmental Dynamics of Mitochondrial Complex I in Mouse Tissues.
Microglia-specific regulation of lipid metabolism in Alzheimer's disease revealed by microglial depletion in 5xFAD Mice.
The emerging landscape of brain glycosylation: from molecular complexity to therapeutic potential.
The interplay of mitochondrial dysfunction and altered metabolic pathways in glioblastoma.
Examination of lipid distributions in hydrogel-expanded mouse brain tissue using imaging mass spectrometry.
Protein glycosylation and synaptic transmission: brain glycogen keeps them separated.
Cerebral fuels within the first week of life in very preterm infants: a cohort study.
Genetic modulation of mitochondrial NAD+ regeneration does not prevent dopaminergic neuron dysfunction caused by mitochondrial complex I impairment.
Lipid Biomarkers in Glioma: Unveiling Molecular Heterogeneity Through Tissue and Plasma Profiling.

Nat Metab. 2025 Oct 16.

Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel.

Anna K Greda, Jemila P Gomes, Vanessa Schmidt-Krueger, Ewa Zurawska-Plaksej, Raphaela Fritsche-Guenther, Ina-Maria Rudolph, Narasimha S Telugu, Cagla Cömert, Jennifer Kirwan, Séverine Kunz, Michael Rothe, Mogens Johannsen, Sebastian Diecke, Peter Bross, Thomas E Willnow.

Sortilin (SORT1) is a lipoprotein receptor that shows genome-wide association with hypercholesterolaemia, explained by its ability to control hepatic output of lipoproteins. Although SORT1 also shows genome-wide association with Alzheimer disease and frontotemporal lobe dementia, the most prevalent forms of age-related dementias, sortilin's contribution to human brain lipid metabolism and health remains unclear. Here we show that sortilin mediates neuronal uptake of polyunsaturated fatty acids carried by apolipoprotein E (apoE). Using humanized mouse strains and induced pluripotent stem cell-based cell models of brain lipid homeostasis, we demonstrate that internalized lipids are converted into ligands for peroxisome proliferator-activated receptor alpha inducing transcription profiles that enable neurons to use long-chain fatty acids as metabolic fuel when glucose is limited. This pathway works with apoE3 but cannot operate with the Alzheimer disease risk factor apoE4, which disrupts sortilin's endocytic activity. Our data indicate a role for the lipoprotein receptor sortilin in metabolic fuel choice in neurons, which may be crucial when glucose supply is limited, such as in the ageing brain.

DOI: https://doi.org/10.1038/s42255-025-01389-5
Hum Mol Genet. 2025 Oct 12. pii: ddaf159. [Epub ahead of print]

Compromised lipid metabolism, mitochondria respiration and neuroprotective effects in iPSC-derived astrocytes from a Smith-Lemli-Opitz syndrome patient.

Keiji Kawatani, Samantha K Baker, Jazmine D W Yaeger, Ruthellen H Anderson, Yingxue Ren, Zonghua Li, Hanmei Bao, Xianlin Han, Kevin R Francis, Takahisa Kanekiyo.

  Smith-Lemli-Opitz syndrome (SLOS) is a rare, autosomal recessive disorder characterized by congenital malformations, intellectual disability, and behavioral abnormalities. SLOS results from mutations in the DHCR7 gene, leading to impaired cholesterol biosynthesis due to dysregulation of 7-dehydrocholesterol reductase. Cholesterol plays crucial roles in neurophysiology, including synaptic formation and neurotransmitter receptor regulation, which likely contribute to neurological manifestations in SLOS patients. While astrocytes are the main cholesterol producing cells in the brain, their specific role in SLOS pathogenesis remains unclear. In this study, we utilized induced pluripotent stem cell (iPSC)-derived astrocytes from a SLOS patient with DHCR7 c.C278T mutation and the isogenic control. We found decreased lipid droplet formation in SLOS iPSC astrocytes compared to controls, accompanied with diminished efflux of cholesterol and apolipoprotein E. Lipidomics revealed reduced cholesterol and cholesterol esters, as well as altered profiles of other lipids in SLOS iPSC astrocytes. While RNA-sequencing identified various genes and pathways affected by the disease status, those related to mitochondria functions were top-ranked. Mitochondrial electron transport chain oxidative phosphorylation gene expression decreased in SLOS iPSC astrocytes, alongside impaired mitochondrial respiration. Furthermore, SLOS iPSC astrocytes less effectively mediated neuroprotection on iPSC neurons than control astrocytes in serum-starvation conditions. SLOS iPSC astrocytes also poorly contributed to synaptic networks when co-cultured with iPSC neurons. Overall, our findings provide mechanistic insights into how DHCR7 disruption impacts astrocyte function, contributing to SLOS neuropathology by dysregulating lipid metabolism, mitochondrial respiration, and impaired neuroprotection.

Keywords:  Astrocyte; DHCR7; Smith-Lemli-Opitz syndrome; iPSC; lipids

DOI:  https://doi.org/10.1093/hmg/ddaf159
ACS Chem Neurosci. 2025 Oct 16.

Region-Specific Quantification of 2-Hydroxyglutarate Enantiomers in Murine Brain during Mitochondrial Complex I Deficiency.

Richard S McCain, Gerardo G Piroli, Holland H Smith, Aman S Sumal, Paul A Grimsrud, William E Cotham, Michael D Walla, Norma Frizzell.

  The Ndufs4-/- mouse is a model of mitochondrial Complex I deficiency that contributes to altered production of the tricarboxylic acid cycle metabolites. We hypothesized that l-2-hydroxyglutarate (l-2-HG) levels would be elevated in the pathologically affected regions of the Ndufs4-/- mouse brain in parallel with metabolic acidosis. We employed a stable isotope dilution method for the concurrent quantification of l-lactate and the distinct 2-HG enantiomers in isolated mouse brain regions. While lactate levels were elevated, as expected in the Ndufs4-/- brain, the levels of l-2-HG and the enantiomer d-2-HG were markedly reduced in a region-specific manner, and this decrease was also reproduced in the Ndufs4-/- serum. The specific and reproducible decreases in 2-HG quantified in Complex I deficiency may have utility as a unique disease biomarker. Quantitative analysis of the mitochondrial proteome of the Ndufs4-/- mouse brainstem indicated an increased abundance of l-2-HG dehydrogenase, suggesting that 2-HG enantiomers are metabolized in the Ndufs4-/- mouse yielding FADH2 to alleviate the bioenergetic deficit.

Keywords:  2-hydroxyglutarate; brainstem; lactate; mass spectrometry; mitochondrial disease; neurometabolic

DOI:  https://doi.org/10.1021/acschemneuro.5c00628
Pediatr Res. 2025 Oct 16.

Closing the gap before using L-lactate to guide newborn care.

Hélène Roumes, Ifrah Omar Ibrahim, Marie-Christine Beauvieux, Chloé Perrot, Olivier Brissaud, Sophie Cramaregeas, Eric Dumas-de-la-Roque, Luc Pellerin, Jean-François Chateil, Olivier Tandonnet, Anne-Karine Bouzier-Sore.

We thank the authors for their insightful commentary on our study investigating sodium L-lactate (NaL) supplementation in preterm infants with metabolic acidosis. Their analysis highlights lactate's expanding role beyond a metabolic byproduct, emphasizing its functions in cellular signaling, antioxidant defense, and neuroprotection. Our study demonstrated that NaL improved acid-base balance without adverse effects, likely through lactate's conversion to bicarbonate and potential support for mitochondrial function. The commentary further explores NaL's translational relevance in neonatal hypoxia-ischemia (NHI), where lactate may serve as a key neuroenergetic substrate and modulate inflammation and gene expression. While the Rice-Vannucci model has limitations, it remains valuable for long-term studies, as shown in our prior work. We agree that larger animal models offer enhanced physiological relevance but face practical constraints. Future research should compare NaL with sodium acetate (NaA), a standard in neonatal care, to assess relative benefits in correcting acidosis and supporting neurodevelopment. We support the call for randomized, multicenter studies with long-term follow-up to fully evaluate NaL's therapeutic potential in preterm and at-risk neonates. IMPACT: L-lactate is a key component of the astrocyte-neuron lactate shuttle, supporting brain energy metabolism. Ibrahim et al. suggest sodium L-lactate as an alternative maintenance fluid for preterm newborns. L-lactate should not be regarded merely as a simple fluid replacement. L-lactate acts as a signaling molecule, impacting cellular metabolism and brain development. Additional research is required to assess the potential benefits and safety of sodium L-lactate in newborns.

DOI: https://doi.org/10.1038/s41390-025-04504-0
Am J Physiol Cell Physiol. 2025 Oct 16.

Postnatal Developmental Dynamics of Mitochondrial Complex I in Mouse Tissues.

Max Siragusa, Belem Yoval-Sánchez, Ivan Guerrero, Alexander Galkin.

  Although the content of mitochondrial enzymes in different tissues can vary greatly, understanding the regulation behind these differences has been hampered by a lack of quantitative knowledge in relation to postnatal development. Here we report a quantitative analysis of developing brain, heart, kidneys, and muscle tissue of C57BL/6J mice, focusing on the content of mitochondrial complex I, a key component of the respiratory chain: We found that in all tissues except kidneys, complex I content gradually increases after birth, reaching a plateau level at around 25 days. Complex I content in muscles does not change significantly until postnatal day 7-10, and then also increases. The greatest increment was found in kidneys, where a 16-fold increase in complex I level after birth was observed. We also found that content of complex I in all postnatal tissues, but muscle, is higher in males than in females. These baseline dynamics of this key mitochondrial flavoprotein serve as a reference for evaluating genetic influences on development and provide a standard for assessing mitochondrial complex I function during postnatal growth.

Keywords:  MItochondria; Postnatal Development; mitochondrial complex I; mouse; tissue specificity

DOI:  https://doi.org/10.1152/ajpcell.00692.2025
Nat Commun. 2025 Oct 15. 16(1): 9156

Microglia-specific regulation of lipid metabolism in Alzheimer's disease revealed by microglial depletion in 5xFAD Mice.

Ziying Xu, Sepideh Kiani Shabestari, Savannah Barannikov, Kevin F Bieniek, Mathew Blurton-Jones, Juan Pablo Palavicini, Xianlin Han.

Abnormal lipid metabolism is observed in Alzheimer's disease (AD), but its contribution to disease progression remains unclear. Genetic studies indicate that microglia, the brain's resident immune cells, influence lipid processing during AD. Here, we show that microglia-the brain's resident immune cells-selectively regulate lipid accumulation that associated with disease pathology in both AD mouse models and human postmortem brains. Using lipidomics and histological analysis, we identify a striking buildup of arachidonic acid-containing bis(monoacylglycero)phosphate in response to amyloid plaques, which depends on microglial activity and the AD risk gene GRN. In contrast, lysophosphatidylcholine and lysophosphatidylethanolamine accumulate independently of microglia, correlating instead with astrocyte activation and oxidative stress. These results connect dysregulated lipid metabolism in AD to distinct brain cell types and molecular pathways. Our findings highlight microglial lipid homeostasis as a potential therapeutic target for modifying disease progression in AD.

DOI: https://doi.org/10.1038/s41467-025-64161-z
Exp Mol Med. 2025 Oct 14.

The emerging landscape of brain glycosylation: from molecular complexity to therapeutic potential.

Youngsuk Seo, Ji Eun Park, Jae Young Yu, Boyoung Lee, Jong Hyuk Yoon, Hyun Joo An.

Glycosylation functions as a pivotal posttranslational modification in proteins and as a distinct biosynthetic process in lipids. In the brain, it plays essential roles in development, function and homeostasis by modulating protein folding, receptor trafficking and intercellular communication. Although glycans constitute less than 1% of the brain's mass, their impact is disproportionately profound. Recent technological advances have uncovered the essential contributions of both protein- and lipid-bound glycans, including N-glycans, O-glycans and gangliosides, to brain physiology and disease. Here we explore the emerging landscape of brain glycosylation, highlighting its distinct roles in neurodevelopment, synaptic organization and immune regulation. Aberrant glycosylation has been implicated in neurodegenerative diseases (for example, Alzheimer's and Parkinson's), psychiatric disorders (for example, depression and schizophrenia) and neurodevelopmental conditions (for example, autism spectrum disorders, attention deficit hyperactivity disorder and dystroglycanopathies). We summarize recent breakthroughs in glycomics technologies, including glycan enrichment, liquid chromatography-tandem mass spectrometry, MALDI-based imaging mass spectrometry and high-throughput omics, which enable molecular and spatial mapping of brain glycosylation. Artificial-intelligence-driven bioinformatics and multi-omics integration are rapidly opening new avenues for deciphering glycan-mediated regulation in brain health and disease. Together, these developments position brain glycosylation as a transformative frontier in neuroscience, with the potential to yield novel diagnostic biomarkers and therapeutic strategies for complex brain disorders.

DOI: https://doi.org/10.1038/s12276-025-01560-8
Contemp Oncol (Pozn). 2025 ;29(3): 217-231

The interplay of mitochondrial dysfunction and altered metabolic pathways in glioblastoma.

Wan Noor Ainun Baharuddin, Abdul Aziz Mohamed Yusoff.

  Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor, characterized by rapid progression, treatment resistance, and poor prognosis, with a survival rate of less than five years despite advances in medical interventions. A hallmark of GBM is metabolic reprogramming, which supports tumor growth and progression. Mitochondrial dysfunction plays a critical role in this metabolic shift by altering energy production and disrupting key cellular pathways. However, the precise molecular mecha-nisms underlying these alterations remain inadequately understood. This review highlights the fundamental contributions of mitochondrial oxidative phosphorylation (OXPHOS) and the electron transport chain (ETC) to GBM pathology. Notably, deficiencies in mitochondrial DNA and its associat-ed molecular components have been identified as key factors contributing to impaired mitochondrial function. Additionally, an imbalance in reactive oxygen species production within the ETC has been implicated in driving cellular and metabolic changes that promote tumor progression. Given the central role of mitochondrial metabolism in GBM, targeting OXPHOS and ETC components presents a promi-sing therapeutic approach. This review also discusses current pharmacolo-gical strategies aimed at modulating mitochondrial respiration, with a focus on drugs and compounds that selectively inhibit OXPHOS complexes. Understanding the intricate relationship between mitochondrial dysfunction and GBM progression may provide valuable insights for developing novel therapeutic interventions, ultimately improving clinical outcomes for patients with this devastating disease.

Keywords:  electron transport chain targeting; glioblastoma metabolism; mitochondrial dysfunction; oxidative phosphorylation

DOI:  https://doi.org/10.5114/wo.2025.153848
Anal Chim Acta. 2025 Dec 01. pii: S0003-2670(25)01023-2. [Epub ahead of print]1377 344629

Examination of lipid distributions in hydrogel-expanded mouse brain tissue using imaging mass spectrometry.

Jacob M Samuel, Nana M Baby, Elijah D Mayo, Tingting Yan, Zhongling Liang, Boone M Prentice.

   BACKGROUND: Imaging is essential in biological research, and imaging mass spectrometry uniquely provides a label-free approach with high molecular specificity. However, imaging mass spectrometry is limited in spatial resolution, which in turn limits the biological structures that can be studied. Custom lens setups and altered optical paths can shrink the diameter of the incident laser beam probe in matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry to achieve high spatial resolutions (<5 μm). However, these research-grade instruments are complex and expensive, making high spatial resolution imaging experiments unrealistic for the broader community. There is a need for inexpensive and widely-accessible means for high spatial resolution imaging.
RESULTS: An alternative method for improving spatial resolution is through physical magnification of the substrate, which has been well established in the subfield of expansion microscopy (ExM). ExM leverages superabsorbent hydrogels for isotropic expansion of tissues and retention of fluorescently labeled analytes. While typical ExM involves covalently anchoring analytes to the hydrogel network, lipid retention without anchoring has been recently demonstrated for imaging mass spectrometry. Herein, we demonstrate expansion imaging mass spectrometry (ExIMS) of expanded brain tissue and examine lipid distributions in both positive and negative ion modes across multiple tissue structures. A linear expansion factor of 4.5-fold is achieved and used to obtain high spatial resolution images of mouse brain cerebellum. Approximately 75 % of lipids in both positive and negative ion modes are detected in expanded tissue compared to unexpanded tissue. Additionally, the majority of lipid distributions across the brain are maintained post-expansion, though lipid delocalization can occur for some lipids in the hippocampus and the granular layer of the cerebellum. Alterations to the hydrogel formulation can significantly affect the ability of ExIMS to maintain accurate lipid distributions in expanded tissue. For example, stronger fixation can better maintain lipid distributions, while gentler digests can better maintain lipid distributions at higher tissue expansion factors.
SIGNIFICANCE: This work provides a methodical analysis of the effect of hydrogel embedding and expansion on lipid distributions across multiple tissue structures, ion polarities, and lipid classes. Computational tools are used to assess the spatial fidelity of lipid distributions prior to and following tissue expansion, which begins to assess the interaction between lipid delocalization and expansion parameters.

Keywords:  Expansion; High resolution; Hydrogel; Imaging mass spectrometry; MALDI

DOI:  https://doi.org/10.1016/j.aca.2025.344629
Brain. 2025 Oct 17. pii: awaf396. [Epub ahead of print]

Protein glycosylation and synaptic transmission: brain glycogen keeps them separated.

Gabriele Trentini, Giulia Cazzanelli, Graziano Lolli.

  Brain glycogen has for long been regarded uniquely as a source of energetic support in situations of emergency or heightened activity. Recently, brain glycogen was found to contain a significant amount of glucosamine, which is used to sustain protein glycosylation. In this update, we highlight that glucosamine synthesis through the hexosamine pathway would subtract glutamine, which is instead indispensable for glutamate and GABA recycling. Brain glycogen seems then to serve an additional role. By providing glucosamine and, through it, inhibiting the hexosamine pathway, glycogen avoids glutamine depletion. In neurological glycogen storage diseases, the short-circuit between the hexosamine pathway and neurotransmitters recycling can cause epileptic seizures, which are the most common acute manifestation in these pathologies. We finally discuss the metabolic and symptomatic superposition of glycogen storage diseases with congenital disorders of glycosylation, concluding that treatments ameliorating the clinical symptoms in some of the discussed pathologies could also be beneficial in the others.

Keywords:  congenital disorders of glycosylation; epilepsy; glucosamine; glutamine; glycogen; glycogen storage diseases

DOI:  https://doi.org/10.1093/brain/awaf396
Arch Dis Child Fetal Neonatal Ed. 2025 Oct 13. pii: fetalneonatal-2025-328701. [Epub ahead of print]

Cerebral fuels within the first week of life in very preterm infants: a cohort study.

REACT Collaborative

   BACKGROUND: Ketones and lactate may contribute towards overall cerebral fuel availability in term infants, yet the availability of such cerebral fuels in very preterm infants is unclear. We undertook a prespecified substudy to explore ketone and lactate concentrations in the first week of life in infants recruited to the REACT trial (real-time continuous glucose monitoring in the newborn): an international multicentre randomised controlled trial of 182 very low birth weight infants investigating the use of continuous glucose monitoring in glycaemic care.
METHODS: Ketone and lactate measurements were prospectively collected over the first week of life using the Nova Biomedical point-of-care meter. A longitudinal analysis was undertaken to explore lactate and ketone concentration trends across time and their relationships with blood glucose, baseline demographics, nutritional support and insulin treatment.
RESULTS: Data were available for 168 infants (85 females) including 2902 blood glucose, 2084 ketone and 2017 lactate samples. The mean (SD) gestational age was 27.4 (2.0) weeks. Lactate concentrations were higher initially, with mean (SD) 1.72 (1.26) mmol/L on day 2 and lowered to 1.19 (1.1) mmol/L on day 7. Ketone concentrations remained consistently low at 0.1 mmol/L. Neither simultaneous blood glucose concentrations, macronutrient intake nor receipt of insulin was consistently related to ketone or lactate concentrations.
CONCLUSION: In this cohort of very preterm infants, there were persistently low concentrations of ketones and relatively higher concentrations of lactate throughout the first week of life. Future research should evaluate changes in these metabolites during episodes of acute hypoglycaemia or hyperglycaemia over more prolonged periods of neonatal intensive care.

Keywords:  Endocrinology; Neonatology

DOI:  https://doi.org/10.1136/archdischild-2025-328701
Front Cell Dev Biol. 2025 ;13 1650462

Genetic modulation of mitochondrial NAD+ regeneration does not prevent dopaminergic neuron dysfunction caused by mitochondrial complex I impairment.

Karis B D'Alessandro, Enrico Zampese, Jenna L E Blum, Britta Kuusik, Alec Palmiotti, Shawn M Davidson, Colleen R Reczek, D James Surmeier, Navdeep S Chandel.

  Dysfunction of mitochondrial complex I (MCI) has been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. Here, we report the effect of expressing MitoLbNOX, a mitochondrial-targeted version of the bacterial enzyme LbNOX, which increases regeneration of NAD+ in the mitochondria to maintain the NAD+/NADH ratio, in dopaminergic neurons with impaired MCI (MCI-Park mice). MitoLbNOX expression did not ameliorate the cellular or behavioral deficits observed in MCI-Park mice, suggesting that alteration of the mitochondrial NAD+/NADH ratio alone is not sufficient to compensate for loss of MCI function in dopaminergic neurons.

Keywords:  NAD+; Parkinson’s disease; dopaminergic neurons; mitochondrial complex I; neurodegeneration; neurometabolism

DOI:  https://doi.org/10.3389/fcell.2025.1650462
Int J Mol Sci. 2025 Oct 09. pii: 9820. [Epub ahead of print]26(19):

Lipid Biomarkers in Glioma: Unveiling Molecular Heterogeneity Through Tissue and Plasma Profiling.

Khairunnisa Abdul Rashid, Norlisah Ramli, Kamariah Ibrahim, Vairavan Narayanan, Jeannie Hsiu Ding Wong.

  Gliomas are aggressive brain tumours with diverse histological and molecular features, complicating accurate diagnosis and treatment. Dysregulated lipid metabolism contributes to glioma progression, and analysing lipid profiles in plasma and tissue may enhance diagnostic and prognostic accuracy. This study investigated lipid dysregulation to identify key lipid signatures that distinguish glioma from other brain diseases and examined the associations between lipid biomarkers in glioma tissue and plasma. Biospecimens from 11 controls and 72 glioma patients of varying grades underwent lipidomic profiling using liquid chromatography-mass spectrometry. Univariate and multivariate analyses identified differentially abundant lipids, and correlation analysis evaluated the associations between tissue and plasma biomarkers. Lipidomic analysis revealed distinct lipid profiles in the tissues and plasma of glioma patients compared to those of controls. Prominent lipid metabolites in glioma tissues included LPC 21:3 (AUC = 0.925), DG 43:11 (AUC = 0.906), and PC 33:1 (AUC = 0.892), which served as effective biomarkers. Conversely, in plasma, lipid metabolites such as phosphatidylethanolamine (PE 21:3, AUC = 0.862), ceramide-1-phosphate (CerP 26:1, AUC = 0.861), and sphingomyelin (SM 24:3, AUC = 0.858) were identified as the most promising lipid biomarkers. Significant positive and negative correlations were observed between the tissue and plasma lipid biomarkers of glioma patients. Lipidomic profiling revealed aberrant lipid classes and pathways in glioma tissues and plasma, enhancing understanding of glioma heterogeneity and potential clinical applications.

Keywords:  glioma; lipid; lipid biomarkers; liquid chromatography-mass spectrometry; metabolic dysregulation

DOI:  https://doi.org/10.3390/ijms26199820