bims-medebr 2025-05-18 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–05–18
seventeen papers selected by
Regina F. Fernández, Johns Hopkins University

The Feud over Lactate and Its Role in Brain Energy Metabolism: An Unnecessary Burden on Research and the Scientists Who Practice It.
Glutamate, a Key for Astrocytes to Participate in Brain Function and Diseases.
The effect of perinatal supplementation of DHA on specialized pro-resolving lipid mediators in the brain of offspring.
Unraveling the Interplay Between Metabolism and Neurodevelopment in Health and Disease.
Regulation of synaptic mitochondria by extracellular vesicles and its implications for neuronal metabolism and synaptic plasticity.
Fatty acid binding proteins and their involvement in anxiety and mood disorders.
Metabolomics: a new frontier in neurodegenerative disease biomarker discovery.
Mitochondrial Oxidative Phosphorylation System Dysfunction in Schizophrenia.
Spatial mapping of the brain metabolome lipidome and glycome.
Snapshots of mitochondrial fission imaged by cryo-scanning transmission electron tomography.
ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression.
Mitochondrial Dysfunction in Genetic and Non-Genetic Parkinson's Disease.
The brain's "dark energy" puzzle upgraded: [18F]FDG uptake, delivery and phosphorylation, and their coupling with resting-state brain activity.
Mitochondrial quality control and transfer communication in neurological disorders and neuroinflammation.
Human milk oligosaccharides improve white matter and interneuron development in a double-hit rat model for preterm brain injury.
Single-cell mitochondrial morphomics reveals cellular heterogeneity and predicts complex I, III, and ATP synthase Inhibition responses.
Molecular insights into human phosphatidylserine synthase 2 and its regulation of SREBP pathways.

Int J Mol Sci. 2025 May 07. pii: 4429. [Epub ahead of print]26(9):

The Feud over Lactate and Its Role in Brain Energy Metabolism: An Unnecessary Burden on Research and the Scientists Who Practice It.

Avital Schurr.

  Ever since the monocarboxylate, lactate, was shown to be more than a useless end-product of anaerobic glycolysis, the members of the brain energy metabolism research community are divided by two issues: First, could lactate replace glucose as the oxidative mitochondrial energy substrate? Second, should glycolysis continue to be divided into aerobic and anaerobic pathways? This opinion paper examined both the history and the reasons for this division and offered a unifying solution. Some readers may find this paper somewhat slanted, although many aspects of my opinion are backed, whenever possible, by data.

Keywords:  astrocyte; bias; brain; energy metabolism; glucose; glycolysis; lactate; neuron; shuttle

DOI:  https://doi.org/10.3390/ijms26094429
Neurochem Res. 2025 May 15. 50(3): 166

Glutamate, a Key for Astrocytes to Participate in Brain Function and Diseases.

Kai Gao, Albert Cheung-Hoi Yu.

Astrocytes support neurons by maintaining health, regulating the environment, and aiding synaptic transmission, while glutamate is vital for excitatory signaling in learning and memory. The "glutamate-glutamine cycle," verified by Hertz and Schousboe, illustrates the interaction between neurons and astrocytes in glutamate regulation. Recent studies show astrocytes not only manage glutamate levels but also influence synaptic activity through gliotransmission and contribute to brain energy via glutamate metabolism. Dysregulation of this signaling is linked to neurological disorders like epilepsy and Alzheimer's. This mini-review will explore research progress on astrocytes and glutamate, highlighting glutamate's role in brain function and disease.

DOI: https://doi.org/10.1007/s11064-025-04418-7
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 May 13. pii: S1388-1981(25)00037-X. [Epub ahead of print] 159629

The effect of perinatal supplementation of DHA on specialized pro-resolving lipid mediators in the brain of offspring.

Stephanie Dubrof, Jillien G Zukaitis, Ishfaque Ahmed, Wenwu Sun, Qun Zhao, Hea Jin Park.

  The perinatal period is crucial for fetal neurological development, relying on omega-3 polyunsaturated fatty acids (PUFAs) for essential processes. Omega-3 PUFA, including docosahexaenoic acid (DHA), are precursors to a novel class of bioactive metabolites called specialized pro-resolving mediators (SPMs), which have been suggested to have a dual purpose in mitigating neuroinflammation while simultaneously supporting cognitive outcomes, implicating a role in offspring neurodevelopment. DHA is evidenced for its role in early brain development, but the underlying mechanism it exerts its cognitive benefits remain unclear. Pregnant sows were fed a control diet (CON; n = 6) or a diet with DHA (n = 6, 75 mg DHA/kg BW/day) from gestation through lactation. At weaning, piglets (n = 2/sow) underwent resting state-functional magnetic resonance imaging (rs-fMRI) to assess brain functional activation. Subsequently, brain tissue from prefrontal cortex, cerebellum, and hippocampus were collected from piglets. Tissue DHA and eicosapentaenoic acid (EPA)-derived SPMs were quantified using LC-MS. Levels of SPMs were higher in the brains of piglets from DHA-fed sows, particularly in the prefrontal cortex and cerebellum, compared to control piglets. Additionally, a distinct association of several prefrontal SPMs with activation of the cerebellar functional network was marked in the piglet offspring. The findings highlight a potential for SPMs to function as mediators for neurodevelopmental programming, through contributing to inflammation resolution and neuronal connectivity. This work underscores the importance of maternal nutrition in shaping offspring brain health and lays the groundwork for targeted interventions leveraging the benefits of DHA and its bioactive metabolites.

Keywords:  Docosahexaenoic acid; Eicosapentaenoic acid; Functional MRI; Pig model; Polyunsaturated fatty acids; Programming; Specialized pro-resolving mediators

DOI:  https://doi.org/10.1016/j.bbalip.2025.159629
CNS Neurosci Ther. 2025 May;31(5): e70427

Unraveling the Interplay Between Metabolism and Neurodevelopment in Health and Disease.

Yanqing He, Kang Xie, Kang Yang, Nianhua Wang, Longbo Zhang.

   BACKGROUND: Neurodevelopment is a multifaceted and tightly regulated process essential for the formation, maturation, and functional specialization of the nervous system. It spans critical stages, including cellular proliferation, differentiation, migration, synaptogenesis, and synaptic pruning, which collectively establish the foundation for cognitive, behavioral, and emotional functions. Metabolism serves as a cornerstone for neurodevelopment, providing the energy and substrates necessary for biosynthesis, signaling, and cellular activities.
RESULTS: Key metabolic pathways, including glycolysis, lipid metabolism, and amino acid metabolism, support processes such as cell proliferation, myelination, and neurotransmitter synthesis. Crucial signaling pathways, such as insulin, mTOR, and AMPK, further regulate neuronal growth, synaptic plasticity, and energy homeostasis. Dysregulation of these metabolic processes is linked to a spectrum of neurodevelopmental disorders, including autism spectrum disorders (ASDs), intellectual disabilities, and epilepsy.
CONCLUSIONS: This review investigates the intricate interplay between metabolic processes and neurodevelopment, elucidating the molecular mechanisms that govern brain development and the pathogenesis of neurodevelopmental disorders. Additionally, it highlights potential avenues for the development of innovative strategies aimed at enhancing brain health and function.

Keywords:  autism spectrum disorders; metabolism; mitochondria; neurodevelopment; neurodevelopmental disorders

DOI:  https://doi.org/10.1111/cns.70427
J Cereb Blood Flow Metab. 2025 May 14. 271678X251337630

Regulation of synaptic mitochondria by extracellular vesicles and its implications for neuronal metabolism and synaptic plasticity.

Yuzhou Zeng, Anna Antoniou.

  Mitochondrial metabolism in neurons is necessary for energetically costly processes like synaptic transmission and plasticity. As post-mitotic cells, neurons are therefore faced with the challenge of maintaining healthy functioning mitochondria throughout lifetime. The precise mechanisms of mitochondrial maintenance in neurons, and particularly in morphologically complex dendrites and axons, are not fully understood. Evidence from several biological systems suggests the regulation of cellular metabolism by extracellular vesicles (EVs), secretory lipid-enclosed vesicles that have emerged as important mediators of cell communication. In the nervous system, neuronal and glial EVs were shown to regulate neuronal circuit development and function, at least in part via the transfer of protein and RNA cargo. Interestingly, EVs have been implicated in diseases characterized by altered metabolism, such as cancer and neurodegenerative diseases. Furthermore, nervous system EVs were shown to contain proteins related to metabolic processes, mitochondrial proteins and even intact mitochondria. Here, we present the current knowledge of the mechanisms underlying neuronal mitochondrial maintenance, and highlight recent evidence suggesting the regulation of synaptic mitochondria by neuronal and glial cell EVs. We further discuss the potential implications of EV-mediated regulation of mitochondrial maintenance and function in neuronal circuit development and synaptic plasticity.

Keywords:  Exosomes; extracellular vesicles; metabolism; mitochondria; synaptic plasticity

DOI:  https://doi.org/10.1177/0271678X251337630
Neurobiol Dis. 2025 May 11. pii: S0969-9961(25)00168-8. [Epub ahead of print]212 106952

Fatty acid binding proteins and their involvement in anxiety and mood disorders.

Matthew J Jones, Taygun C Uzuneser, Steven R Laviolette.

  Anxiety and mood disorders represent the most prevalent neuropsychiatric conditions. Nevertheless, current pharmacotherapies often have a host of adverse side effects. Emerging evidence suggests modulation of lipid signaling pathways - particularly those involved in the endocannabinoid (eCB) system, may offer promising new targets for the treatment of anxiety and depression. Polyunsaturated fatty acids (PUFA) and their metabolic derivatives, including the eCB ligands, have garnered significant attention for their roles in neuropsychiatric disease mechanisms. Intracellular transportation of these lipids is facilitated by fatty acid binding proteins (FABP), which are increasingly recognized as key regulators of lipid signaling. Accumulating evidence indicates that FABPs may impact the development of neuropsychiatric disorders by mediating the signaling pathways of PUFAs and eCB ligands. In this review, we investigate the role of FABPs in two major categories of neuropsychiatric conditions - anxiety disorders and clinical depression. We begin by examining several neuropathophysiological mechanisms through which FABPs can impact these conditions, focusing on their role as lipid chaperones. These mechanisms include the trafficking of eCB ligands, as well as oleoylethanolamide and palmitoylethanolamide; modulation of inflammatory responses through PUFA transport and PPAR activation; regulation of PUFA availability to support neurogenesis; influence on stress-related pathways, including NMDA receptor activation and the hypothalamic-pituitary-adrenal axis; and the facilitation of dopamine receptor trafficking and localization. Next, we discuss preclinical evidence linking FABP function to anxiety- and depression-related behaviours. Finally, we propose that pharmacologically targeting FABP-mediated pathways holds considerable potential as a novel therapeutic strategy for addressing the symptoms associated with mood and anxiety disorders.

Keywords:  Anxiety; Depression; Fatty acid binding proteins; Lipids

DOI:  https://doi.org/10.1016/j.nbd.2025.106952
Metabolomics. 2025 May 15. 21(3): 67

Metabolomics: a new frontier in neurodegenerative disease biomarker discovery.

Krishan Kumar Verma, Praveen Kumar Gaur, Sonia Lal Gupta, Kanak Lata, Rahul Kaushik, Vikas Sharma.

   BACKGROUND: Neurodegenerative disorders are a group of debilitating diseases affecting the central nervous system, and are characterized by the progressive loss of neurons, leading to declines in cognitive function, movement, and overall quality of life. While the exact causes remain elusive, it's believed that a combination of genetic, environmental, and lifestyle factors contribute to their development. Metabolites, the end products of cellular processes, reflect the physiological state of an organism. By analysing these molecules, researchers can gain a deeper understanding of the underlying metabolic changes associated with neurodegenerative disorders.
AIM OF REVIEW: This review aims to explore the possibilities between metabolites and their association with neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS) and Huntington's disease (HD).
KEY SCIENTIFIC CONCEPTS OF REVIEW: Metabolomic studies could potentially illuminate altered biochemical pathways, facilitating earlier detection and treatment of these conditions. Metabolomic investigations have revealed the role of oxidative stress, alterations in glucose and fat metabolism, mitochondrial dysfunction, apoptosis, glutamate excitotoxicity and alterations in myelin composition in neurodegenerative disorders. The common metabolic biomarkers identified includes glutamate, taurine, uric acid, branched chain amino acids, acylcarnitine, creatinine, choline, with some more amino acids and lipids. Metabolomics offers valuable insights into disease mechanisms and potential therapeutic targets by identifying biochemical and metabolic alterations, but still there are several aspects to be explored for accurate mapping of metabolites with specific pathway involved in the disease.

Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Huntington’s disease; Metabolomics; Multiple sclerosis; Parkinson’s disease

DOI:  https://doi.org/10.1007/s11306-025-02267-7
Int J Mol Sci. 2025 May 06. pii: 4415. [Epub ahead of print]26(9):

Mitochondrial Oxidative Phosphorylation System Dysfunction in Schizophrenia.

Constanza Morén, David Olivares-Berjaga, Albert Martínez-Pinteño, Miquel Bioque, Natàlia Rodríguez, Patricia Gassó, Lourdes Martorell, Eduard Parellada.

  Schizophrenia (SCZ) is a severe, chronic mental disorder of unknown etiology and limited therapeutic options. Bioenergetic deficits in the oxidative phosphorylation system (OXPHOS) during early postnatal brain development may underlie disrupted neuronal metabolism and synaptic signaling, contributing to the neurodevelopmental and behavioral disturbances observed in patients. This narrative review summarizes updated evidence linking mitochondrial-OXPHOS dysfunction to SCZ pathophysiology. The novelty lies in the focus on OXPHOS dysfunction at the enzymatic/functional level, rather than on genetic, transcriptional, or oxidative parameters. While complex I impairment has long been highlighted and proposed as a peripheral marker of the disease, recent studies also report alterations in other OXPHOS complexes and their precursors. These findings suggest that OXPHOS dysfunction is not isolated to a single enzymatic component but affects broader mitochondrial function, alongside oxidative stress, contributing to disease progression through mechanisms involving apoptosis, accelerated aging, and synaptic deterioration. OXPHOS dysfunction in both central and peripheral tissues further supports its relevance to SCZ. Overall, the literature points to mitochondrial OXPHOS abnormalities as a significant biological feature of SCZ. Whether these alterations are causal factors or consequences of disease processes remains unclear. Understanding OXPHOS dysregulation may open new avenues for targeted therapies.

Keywords:  OXPHOS; bioenergetics; metabolism; mitochondria; schizophrenia

DOI:  https://doi.org/10.3390/ijms26094415
Nat Commun. 2025 May 12. 16(1): 4373

Spatial mapping of the brain metabolome lipidome and glycome.

Harrison A Clarke, Xin Ma, Cameron J Shedlock, Terrymar Medina, Tara R Hawkinson, Lei Wu, Roberto A Ribas, Shannon Keohane, Sakthivel Ravi, Jennifer L Bizon, Sara N Burke, Jose Francisco Abisambra, Matthew E Merritt, Boone M Prentice, Craig W Vander Kooi, Matthew S Gentry, Li Chen, Ramon C Sun.

Metabolites, lipids, and glycans are fundamental but interconnected classes of biomolecules that form the basis of the metabolic network. These molecules are dynamically channeled through multiple pathways that govern cellular physiology and pathology. Here, we present a framework for the simultaneous spatial analysis of the metabolome, lipidome, and glycome from a single tissue section using mass spectrometry imaging. This workflow integrates a computational platform, the Spatial Augmented Multiomics Interface (Sami), which enables multiomics integration, high-dimensional clustering, spatial anatomical mapping of matched molecular features, and metabolic pathway enrichment. To demonstrate the utility of this approach, we applied Sami to evaluate metabolic diversity across distinct brain regions and to compare wild-type and Ps19 Alzheimer's disease (AD) mouse models. Our findings reveal region-specific metabolic demands in the normal brain and highlight metabolic dysregulation in the Ps19 model, providing insights into the biochemical alterations associated with neurodegeneration.

DOI: https://doi.org/10.1038/s41467-025-59487-7
J Cell Sci. 2025 May 01. pii: jcs263639. [Epub ahead of print]138(9):

Snapshots of mitochondrial fission imaged by cryo-scanning transmission electron tomography.

Peter Kirchweger, Sharon Grayer Wolf, Neta Varsano, Tali Dadosh, Guenter P Resch, Michael Elbaum.

  Mitochondria undergo constant remodeling via fission, fusion, extension and degradation. Fission, in particular, depends on the accumulation of mitochondrial fission factor (MFF) and subsequent recruitment of the dynamin-related protein DRP1 (also known as DNM1L). We used cryo-scanning transmission electron tomography (cryo-STET) to investigate mitochondrial morphologies in MFF mutant (MFF-/-) mouse embryonic fibroblast (MEF) cells in ATP-depleting conditions that normally induce fission. The capability of cryo-STET to image through the cytoplasmic volume to a depth of 1 µm facilitated visualization of intact mitochondria and their surroundings. We imaged changes in mitochondrial morphology and cristae structure, as well as contacts with the endoplasmic reticulum (ER), degradative organelles and the cytoskeleton at stalled fission sites. We found disruption of the outer mitochondrial membrane at contact sites with the ER and degradative organelles at sites of mitophagy. We identified fission sites where the inner mitochondrial membrane is already separated while the outer membrane is still continuous. Although MFF is a general fission factor, these observations demonstrate that mitochondrial fission can proceed to the final stage in its absence. The use of cryo-STET allays concerns about the loss of structures due to sample thinning required for tomography using cryo-transmission electron microscopy.

Keywords:  Cryo-ET; Cryo-FM; Cryo-STET; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fission factor

DOI:  https://doi.org/10.1242/jcs.263639
Nat Cell Biol. 2025 May;27(5): 847-862

ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression.

Che-Chia Hsu, Chi-Yun Wang, Rajesh Kumar Manne, Zhen Cai, Vasudevarao Penugurti, Rajni Kant, Ling Bai, Bo-Syong Pan, Tingjin Chen, Yuan-Ru Chen, Hsin-En Wu, Yan Jin, Haiwei Gu, Chia-Yang Li, Hui-Kuan Lin.

MPC1 and MPC2 are two well-known components of the mitochondrial pyruvate carrier (MPC) complex maintaining MPC activity to transport pyruvate into mitochondria for tricarboxylic acid (TCA) cycle entry in mammalian cells. It is currently unknown whether there is an additional MPC component crucially maintaining MPC complex activity for pyruvate mitochondrial import. Here we show that ALDH4A1, a proline-metabolizing enzyme localized in mitochondria, serves as a previously unrecognized MPC component maintaining pyruvate mitochondrial import and the TCA cycle independently of its enzymatic activity. Loss of ALDH4A1 in mammalian cells impairs pyruvate entry to mitochondria, resulting in defective TCA cycle entry. ALDH4A1 forms an active trimeric complex with MPC1-MPC2 to maintain the integrity and oligomerization of MPC1-MPC2 and facilitates pyruvate transport in an in vitro system. ALDH4A1 displays tumour suppression by maintaining MPC complex activity. Our study identifies ALDH4A1 as an essential component of MPC for pyruvate mitochondrial import, TCA cycle entry and tumour suppression.

DOI: https://doi.org/10.1038/s41556-025-01651-8
Int J Mol Sci. 2025 May 07. pii: 4451. [Epub ahead of print]26(9):

Mitochondrial Dysfunction in Genetic and Non-Genetic Parkinson's Disease.

Martina Lucchesi, Letizia Biso, Marco Bonaso, Biancamaria Longoni, Bianca Buchignani, Roberta Battini, Filippo Maria Santorelli, Stefano Doccini, Marco Scarselli.

  Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD) pathogenesis, contributing to increased oxidative stress and impaired endo-lysosomal-proteasome system efficiency underlying neuronal injury. Genetic studies have identified 19 monogenic mutations-accounting for ~10% of PD cases-that affect mitochondrial function and are associated with early- or late-onset PD. Early-onset forms typically involve genes encoding proteins essential for mitochondrial quality control, including mitophagy and structural maintenance, while late-onset mutations impair mitochondrial dynamics, bioenergetics, and trafficking. Atypical juvenile genetic syndromes also exhibit mitochondrial abnormalities. In idiopathic PD, environmental neurotoxins such as pesticides and MPTP act as mitochondrial inhibitors, disrupting complex I activity and increasing reactive oxygen species. These converging pathways underscore mitochondria as a central node in PD pathology. This review explores the overlapping and distinct mitochondrial mechanisms in genetic and non-genetic PD, emphasizing their role in neuronal vulnerability. Targeting mitochondrial dysfunction finally offers a promising therapeutic avenue to slow or modify disease progression by intervening at a key point of neurodegenerative convergence.

Keywords:  Parkinson’s disease; genetic PD; mitochondrial dysfunction; neurotoxins; oxidative stress

DOI:  https://doi.org/10.3390/ijms26094451
J Cereb Blood Flow Metab. 2025 May 15. 271678X251329707

The brain's "dark energy" puzzle upgraded: [18F]FDG uptake, delivery and phosphorylation, and their coupling with resting-state brain activity.

Tommaso Volpi, John J Lee, Andrei G Vlassenko, Manu S Goyal, Maurizio Corbetta, Alessandra Bertoldo.

  The brain's resting-state energy consumption is expected to be driven by spontaneous activity. We previously used 50 resting-state fMRI (rs-fMRI) features to predict [18F]FDG SUVR as a proxy of glucose metabolism. Here, we expanded on our effort by estimating [18F]FDG kinetic parameters Ki (irreversible uptake), K1 (delivery), k3 (phosphorylation) in a large healthy control group (n = 47). Describing the parameters' spatial distribution at high resolution (216 regions), we showed that K1 is the least redundant (strong posteromedial pattern), and Ki and k3 have relevant differences (occipital cortices, cerebellum, thalamus). Using multilevel modeling, we investigated how much spatial variance of [18F]FDG parameters could be explained by a combination of a) rs-fMRI variables, b) cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) from 15O PET. Rs-fMRI-only models explained part of the individual variance in Ki (35%), K1 (14%), k3 (21%), while combining rs-fMRI and CMRO2 led to satisfactory description of Ki (46%) especially. Ki was sensitive to both local rs-fMRI variables (ReHo) and CMRO2, k3 to ReHo, K1 to CMRO2. This work represents a comprehensive assessment of the complex underpinnings of brain glucose consumption, and highlights links between 1) glucose phosphorylation and local brain activity, 2) glucose delivery and oxygen consumption.

Keywords:  Brain glucose metabolism; kinetic modeling; microparameters; multilevel modeling; spontaneous activity

DOI:  https://doi.org/10.1177/0271678X251329707
Front Immunol. 2025 ;16 1542369

Mitochondrial quality control and transfer communication in neurological disorders and neuroinflammation.

Yinrui Ma, Rui Song, Chenyang Duan.

  Mitochondria, as the primary energy factories of cells, play a pivotal role in maintaining nervous system function and regulating inflammatory responses. The balance of mitochondrial quality control is critical for neuronal health, and disruptions in this balance are often implicated in the pathogenesis of various neurological disorders. Mitochondrial dysfunction not only exacerbates energy deficits but also triggers neuroinflammation through the release of damage-associated molecular patterns (DAMPs), such as mitochondrial DNA (mtDNA) and reactive oxygen species (ROS). This review examines the mechanisms and recent advancements in mitochondrial quality control in neurological diseases, focusing on processes such as mitochondrial fusion and fission, mitophagy, biogenesis, and protein expression regulation. It further explores the role of mitochondrial dysfunction and subsequent inflammatory cascades in conditions such as ischemic and hemorrhagic stroke, neurodegenerative diseases and brain tumors. Additionally, emerging research highlights the significance of mitochondrial transfer mechanisms, particularly intercellular transfer between neurons and glial cells, as a potential strategy for mitigating inflammation and promoting cellular repair. This review provides insights into the molecular underpinnings of neuroinflammatory pathologies while underscoring the translational potential of targeting mitochondrial quality control for therapeutic development.

Keywords:  mitochondrial; mitochondrial quality control; mitochondrial transfer; neuroinflammation; neurological disorders

DOI:  https://doi.org/10.3389/fimmu.2025.1542369
Neuropharmacology. 2025 May 09. pii: S0028-3908(25)00213-8. [Epub ahead of print] 110507

Human milk oligosaccharides improve white matter and interneuron development in a double-hit rat model for preterm brain injury.

Myrna J V Brandt, Juliette Van Steenwinckel, Bobbie-Louise Van Emst, Julia Lohr, Marko Mank, Lidewij Schipper, Louise Harvey, Manon J N L Benders, Caroline G M de Theije.

  Mother's own milk is the preferred source of nutrition for preterm infants due to its beneficial compounds, including human milk oligosaccharides (HMOs). HMOs support microbiota and immune development, but their effect on the preterm brain remains unstudied. Here, we examined the therapeutic potential of HMOs and short-chain galacto- and long-chain fructo-oligosaccharides (scGOS/lcFOS) in a preclinical model for encephalopathy of prematurity. Pregnant Wistar rats were injected with 10μg/kg lipopolysaccharides at embryonic day 20, and pups were exposed to hypoxia (8%O2, 140min) at postnatal day (P)4 (fetal inflammation and postnatal hypoxia; FIPH). From P1, FIPH-pups of both sexes were treated intragastrically with HMOs, scGOS/lcFOS (9:1), or water. Transcriptomic analysis of CD11b/c+ microglia was performed at P6, while immunohistochemical, microbial and short-chain fatty acid (SCFA) analyses were performed at P20. Decreased cortical myelin in FIPH animals was rescued exclusively by HMOs. Furthermore, both HMOs and scGOS/lcFOS treatments normalized reduced parvalbumin+ interneuron numbers in the hippocampus, potentially through promoting beneficial bacteria, including Lactobacillus and Bifidobacterium, and cecal acetic acid content. Interestingly, treatment with HMOs more effectively restored FIPH-induced upregulation of microglial genes associated with immune activation and normalized persistent activated microglial morphology in FIPH-males. HMOs supplementation holds promise to improve neurodevelopmental outcomes following preterm birth.

Keywords:  Encephalopathy of prematurity; human milk oligosaccharides; hypoxia; inflammation; interneuron; myelin deficits; prebiotics

DOI:  https://doi.org/10.1016/j.neuropharm.2025.110507
Sci Rep. 2025 May 14. 15(1): 16715

Single-cell mitochondrial morphomics reveals cellular heterogeneity and predicts complex I, III, and ATP synthase Inhibition responses.

Ratneswary Sutharsan, Maddi Biaut Hontaas, Yan Li, Hao Xiong, Hartwig Preckel, Carolyn M Sue, Gautam Wali.

Mitochondrial heterogeneity drives diverse cellular responses in neurodegenerative diseases, complicating the evaluation of mitochondrial dysfunction. In this study, we describe a high-throughput imaging and analysis approach to investigate cell-to-cell mitochondrial variability. We applied known mitochondrial function inhibitors - rotenone, antimycin, and oligomycin to inhibit complexes I, III, and V (ATP synthase) function in human induced pluripotent stem cell-derived cortical neurons, a model commonly used in neurodegenerative disease research. We captured a large number of cell images and extracted a diverse range of mitochondrial morphological features related to shape, size, texture, and spatial distribution, for an unbiased and comprehensive analysis of mitochondrial morphology. Group-level cell analysis, which examines the collective responses of cells exposed to the same mitochondrial inhibitor, showed that cells treated with rotenone, antimycin, or oligomycin clustered together based on their shared morphological changes. Rotenone and antimycin, both targeting different complexes of the electron transport chain, formed sub-clusters within a larger cluster. In contrast, oligomycin, which inhibits ATP synthase, resulted in a distinct cluster likely due to its differing effect on ATP production. Single-cell analysis using dimensionality reduction techniques revealed distinct subpopulations of cells with varying degrees of sensitivity to each mitochondrial inhibitor, identifying the most affected cells. Mitochondrial feature differential expression analysis showed that neurite-related mitochondrial features, such as intensity and size, were more severely impacted than cell body-related mitochondrial features, particularly with rotenone and antimycin, which target the electron transport chain. In contrast, oligomycin which affects ATP synthesis by directly inhibiting ATP synthase showed relatively less severe alterations in neurite-related mitochondrial features, highlighting a distinct effect of the mode of action between inhibitors. By incorporating the most affected cells into machine learning models, we significantly improved the prediction accuracy of mitochondrial dysfunction outcomes - 81.97% for antimycin, 75.12% for rotenone, and 94.42% for oligomycin. This enhancement underscores the value of targeting highly responsive cell subpopulations, offering a more precise method for evaluating mitochondrial modulators and therapeutic interventions in neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41598-025-99972-z
Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2501177122

Molecular insights into human phosphatidylserine synthase 2 and its regulation of SREBP pathways.

Dongyu Li, Hongwen Chen, Goncalo Vale, Nadia Elghobashi-Meinhardt, Alexandra Hatton, Shunxing Rong, Jeffrey G McDonald, Xiaochun Li.

  Homologous proteins share similar sequences, enabling them to work together in cells to support normal physiological functions. Phosphatidylserine synthases 1 and 2 (PSS1 and PSS2) are homologous enzymes that catalyze the synthesis of phosphatidylserine (PS) from different substrates. PSS2 shows a preference for phosphatidylethanolamine (PE) as its substrate, whereas PSS1 can utilize either PE or phosphatidylcholine. Previous studies showed that inhibiting PSS1 promotes SREBP-2 cleavage. Interestingly, despite their homology, our findings reveal that PSS2 exerts an opposing effect on the cleavage of both SREBP-1 and SREBP-2. We resolved the cryo-electron microscopy (cryo-EM) structure of human PSS2 at 3.3 Å resolution. Structural comparison of the catalytic cavities between PSS1 and PSS2 along with molecular dynamics simulations uncovers the molecular details behind the substrate preference of PSS2 for PE. The lipidomic analysis showed that PSS2 deficiency leads to PE accumulation in the endoplasmic reticulum, which has been shown to inhibit the cleavage of sterol regulatory element-binding proteins (SREBPs) in mice. Thus, our findings reveal the intricate network of intracellular phospholipid metabolism and underscore the distinct regulatory roles of homologous proteins in cellular activities.

Keywords:  SREBP; cryo-EM; phosphatidylethanolamine; phosphatidylserine synthases

DOI:  https://doi.org/10.1073/pnas.2501177122