bims-medebr 2025-11-30 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–11–30
twenty-six papers selected by
Regina F. Fernández, Johns Hopkins University

Inhibition of autophagy-lysosomal function exacerbates microglial and monocyte lipid metabolism reprograming and dysfunction after brain injury.
Consumption of L-Proline as Energy Substrate by Cultured Primary Rat Astrocytes.
The Involvement of Ceramide, Sphingosine-1-Phosphate and Ganglioside GM1 in Regulating Some Nervous System Functions.
Multi-omic analysis reveals lipid dysregulation associated with mitochondrial dysfunction in parkinson's disease brain.
Activity-dependent mitochondrial transport in peri-synaptic glia drives motor function.
Fat for thought: Lipid regulation of neural stem cell fate.
MICU2 controls mitochondrial calcium signaling and migration in neurons during development.
Spatially Resolved Mapping of Monoacylglycerol Lipase Activity in the Brain.
Neuronal subtype-specific metabolic changes in neurodegenerative and neuropsychiatric diseases predicted via a systems biology-based approach.
Harnessing Nanotechnology to Rewire Lipid Metabolism: A Novel Therapeutic Avenue for Brain Cancer.
Loss-of-function variant of SLC27A3 causes mitochondrial dysfunction and a metabolic neurodevelopmental disorder via impaired fatty acid transport.
Knockout of Perilipin-2 in Microglia Alters Lipid Droplet Accumulation and Response to Alzheimer's Disease Stimuli.
Iron Deficiency Impairs Mitochondrial Energetics and Early Axonal Growth and Branching in Developing Hippocampal Neurons.
Lipidomics Reveals Dysregulated Lipid Profiles in Lipopolysaccharide Administration-Induced Cognitive Impairments.
Selected Lipidome Components and Their Association with Perinatal Depression.
Omega-3 Fatty Acid Derived Neuroactive Lipids - Docosahexaenoyl-Glycine and Its Epoxide Metabolites are Multifunctional Lipid Mediators.
Upregulation of sphingomyelin and ABCA8 in response to TDP-43 pathology in amyotrophic lateral sclerosis brain.
Quantification of esterified oxylipins following HILIC-fractionation of lipid classes.
Rewiring Lipid Metabolism: The Central Role of CPT1 in Metabolic Dysfunction.
Inhibition of fatty acid binding protein 5 prevents stress-induced anxiogenic and depressive-like symptoms through modulation of hippocampal neurogenesis, cannabinoid and neurotrophic signaling in the limbic circuitry.
Hydroxycarboxylic Acid Receptor 2 Mediates β-hydroxybutyrate's Antiseizure Effect in Mice.
Synaptic mitochondrial respiration differs between the prefrontal cortex and hippocampus in female, but not male, mice: no effect of chronic stress history.
Lipidomic Signatures in Microglial Extracellular Vesicles During Acute Inflammation: A Gateway to Neurological Biomarkers.
Neuronal activity-induced GLUT3 plasma translocation supports energy demands for memory acquisition.
ATG2 is a triglyceride transfer protein.
Aging increases susceptibility to high-fat diet-induced neurobehavioral and mitochondrial dysfunction in zebrafish.

Res Sq. 2025 Oct 21. pii: rs.3.rs-7682363. [Epub ahead of print]

Inhibition of autophagy-lysosomal function exacerbates microglial and monocyte lipid metabolism reprograming and dysfunction after brain injury.

Marta Lipinski, Amir Mehrabani-Tabari, Nivedita Hegdekar, Brian R Herb, Sazia Arefin Kachi, Chinmoy Sarkar, Sagarina Thapa, Dexter Nguyen, Yulemni Morel, Mehari Weldemariam, Ludovic Muller, W Andrews, Marcia Cortes-Gutierrez, Xiaoxuan Fan, Natarajan Ayithan, Olivia Pettyjohn-Robin, Sabrina Bustos, Lacey Greer, Jessica Gore, Maureen Kane, Seth Ament, Jace Jones.

CNS has an overall higher level of lipids than all tissues except adipose and contains up to 25% of total body cholesterol. Recent data demonstrate a complex crosstalk between lipid metabolism and inflammation, suggesting potential contribution of the lipid-rich brain environment to neuroinflammation. While recent data support the importance of brain lipid environment to inflammatory changes observed in age related chronic neurodegenerative diseases, in vivo interactions between lipid environment, lipid metabolism and neuroinflammation in acute brain disease and injury remain poorly understood. Here we utilize a mouse model of traumatic brain injury (TBI) to demonstrate that acute neurotrauma leads to widespread lipid metabolism reprograming in all microglial and brain associated and infiltrating monocyte populations. Additionally, we identify unique microglial and monocyte populations with higher degree of lipid metabolism reprograming and pronounced accumulation of neutral storage lipids, including cholesteryl esters and triglycerides. These lipids accumulate not only in lipid droplets but also in the microglial and monocyte lysosomes and are associated with lysosomal dysfunction and inhibition of autophagy after TBI. Our data indicate that lipid accumulation in these cells is the result of altered lipid handling rather than lipid synthesis and is triggered by phagocytosis of lipid-rich myelin debris generated after TBI. Finally, we use mice with autophagy defects in microglia and monocytes to demonstrate that further inhibition of autophagy leads to more pronounced lipid metabolism reprograming and exacerbated cellular lipid accumulation. Our data suggest a pathological feedback loop, where lipid phagocytosis causes inhibition of autophagy-lysosomal function, which in turn exacerbates cellular lipid retention, reprograming and inflammation.

DOI: https://doi.org/10.21203/rs.3.rs-7682363/v1
Neurochem Res. 2025 Nov 26. 51(1): 1

Consumption of L-Proline as Energy Substrate by Cultured Primary Rat Astrocytes.

Paul Spellerberg, Ralf Dringen.

  The catabolism of the proteinogenic amino acid L-proline in mammalian cells is mediated by mitochondrial enzymes that can oxidize proline to provide energy for mitochondrial ATP regeneration. To investigate the potential of astrocytes to consume and metabolize L-proline, we incubated cultured primary rat astrocytes with L-proline in the absence or the presence of other energy substrates and investigated L-proline consumption, cellular ATP content and cell viability. In the absence of glucose, the cells consumed L-proline which allowed the cells to maintain a high cellular ATP level as long as extracellular L-proline was detectable. This L-proline consumption was saturable and followed apparent Michaelis-Menten kinetics with a calculated KM value of around 320 µM and a Vmax value of around 100 nmol/(h x mg). In contrast to L-proline, D-proline was not consumed by the cells and was unable to prevent a cellular ATP loss in starved astrocytes. L-Proline consumption was lowered in a concentration-dependent manner by known inhibitors of proline dehydrogenase. The potential of 1 mM L-proline to maintain a high cellular ATP content in starved astrocytes and to prevent cell death was almost identical to that found for 1 mM glucose and a co-application of both substrates had additive ATP-maintaining effects. The presence of L-proline hardly affected the consumption of glucose, while glucose, glucose-derived lactate as well as other energy substrates severely slowed down the astrocytic L-proline consumption. In addition, application of L-proline prevented the rapid loss in cellular ATP level and the subsequent toxicity induced in glucose-deprived astrocytes in the presence of inhibitors of the mitochondrial uptake of pyruvate and fatty acids. These protective effects of proline were abolished by an inhibitor of proline dehydrogenase. The data presented demonstrate that L-proline is an excellent energy substrate for cultured astrocytes especially for conditions of limited availability of other energy substrates.

Keywords:  ATP; Astrocytes; Energy; Metabolism; Mitochondria; Proline

DOI:  https://doi.org/10.1007/s11064-025-04618-1
Int J Mol Sci. 2025 Nov 17. pii: 11118. [Epub ahead of print]26(22):

The Involvement of Ceramide, Sphingosine-1-Phosphate and Ganglioside GM1 in Regulating Some Nervous System Functions.

Paola Giussani, Laura Mauri, Sandro Sonnino.

  Sphingolipids are a large group of molecules, crucial components of all mammalian cells, that are particularly abundant in the central and peripheral nervous system and associated with important human brain functions. Sphingolipids are necessary for membrane organization and driving functions. Ceramide, sphingosine-1-phosphate and GM1, show bioactive properties. Ceramide and sphingosine-1-phosphate play a crucial role in the regulation of physio-pathological conditions. Small changes in their levels, in the ratio sphingosine-1-phosphate/ceramide as well as in chain length profiles of sphingolipids contribute to alter signaling pathways in neurons and glia, contributing to various neurological disorders. GM1 is considered a neurotrophic and neuroprotective compound and seems to be necessary for the correct functioning of neuronal membrane receptors, suggesting that a reduction in its level in the brain can be involved in neurodegenerative diseases. In this review, we give an overview of sphingolipid metabolism, summarizing the role of ceramide, sphingosine-1-phosphate, and GM1 in maintaining human health.

Keywords:  ceramide; gangliosides; glycosphingolipids; nervous system; sphingolipids; sphingosine-1-phosphate

DOI:  https://doi.org/10.3390/ijms262211118
Nat Commun. 2025 Nov 25. 16(1): 10490

Multi-omic analysis reveals lipid dysregulation associated with mitochondrial dysfunction in parkinson's disease brain.

Jenny Hällqvist, Christina E Toomey, Rui Pinto, Tomas Baldwin, Ivan Doykov, Anna Wernick, Mesfer Al Shahrani, James R Evans, Joanne Lachica, Simon Pope, Simon Heales, Simon Eaton, Kevin Mills, Sonia Gandhi, Wendy E Heywood.

Parkinson's disease (PD) is an increasingly prevalent neurodegenerative disorder, largely sporadic in origin, with limited understanding of age- and region-specific lipid alterations in the human brain. Dysregulation of glycosphingolipid catabolism has been implicated in PD, yet comprehensive spatiotemporal profiling remains sparse. Here, we performed targeted lipidomics across eight anatomically distinct brain regions in post-mortem controls, mid-stage, and late-stage PD cases using high-precision tissue dissection. Each region displayed distinct lipid signatures, with several age-associated alterations-most notably in hexosylceramides, including glucosylceramide. In PD, glycosphingolipids were reduced in subcortical regions but elevated in cortical regions, particularly gangliosides, HexCer, and Hex2Cer, accompanied by increased sphingolipids and decreased phospholipids. The most pronounced mid-stage changes occurred in the putamen, where very long chain ceramide species and plasmalogen PE decreased, then normalising in late-stage disease. Lyso-phosphatidylcholine increased progressively throughout PD progression. Integrating proteomic data, we observed sphingomyelin levels associated with PD-related proteins, while dysregulated mitochondrial function correlated with antioxidant plasmalogens, long-chain ceramides, lyso-phosphatidylcholine, and HexCer in the putamen. These findings highlight region- and stage-specific lipid alterations in PD and their potential convergence with mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41467-025-65489-2
bioRxiv. 2025 Oct 25. pii: 2021.11.29.470476. [Epub ahead of print]

Activity-dependent mitochondrial transport in peri-synaptic glia drives motor function.

Dunham D Clark, Sonja A Zolnoski, Emily L Heckman, Michael R Kann, Sarah D Ackerman.

Neurons have an outsized metabolic demand, requiring continuous metabolic support from non-neuronal cells called glia. When this support fails, toxic metabolic byproducts accumulate, ultimately leading to excitotoxicity and neurodegeneration. Astrocytes, the primary synapse-associated glial cell type, are known to provide essential metabolites ( e.g. lactate) to sustain neuronal function. Here, we leverage the well-characterized Drosophila motor circuit to investigate another means of astrocyte-to-neuron metabolic support: activity-dependent trafficking of astrocyte mitochondria. Following optogenetic activation, motor neuron mitochondria migrate away from synapses. By contrast, astrocytic mitochondria accumulated peri-synaptically, and at times, were transferred into neighboring neurons. A genetic screen identified the mitochondrial adaptor protein Milton as a key regulator of this process. Astrocyte-specific milton knockdown disrupted regular mitochondrial trafficking, resulting in locomotor deficits, dysfunctional motor activity, and altered synapse number at the neuromuscular junction. These findings suggest that astrocytes dynamically redistribute mitochondria to buffer metabolic demand at synapses, highlighting a potential mechanism by which glia protect neural circuits from metabolic failure and neurodegeneration.

DOI: https://doi.org/10.1101/2021.11.29.470476
Biomed Pharmacother. 2025 Nov 22. pii: S0753-3322(25)00979-5. [Epub ahead of print]193 118785

Fat for thought: Lipid regulation of neural stem cell fate.

Joan Cabot, Ain Justin Santillan, Paula Férnandez-García, Victoria Llado, Manuel Torres, Pablo V Escribá, Enrico Castroflorio.

  Lipids are increasingly recognized as critical regulators of neurogenesis and neural differentiation, with functions that extend beyond their well-known roles as structural membrane components or energy substrates. Evidence demonstrates that specific lipid species and their bioactive derivatives modulate neural stem cell behavior, influencing proliferation, lineage specification, and maturation. These effects are mediated through multiple mechanisms, including activation of lipid-responsive nuclear receptors, remodeling of membrane microdomains, and metabolic reprogramming of progenitor cells. In addition, interactions between lipids and lipid-binding proteins or enzymes that control lipid turnover have emerged as central nodes governing neuronal fate decisions. Within the neurogenic niches of the developing and adult brain, dynamic alterations in lipid composition shape cellular behavior, and perturbations in lipid signaling are increasingly associated with neurodevelopmental and neuropsychiatric disorders. Here, we review recent advances elucidating how lipids orchestrate neurogenesis and neural differentiation and explore the therapeutic potential of targeting lipid pathways to promote brain repair and modulate disease.

Keywords:  PUFAs; differentiation; lipids; membrane; neurodevelopment; neurogenesis; neuroprotection

DOI:  https://doi.org/10.1016/j.biopha.2025.118785
Cell Rep. 2025 Nov 20. pii: S2211-1247(25)01355-5. [Epub ahead of print]44(12): 116583

MICU2 controls mitochondrial calcium signaling and migration in neurons during development.

Elena Berezhnaya, Benjamín Cartes-Saavedra, Raghavendra Singh, Macarena Rodríguez-Prados, Orly Reiner, Fowzan S Alkuraya, György Hajnóczky.

  Neurological disorders are linked to mitochondrial dysfunction and calcium overload. Mitochondrial calcium uptake is mediated by the mitochondrial calcium uniporter (mtCU), regulated by MICU1, which can be either homodimerized or heterodimerized with MICU2 or MICU3. Though MICU2 is scarce in the adult brain, MICU2 loss in patients leads to a neurodevelopmental disorder. We hypothesized that MICU2 is required for developmental calcium signaling and neuronal migration. MICU2 is present in the developing mouse brain but disappears by maturation, contrasting with other mtCU subunits that increase. MICU2 loss in mice does not affect cytoplasmic calcium but augments the mitochondrial matrix calcium rise in primary cortical neurons, leading to neuronal overmigration in the cortex and behavioral changes at 2 but not 12 months. Consistently, mitochondrial calcium uptake is not significantly affected in the adult animal cortex. MICU2-deficient patient fibroblasts copy the mitochondria-confined calcium alteration in developing neurons. Thus, MICU2 is important during neurodevelopment, likely by regulating the mtCU, and is eliminated by brain maturation.

Keywords:  CP: cell biology; CP: neuroscience; MCU; MICU2; MICU3; anxiety; brain development; calcium signaling; mitochondria; neurodevelopmental disorders; neurons; radial migration

DOI:  https://doi.org/10.1016/j.celrep.2025.116583
ACS Chem Neurosci. 2025 Nov 28.

Spatially Resolved Mapping of Monoacylglycerol Lipase Activity in the Brain.

Daan van der Vliet, Alex X Y Klinkenberg, Rik Platte, Kieran Higgins, Susanne Prokop, Mirjam C W Huizenga, Lars Kraaijevanger, Noëlle van Egmond, Verena M Straub, Maarten H P Kole, Pal Pacher, István Katona, Inge Huitinga, Mario van der Stelt.

  Visualizing signaling systems in the brain with high spatial resolution is critical to understanding brain function and to develop therapeutics. Especially, enzymes are often regulated on the post-translational level, resulting in a disconnect between protein levels and activity. Conventional antibody-based methods have limitations, including potential cross-reactivity and the inability of antibodies to discriminate between active and inactive enzyme states. Monoacylglycerol lipase (MAGL), an enzyme degrading the neuroprotective endocannabinoid 2-arachidonoylglycerol, is the target of inhibitors currently in clinical trials for the treatment of several neurological disorders. To support translational and (pre)clinical studies and fully realize the therapeutic opportunities of MAGL inhibitors, it is essential to map the spatial distribution of MAGL activity throughout the brain in both health and disease. Here, we introduce selective fluorescent activity-based probes for MAGL enabling direct visualization of its enzymatic activity in lysates, cultured cells, and tissue sections. We show that oxidative stress, which inactivates MAGL through the oxidation of regulatory cysteines, reduces probe labeling, thereby validating the probes activity-dependence. Extending this approach, we developed an activity-based histology protocol to visualize MAGL activity in fresh-frozen mouse and human brain tissues. This approach revealed robust MAGL activity in astrocytes and presynaptic terminals within the mouse hippocampus and further allows detection of MAGL activity in the human cerebral cortex. Collectively, these findings establish selective activity-based probes as powerful tools mapping MAGL activity with high spatial resolution across mammalian brain tissue.

Keywords:  activity-based probe; endocannabinoid; fluorescence; hippocampus; histology; microscopy; monoacylglycerol lipase

DOI:  https://doi.org/10.1021/acschemneuro.5c00638
bioRxiv. 2025 Nov 04. pii: 2025.11.03.686281. [Epub ahead of print]

Neuronal subtype-specific metabolic changes in neurodegenerative and neuropsychiatric diseases predicted via a systems biology-based approach.

Boyu Jiang, Shuang Wang, Junkai Xie, Hyunjin Kim, Anke M Tukker, Juexin Wang, Aaron B Bowman, Chongli Yuan, Priyanka Baloni.

Understanding how distinct neuronal subtypes contribute to Alzheimer's disease (AD) pathology remains a major challenge. Patient-derived induced pluripotent stem cell (iPSC) studies have shown neuronal subtype-specific molecular and pathological signatures, yet the underlying metabolic shifts driving this selective vulnerability are not completely understood. Here we present iNeuron-GEM, the first manually curated, genome-scale metabolic network of human neurons that integrates transcriptomic and metabolic knowledge to resolve subtype-specific metabolic states. By coupling iNeuron-GEM with single nucleus RNA sequencing data from post-mortem human cohort studies, ROSMAP and SEA-AD, we capture neuronal subtype-specific metabolic features and fluxes and identify perturbations in lipid and energy metabolism across excitatory and inhibitory neurons. Integrative analysis with NPS-AD data shows overlapping metabolic disruptions in AD and schizophrenia (SCZ), suggesting shared molecular vulnerabilities between neurodegenerative and neuropsychiatric disorders. We also developed a computational pipeline to infer transcriptional regulation of metabolic pathways and identify NR6A1 and NR3C1 as important regulators of lipid dysregulation in AD neurons. Our study establishes iNeuron-GEM as a framework to identify neuronal subtype-specific metabolic vulnerabilities in complex brain disorders.

DOI: https://doi.org/10.1101/2025.11.03.686281
Mol Pharm. 2025 Nov 27.

Harnessing Nanotechnology to Rewire Lipid Metabolism: A Novel Therapeutic Avenue for Brain Cancer.

Somya Ranjan Dash, Krushna Chandra Hembram, Subhajit Chateerjee, Chinmay Das, Biswajit Das.

  The uncontrolled proliferation of abnormal brain cells characterizes brain cancer. It is lethal and develops resistance upon treatment with commonly available modalities, such as chemotherapy and radiotherapy. Findings showed that the altered metabolic programming in brain cancer is one of the major hallmarks that supports the energy expenditures of the malignant cells. As evidenced, brain tumors showed elevated de novo lipid synthesis to support membrane biosynthesis, activation of oncogenic signaling, and energy storage. The most common enzymes required for lipid biosynthesis include fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), and sterol regulatory element-binding proteins (SREBPs), which are found to be upregulated during brain cancer progression. Importantly, altered lipid metabolism not only fuels tumor growth but also modulates the tumor microenvironment (TME), restricting the infiltration of immune cells, inactivating the immune cells, and ultimately promoting the development of therapeutic resistance. Therefore, unraveling how lipid biosynthesis fuels brain cancer progression is of greater importance than ever so that it could unlock new avenues for developing precise and effective targeted therapies. In the past few years, the use of nanotechnology-based delivery systems has shown promising results in selective targeting of lipid metabolic pathways while minimizing secondary toxicities, paving the way for more effective and personalized treatment approaches. This review explains how lipid biosynthesis drives brain cancer progression and the potential of a nanotechnology-based approach to modulate the abnormal lipid metabolism in brain cancer.

Keywords:  brain cancer; lipid biosynthesis; metabolic rewiring; nanotechnology; therapeutic resistance; tumor microenvironment

DOI:  https://doi.org/10.1021/acs.molpharmaceut.5c01091
J Hum Genet. 2025 Nov 25.

Loss-of-function variant of SLC27A3 causes mitochondrial dysfunction and a metabolic neurodevelopmental disorder via impaired fatty acid transport.

S Rehan Ahmad, Nazim Nasir, Anupriya Kumari, Atiq Ul Hassan.

Inborn errors of metabolism (IEMs) lead to early-onset neurodegenerative disorders often caused by mitochondrial dysfunction. In this study, we identified a homozygous frameshift mutation (c.283dupG; p.Cys65LeufsTer13) in SLC27A3, identified through exome sequencing in a 2-month-old female proband presenting with developmental regression, hypotonia, seizure, feeding difficulty, and bilateral putaminal lesions on brain magnetic resonance imaging (MRI). The mutation results in a truncated, non-functional protein and complete loss of SLC27A3 expression in proband-derived fibroblasts. Results show the absence of SLC27A3 and aberrant mitochondrial morphology with clumped networks. Metabolic profiling showed elevated acyl-carnitine levels in the cytosol of proband cells, indicative of disrupted fatty acid oxidation. Additionally, mitochondrial respiratory chain activity was significantly reduced, and flow cytometry revealed increased cell death in mutant cells compared to controls. Protein-protein interaction analysis revealed SLC27A3 networks linked to fatty acid metabolism, ER-associated degradation (ERAD), and ion transport. GO enrichment demonstrated strong associations with transporter activity, protein homeostasis, and ER-mitochondrial membrane networks. Regional expression profiling showed high SLC27A3 transcript levels in the basal ganglia, correlating with the observed neuropathology. These findings position SLC27A3 as a critical lipid transporter involved in neuronal energy metabolism and proteostasis, and implicate its loss in mitochondrial encephalopathy. This study expands the genotypic and phenotypic spectrum of metabolic neurodevelopmental disorders and highlights the importance of fatty acid transport proteins in mitochondrial health and brain development. Our findings propose SLC27A3 as a novel candidate gene for early-onset mitochondrial disorders.

DOI: https://doi.org/10.1038/s10038-025-01435-w
Cells. 2025 Nov 13. pii: 1783. [Epub ahead of print]14(22):

Knockout of Perilipin-2 in Microglia Alters Lipid Droplet Accumulation and Response to Alzheimer's Disease Stimuli.

Isaiah O Stephens, Lance A Johnson.

  Lipid droplets (LDs) are emerging as key regulators of metabolism and inflammation, with their buildup in microglia linked to aging and neurodegeneration. Perilipin-2 (Plin2) is a ubiquitously expressed LD-associated protein that stabilizes lipid stores; in peripheral tissues, its upregulation promotes lipid retention, inflammation, and metabolic dysfunction. Yet, its role in microglia remains unclear. Using CRISPR-engineered Plin2 knockout (KO) BV2 microglia, we examined how Plin2 contributes to lipid accumulation, bioenergetics, and immune function. Compared to wild-type (WT) cells, Plin2 KO microglia showed markedly reduced LD burden under basal and oleic acid-loaded conditions. Functionally, this was linked to enhanced phagocytosis of zymosan particles, even after lipid loading, indicating improved clearance capacity. Transcriptomics revealed genotype-specific responses to amyloid-β (Aβ), especially in mitochondrial metabolism pathways. Seahorse assays confirmed a distinct bioenergetic profile in KO cells, with reduced basal respiration and glycolysis but preserved mitochondrial capacity, increased spare reserve, and a blunted glycolytic response to Aβ. Together, these findings establish Plin2 as a regulator of microglial lipid storage and metabolic state, with its loss reducing lipid buildup, enhancing phagocytosis, and altering Aβ-induced metabolic reprogramming. Targeting Plin2 may represent a strategy to reprogram microglial metabolism and function in aging and neurodegeneration.

Keywords:  Alzheimer’s disease; lipid droplets; lipidomics; microglia; neuroinflammation; phagocytosis

DOI:  https://doi.org/10.3390/cells14221783
bioRxiv. 2025 Oct 15. pii: 2025.10.15.682603. [Epub ahead of print]

Iron Deficiency Impairs Mitochondrial Energetics and Early Axonal Growth and Branching in Developing Hippocampal Neurons.

Daniel C Mendez, Karishma Devgun, Timothy R Monko, Luke H Carlson, Daniel J Mickelson, Lorene M Lanier, Michael K Georgieff, Thomas W Bastian.

Each stage of neuronal development (i.e., proliferation, differentiation, migration, neurite outgrowth and synapse formation) requires functional and highly coordinated metabolic activity to ultimately ensure proper sculpting of complex neural networks. Energy deficits underlie many neurodevelopmental, neuropsychiatric and neurodegenerative diseases implicating mitochondria as a potential therapeutic target. Iron is necessary for neuronal energy output through its direct role in mitochondrial oxidative phosphorylation. Iron deficiency (ID) reduces mitochondrial respiratory and energy capacity in developing hippocampal neurons, causing permanently simplified dendritic arbors and impaired learning and memory. However, the effect of ID on early axonogenesis has not been explored. We used an embryonic mixed-sex primary mouse hippocampal neuron culture model of developmental ID to evaluate mitochondrial respiration and dynamics and effects on axonal morphology. At 7 days in vitro (DIV), ID impaired mitochondrial oxidative phosphorylation capacity and stunted growth of both the primary axon and branches, without affecting branch number. Mitochondrial motility was not altered by ID, suggesting that mitochondrial energy production --- not trafficking --- underlie the axon morphological deficits. These findings provide the first link between iron-dependent neuronal energy production and early axon structural development and emphasize the importance of maintaining sufficient iron during gestation to prevent the negative consequences of ID on brain health across the lifespan.
Significance Statement: This study used a primary mouse hippocampal neuron culture model of iron deficiency to address an important gap in knowledge of how disruption of iron-regulated mitochondrial activities affects axonal development. After axon initiation but prior to rapid dendrite outgrowth, iron chelation reduced mitochondrial oxidative phosphorylation capacity and stunted the growth of the primary axon and branches but without affecting branch number. Mitochondrial motility was not altered in iron-deficient axons, indicating that reduced neuronal energetic capacity and not impaired axonal mitochondrial trafficking may underlie these morphological deficits. Both iron and mitochondrial dyshomeostasis underlies many neurodevelopmental, neuropsychiatric, and neurodegenerative disorders, which can have origins during the period of fetal-neonatal development when rapid axon growth/branching occurs. This study highlights the importance of advancing knowledge on the effects of mitochondrial deficits in early life as it pertains to optimizing brain health throughout the lifespan.

DOI: https://doi.org/10.1101/2025.10.15.682603
Brain Res Bull. 2025 Nov 24. pii: S0361-9230(25)00467-8. [Epub ahead of print] 111655

Lipidomics Reveals Dysregulated Lipid Profiles in Lipopolysaccharide Administration-Induced Cognitive Impairments.

Yali Lu, Yuanyuan Chen, Liangqian Ye, Jun Zhong.

  Sepsis-associated encephalopathy is a frequent complication in critically ill patients and is associated with long-term cognitive impairments. However, the pathophysiology of septic encephalopathy underlying cerebral metabolism, cognition, learning, and memory capabilities is poorly understood. In this study, LC/MS-MS-based metabolomics was used to investigate the cognitive deficit mechanism underlying bacterial lipopolysaccharide (LPS)-induced sepsis-associated encephalopathy. Mice were randomly divided into the vehicle (control), LPS, and LPS + minocycline (LPS+Mino) groups. Minocycline was administered 30min after the LPS administration and daily afterward for 2 days. Behavioral tests were performed starting from day 6 with open field, fear conditioning tests, and T-maze, respectively. LPS-induced sepsis caused a profound alteration of the lipid profile in multiple brain regions. Analyses of lipid profiles revealed that the lipidome was differentially affected among the different brain areas in the LPS-induced septic brain. Following the injection of LPS, more lipid categories were impacted in the cerebral cortex. And glycerophospholipids contributed to a large proportion of those significantly modified lipids in the nucleus accumbens (NAc) and hippocampus. Furthermore, the length and unsaturation of fatty acids were also differentially affected in the LPS-induced septic brain. After being treated with minocycline, the dysregulated lipidomic profiles can be partially reversed, demonstrating the critical roles of dysregulated lipidome in sepsis-associated encephalopathy. Collectively, our results show that sepsis-associated encephalopathy differentially reprograms the lipidomic metabolism among the brain areas, which may underlie its cognitive deficits.

Keywords:  Cognitive Impairments; Lipidomics; Sepsis-associated encephalopathy

DOI:  https://doi.org/10.1016/j.brainresbull.2025.111655
Nutrients. 2025 Nov 17. pii: 3590. [Epub ahead of print]17(22):

Selected Lipidome Components and Their Association with Perinatal Depression.

Dominika Ładno, Beata Nowak, Aleksandra Palka, Dominik Strzelecki, Oliwia Gawlik-Kotelnicka.

  Background/Objectives: Perinatal depression affects approximately 21% of pregnant women and 15% postpartum, significantly impacting both maternal and child health. Lipid metabolism alterations, particularly involving fatty acids and lecithin, have been associated with mood disorders during the perinatal period. Omega-3 PUFAs (polyunsaturated fatty acids) play a key role in mood regulation and neuroinflammatory processes, while lecithin significantly influences neurotransmitter synthesis. Methods: A narrative review was conducted using PubMed, Scopus and Google Scholar for relevant articles which were qualitatively analyzed. Most of the literature included was published between 2020 and 2025 with selected earlier studies used, primarily, to outline the theoretical background. Results: This narrative review highlights substantial evidence linking components of lipidome, particularly omega-3 fatty acids and lecithin, and the occurrence of perinatal depression. Omega-3 deficiency increases antenatal depression risk by up to 6-fold. Inflammation, manifested by elevated levels of inflammatory markers (interleukin-6, tumor necrosis factor, C-reactive protein), and kynurenine pathway activation appear as central mechanisms, both of which can be modulated by PUFAs. Supplementation shows variable outcomes, with greatest efficiency for eicosapentaeonic acid (EPA)-predominant formulations (EPA/DHA ≥ 1.5). Choline is essential for fetal neurodevelopment, though evidence on lecithin and choline is inconclusive. Presumably, excessive intake and trimethylamine N-oxide (TMAO) production may contribute to depressive symptoms. Conclusions: Omega-3 PUFAs deficiency may increase the risk of perinatal depression, while supplementation appears beneficial for prevention. The findings regarding other lipid-derived compounds, specifically choline and lecithin, are inconclusive. Despite promising findings, further research is necessary to confirm the effectiveness of dietary interventions.

Keywords:  lipidome; lipids; perinatal depression

DOI:  https://doi.org/10.3390/nu17223590
bioRxiv. 2025 Oct 17. pii: 2025.10.17.681057. [Epub ahead of print]

Omega-3 Fatty Acid Derived Neuroactive Lipids - Docosahexaenoyl-Glycine and Its Epoxide Metabolites are Multifunctional Lipid Mediators.

Justin S Kim, Luca Franchini, Yevgen Yudin, Anna N Denissiouk, Tibor Rohacs, Cesare Orlandi, Aditi Das.

Lipid mediators derived from ω-3 and ω-6 polyunsaturated fatty acids (PUFAs) support neurological health in part through their oxidative and non-oxidative transformation into a diverse array of bioactive molecules. Among these are lipidated neurotransmitters, formed via conjugation of neurotransmitters with fatty acids such as arachidonic acid (AA) or docosahexaenoic acid (DHA). Previous studies links these lipidated neurotransmitters to beneficial outcomes in neurological diseases. Here, we focus on two such endogenous lipidated neurotransmitters, arachidonoyl glycine (NA-Gly) and docosahexaenoyl glycine (DHA-Gly) and demonstrate their further biotransformation by cytochrome P450 enzymes into epoxidized metabolites. These metabolites are structurally multifunctional, combining both epoxide and glycine moieties. In lipopolysaccharide-stimulated microglial cells, we observe increased formation of NA-Gly and DHA-Gly, correlating with their anti-inflammatory effects. Functionally, these lipidated glycines are selective and act as inverse agonists of G protein-coupled receptor 55 (GPR55) and selectively potentiate transient receptor potential vanilloid 4 (TRPV4), but not TRPV1 or TRPM3 channels. Together, our findings identify NA-Gly, DHA-Gly, and their epoxide derivatives as multifunctional lipid mediators with anti-inflammatory properties and selective receptor modulation, positioning them as potential therapeutic leads in neuroinflammation and reinforce the critical side role of glycine in brain function.
Significance: Lipidated neurotransmitters derived from omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) contribute to neurological health through their conversion into a diverse array of bioactive signaling molecules. In this study, we study docosahexaenoyl glycine (DHA-Gly) and demonstrate their further enzymatic transformation by cytochrome P450 epoxygenases into epoxidized derivatives. These structurally distinct metabolites exhibit anti-inflammatory activity in microglial cells and interact with GPR55 and TRPV4, but not TRPV1 or TRPM3. Our findings highlight a new class of multifunctional lipid mediators with therapeutic potential for targeting neuroinflammation and related neurological disorders.

DOI: https://doi.org/10.1101/2025.10.17.681057
Brain Pathol. 2025 Nov 23. e70053

Upregulation of sphingomyelin and ABCA8 in response to TDP-43 pathology in amyotrophic lateral sclerosis brain.

Finula I Isik, Russell Pickford, Nicolas Dzamko, Kerry-Anne Rye, Woojin Scott Kim.

  Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by the degeneration of motor neurons and the presence of TAR DNA-binding protein 43 (TDP-43) aggregation in the brain. Dyslipidemia is a common feature of ALS, and increasing evidence indicates that lipid dysregulation in the central nervous system underlies ALS pathology. Sphingomyelin is a sphingolipid that is highly enriched in the human brain. However, very little is known about changes in sphingomyelin in the context of ALS brain. We therefore undertook a comprehensive analysis of sphingomyelin in the disease-affected motor cortex and disease-unaffected cerebellum in sporadic ALS with TDP-43 pathology using liquid chromatography-mass spectrometry. We found that sphingomyelin was significantly increased in the ALS motor cortex compared to controls and was strongly associated with disease duration. In contrast, sphingomyelin was unaltered in the cerebellum. The increase in sphingomyelin was associated with an upregulation of ATP-binding cassette subfamily A member 8 (ABCA8), a sphingomyelin transporter, only in the motor cortex of ALS. Importantly, both sphingomyelin and ABCA8 were associated with TDP-43 only in the motor cortex. These results suggest that increases in sphingomyelin and ABCA8 could be a protective response against TDP-43 pathology.

Keywords:  ABCA8; TDP‐43; amyotrophic lateral sclerosis; motor cortex; sphingomyelin

DOI:  https://doi.org/10.1111/bpa.70053
J Lipid Res. 2025 Nov 21. pii: S0022-2275(25)00213-5. [Epub ahead of print] 100950

Quantification of esterified oxylipins following HILIC-fractionation of lipid classes.

Luca M Wende, Laura Carpanedo, Lilli Scholz, Nadja Kampschulte, Annette L West, Philip C Calder, Nils Helge Schebb.

  Several oxylipins are lipid mediators derived from the oxidation of polyunsaturated fatty acids (PUFAs). The majority of oxylipins in biological samples occurs esterified in neutral lipids (nLs) and phospholipids (PLs). They are commonly quantified indirectly following alkaline hydrolysis providing excellent sensitivity but the information in which lipid classes the oxylipins occurred in is lost. The direct analysis of oxidized lipids is currently not sensitive enough to detect all esterified oxylipins. Here, a new hydrophilic interaction liquid chromatography (HILIC) based lipid class fractionation using solid-phase extraction (SPE) cartridges was developed separating lipids into nLs and 4 PL fractions using a single column. Esterified oxylipins in the fractions were quantified following alkaline hydrolysis to sensitively pinpoint in which lipid classes they are bound in plasma. The fractionation was extensively characterized for different lipid extracts demonstrating high separation efficiency and recovery using labeled standards and untargeted analysis of endogenous lipids. Esterified oxylipins in the fractions were quantitatively detected. Based on the results from two independent human plasma pools including SRM1950 it is shown that: hydroxy-linoleic acid- and hydroxy-α-linolenic acid-derived oxylipins are preferably bound to nLs whereas long chain hydroxy-PUFAs and PUFAs (i.e. ARA EPA and DHA) are predominantly esterified to phospholipid classes. Supplementation of n3-PUFAs for 12 months led to an increase in EPA- and -DHA-derived oxylipins in all lipid fractions with the highest increase of hydroxy-PUFAs in nLs. This demonstrates a precursor PUFA-dependent binding of oxylipins and a direct effect of diet on esterified oxylipins in plasma.

Keywords:  esterified oxylipins; fish oil; glycerophospholipids; human plasma; hydrophilic interaction liquid chromatography; lipidomics; nutrition; omega-3 fatty acids; oxidized lipids; solid-phase extraction

DOI:  https://doi.org/10.1016/j.jlr.2025.100950
Prog Biophys Mol Biol. 2025 Nov 20. pii: S0079-6107(25)00064-1. [Epub ahead of print]

Rewiring Lipid Metabolism: The Central Role of CPT1 in Metabolic Dysfunction.

Dan Ni, Yuxuan Liu, Xiaofang Lin, Manqing Luo, Chuanhuan Deng, Jing Li, Pengfei Liang, Zhenguo Liu, Bimei Jiang.

  Carnitine palmitoyltransferase 1 (CPT1) serves as a critical gatekeeper in mitochondrial fatty acid oxidation and plays a central role in systemic energy homeostasis. The CPT1 family comprises three isoforms-CPT1A, CPT1B, and CPT1C-which exhibit distinct tissue distributions and regulatory features, enabling specialized metabolic functions in the liver, heart, skeletal muscle, and brain. CPT1 activity is tightly controlled through multiple mechanisms, including inhibition by malonyl-CoA, epigenetic modifications, and protein-protein interactions, all of which coordinate nutrient sensing and energy adaptation. Dysregulation of CPT1 has been implicated in the development of various metabolic disorders, including obesity, metabolic (dysfunction)-associated fatty liver disease (MAFLD), diabetic cardiomyopathy, and metabolic syndrome. This review summarizes recent advances in understanding the regulatory landscape and pathological roles of CPT1 and further discusses emerging therapeutic strategies. While CPT1-targeted interventions hold promise, challenges such as isoform specificity, off-target effects, and tissue-selective delivery must be addressed to achieve precision metabolic modulation.

Keywords:  CPT1; Energy Metabolism; Fatty Acid Oxidation; Metabolic Diseases

DOI:  https://doi.org/10.1016/j.pbiomolbio.2025.11.002
Neurobiol Dis. 2025 Nov 22. pii: S0969-9961(25)00418-8. [Epub ahead of print]217 107201

Inhibition of fatty acid binding protein 5 prevents stress-induced anxiogenic and depressive-like symptoms through modulation of hippocampal neurogenesis, cannabinoid and neurotrophic signaling in the limbic circuitry.

Taygun C Uzuneser, Matthew J Jones, Mohammed H Sarikahya, Dana Gummerson, Shawn N Whitehead, Daniel B Hardy, Walter J Rushlow, Steven R Laviolette.

  The endocannabinoid (eCB) system modulates many biological processes, including adult neurogenesis, emotional behaviour and stress-related signaling pathways. Intrinsic levels of eCB ligands, such as anandamide, are regulated in part, by fatty acid binding protein 5 (FABP5), a chaperone protein that transports anandamide for hydrolysis. Here, using preclinical rodent models, we examined the effects of pharmacological FABP5 inhibition on anxiety- and depressive-like behaviours and associated molecular signaling pathways, following exposure to chronic stress. In addition, we investigated the impacts of chronic stress on hippocampal neurogenesis and how FABP5 inhibition may modulate stress-induced deficits in hippocampal neurogenic mechanisms. Remarkably, we report that anxiety- and depressive-like behaviours are strongly prevented by systemic FABP5 inhibition and associated with altered transcription of IGF-1, CB2 and GPR55 receptors as well as by altered phosphorylation of Erk1/2, Akt and p70S6 kinase pathways in the limbic circuitry. Finally, FABP5 inhibition potently blocked stress-induced reductions in hippocampal neurogenesis, identifying FABP5 inhibition as a promising pharmacotherapeutic candidate for stress-induced mood and anxiety symptoms.

Keywords:  Adult neurogenesis; Anxiety; Depression; Endocannabinoids; Fatty acid binding protein 5; Limbic system; Pharmacotherapy

DOI:  https://doi.org/10.1016/j.nbd.2025.107201
Ann Neurol. 2025 Nov 26.

Hydroxycarboxylic Acid Receptor 2 Mediates β-hydroxybutyrate's Antiseizure Effect in Mice.

Soudabeh Naderi, John Williamson, Huayu Sun, Suchitra Joshi, Rachel Jane Spera, Savaira Zaib, Supriya Sharma, Chengsan Sun, Andrey Brodovskiy, Ifrah Zawar, Jaideep Kapur.

OBJECTIVE: The ketogenic diet, a high-fat, low-carbohydrate regimen, is often used to treat drug-resistant seizures and is being studied for Alzheimer's disease and other neuropsychiatric disorders. However, its mechanism of action remains unclear. β-hydroxybutyrate, a primary circulating ketone body produced by the ketogenic diet, may mediate its effects on seizures by binding to a recently identified Gi-coupled receptor: hydrocarboxylic acid receptor 2 (HCAR2).
METHODS: RNAscope in situ hybridization assay and real-time quantitative polymerase chain reaction were used to assess HCAR2 expression in the mouse brain. We generated HCAR2-/- using the CRISPR-Cas technique on an S129 mouse background. Whole-cell current-clamp was performed to measure the passive and active membrane properties of hippocampal dentate granule cells. The voltage-clamp was performed to record synaptic currents. Two complementary in vivo mouse models-continuous hippocampal stimulation to induce status epilepticus (SE) and kindling-were used to induce seizures.
RESULTS: HCAR2 was localized in dentate granule cells and microglia. In mice with HCAR2, β-hydroxybutyrate reduced neuronal excitability by hyperpolarizing the resting membrane potential, raising the action potential threshold, and reducing the firing frequency of dentate granule cells. β-hydroxybutyrate suppressed excitatory synaptic transmission. These effects were nullified in HCAR2-/- mice. HCAR2-/- mice showed no cognitive impairment. Moreover, β-hydroxybutyrate did not affect seizures in HCAR2-/- mice. However, it diminished both the duration and severity of seizures in HCAR2+/+ mice.
INTERPRETATION: These findings demonstrate that HCAR2 mediates β-hydroxybutyrate's antiseizure effects by regulating neuronal excitability and synaptic transmission. These studies propose a new mechanism for the antiseizure action of the ketogenic diet. ANN NEUROL 2025.

DOI: https://doi.org/10.1002/ana.78098
Res Sq. 2025 Oct 15. pii: rs.3.rs-7643085. [Epub ahead of print]

Synaptic mitochondrial respiration differs between the prefrontal cortex and hippocampus in female, but not male, mice: no effect of chronic stress history.

Gladys A Shaw, Amy J Wegener, Hannah Stadtler, Gretchen N Neigh.

We evaluated the impact of chronic repeated predation stress (CRPS) on presentation of anxiety-like behavior and synaptic mitochondrial respiration within the prefrontal cortex (PFC) and hippocampus (HPC). Male and female C57Bl/6NTac mice were subject to CRPS for 15 days during their adolescent (PND36-50) and early adult (PND57-71) stages. All animals were assessed for anxiety-like behavior in the open-field assay in adulthood. Brains were collected (PND106-108) and immediately used to assess synaptic mitochondrial respiration with the SeahorseXFe24 instrument. CRPS induced anxiety-like behavior in both male and female mice in the open field, despite not observing stress effects on mitochondrial respiration within either sex. However, females displayed significant region-specific differences that were not reflected within the males. PFC mitochondria respiration was higher the synaptic mitochondrial respiration rates in the HPC across all mitochondrial dynamics in female, but not male, mice. To further understand regional differences in mitochondrial respiration, we analyzed expression of ESR2 and UCP2 as both are indicated in regulation of mitochondrial dynamics. In the HPC, females expressed higher levels of both genes compared to males which may contribute to regional differences in females. Further, hippocampal ESR2 expression was elevated by CRPS in both sexes, suggesting a potential mechanism by which synaptic mitochondria are protected.

DOI: https://doi.org/10.21203/rs.3.rs-7643085/v1
J Neurochem. 2025 Nov;169(11): e70309

Lipidomic Signatures in Microglial Extracellular Vesicles During Acute Inflammation: A Gateway to Neurological Biomarkers.

Nikita Ollen-Bittle, Wenxuan Wang, Kimberly Molina Bean, Shuang Zhao, Adriana Zardini Buzatto, Yifei Dong, Liang Li, Shawn N Whitehead.

  Extracellular vesicles (EVs) are membrane-bound vesicles released from all cells throughout the body, including the central nervous system, and are known to carry both membrane-bound proteins and cargo reflective of their cell of origin. EVs show promise as neurological disease biomarkers due to their molecular makeup reflecting their parent-cell composition signature and due to their ability to cross the blood-brain barrier. To date, the vast majority of research in this field has explored the protein profiles of EVs; however, lipids play an important role not only in the formation of EVs, but also in mediating cellular function and the pathological progression of many neurodegenerative conditions. Herein, we take a critical first step in determining the potential utility of EV lipids as biomarkers in neurological disease. In vitro we exposed BV-2 microglia to either control media or media containing lipopolysaccharides (LPS), a known pro-inflammatory stimulus, for 24 h then isolated both the cells and their EVs and performed LC-MS/MS. For the first time, we reveal distinct lipidomic changes can differentiate resting versus pro-inflammatory microglia and their EVs, while distinct lipids are preserved between EVs and their parent cell. Moreover, we add to current literature by demonstrating acute pro-inflammatory activation of microglia results in the activation and suppression of distinct lipidomic pathways. Finally, we demonstrate that analysis of lipid-based relationships between parent cells and their EVs may be a useful tool to infer cellular function. This study is the first of its kind to demonstrate that lipidomic analysis can not only differentiate the functional state of cells in vitro but can also differentiate their EVs. We lay the first brick in a foundation to support future research into EV lipids as novel and exciting biomarker candidates in neurological disease.

Keywords:  LC‐MS/MS; biomarkers; extracellular vesicles; lipidomics; lipids; microglia; neurological disease

DOI:  https://doi.org/10.1111/jnc.70309
Commun Biol. 2025 Nov 28. 8(1): 1716

Neuronal activity-induced GLUT3 plasma translocation supports energy demands for memory acquisition.

Xin-Yue Wei, Ze-Ming Zou, Zhong-Xiao Yao, Shuai-Wen Teng, Xin-Yu Wei, Wen-Jie Tang, Xiao-Lin Chen, Yun-Zhang He, Zhe-Yu Chen.

Glucose transporter 3 (GLUT3) is crucial for glucose uptake in neurons and rapidly translocates to the plasma membrane in response to neural activity. However, the precise molecular mechanisms and physiological roles of this translocation remain elusive, hindering our understanding of how glucose metabolism supports brain function. This study found that PKCε phosphorylates Thr232 and Ser246 of GLUT3 upon neuronal activation, enhancing its binding to KLC1 and promoting GLUT3 plasma membrane insertion. To investigate the function of GLUT3 plasma translocation, we developed a peptide, TAT-GLUT3(2D), which disrupts GLUT3-KLC1 binding and blocks activity-dependent translocation of GLUT3. By utilizing TAT-GLUT3(2D), we showed that blockage of activity-induced GLUT3 neuronal surface translocation leads to decreased glucose uptake and ATP production, impairing memory acquisition without affecting memory consolidation or retrieval in mice. Our results suggest that PKCε-mediated phosphorylation of GLUT3 is a key regulator of neuronal activity-induced GLUT3 plasma membrane insertion and memory acquisition, advancing our understanding of the energy supply needed for memory acquisition.

DOI: https://doi.org/10.1038/s42003-025-09119-z
Proc Natl Acad Sci U S A. 2025 Dec 02. 122(48): e2517469122

ATG2 is a triglyceride transfer protein.

Justin L Korfhage, Helin Elhan, Neng Wan, Yingying Lu, Lisa Kauffmann, Govindaiah Pilli, Devin M Fuller, Anna M Rios, Karin M Reinisch, Krishna Rao Maddipati, Abdou Rachid Thiam, Thomas J Melia.

  Bridge-like lipid transfer proteins (BLTPs) are established to function in phospholipid transport between bilayers at organelle-organelle contact sites. However, the BLTP ATG2A also associates with lipid droplets in cells, which present a unique phospholipid monolayer topology and which are composed of many additional types of lipids. Whether BLTPs are active in this environment and which lipid species are substrates for transport has been unknown. Here, we use synthetic organelles with bilayers (liposomes), monolayers (artificial lipid droplets), or a mixture of the two membrane structures to demonstrate the tight binding of ATG2 specifically to monolayers via its collection of COOH-terminal amphipathic helices. This stable binding enables ATG2 to transfer phospholipids much more effectively. Unexpectedly, the neutral lipid triacylglycerol is also rapidly transported, with kinetics similar to those of phospholipid transport. Lipidomics of purified ATG2A suggests that a similar transfer of both phospholipids and triacylglycerol occurs in cells. Our work implies that BLTPs likely collect on LDs as part of a broad lipid homeostasis program, which will include the movement of both phospholipids and neutral lipids.

Keywords:  ATG2A; bridge-like lipid transfer; lipid droplet

DOI:  https://doi.org/10.1073/pnas.2517469122
Prog Neuropsychopharmacol Biol Psychiatry. 2025 Nov 20. pii: S0278-5846(25)00318-5. [Epub ahead of print]143 111564

Aging increases susceptibility to high-fat diet-induced neurobehavioral and mitochondrial dysfunction in zebrafish.

Victor L Picolo, Letícia A Tavares, Whitney R Santos, Nathasha P Lopes, Ethiane R Dos Santos, Wembley R Vilela, Angelica Amato, Paula Q Bellozi, Jair T Goulart, Cesar K Grisolia, Daniel Ardisson-Araújo, Andreza F de Bem.

  Aging and unhealthy eating habits independently and synergistically disrupt central nervous system (CNS) homeostasis, increasing susceptibility to neurological and behavioral disorders. Mitochondria plays a critical role in maintaining neuronal survival and activity, representing a central player in the pathogenesis of neurodegenerative diseases. Here, we used zebrafish as a model to investigate how aging and a high-fat diet (HFD) affect brain bioenergetics and behavior. Young (4-6 months) and aged (17-22 months) male zebrafish were fed either a standard diet or an HFD based on boiled chicken egg yolk for 14 days. Brain mitochondria was evaluated using high-resolution respirometry, transmission electron microscopy (TEM), and qRT-PCR. HFD impaired the metabolic health of both young and aged animals, promoting weight gain, increased abdominal length, and elevated fasting glucose levels. Aging intensified the HFD detrimental effects on behavior: aged HFD-fed zebrafish displayed increased anxiety-like behavior in the novel tank test, and impaired cognitive performance in the T-maze test. Notably, HFD had no significant effect on aggressive behavior regardless of age. Mitochondrial responses to HFD differed by age: while cerebral bioenergetic function declined in young fish, aged animals showed an opposite trend. TEM analysis revealed increased accumulation of fragmented mitochondria in HFD group, indicating potential mitochondrial dysfunction. RT-qPCR showed upregulation of genes involved in the electron transport chain, especially in aged zebrafish. In conclusion, our findings demonstrate an age-dependent vulnerability to the effects of HFD on both neurobehavioral and mitochondrial parameters.

Keywords:  Aging; Brain metabolism; Cognitive behavior; High fat diet; Mitochondrial function; Zebrafish

DOI:  https://doi.org/10.1016/j.pnpbp.2025.111564