bims-medebr 2025-02-16 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–02–16
nineteen papers selected by
Regina F. Fernández, Johns Hopkins University

The ELOVL proteins: Very and ultra long-chain fatty acids at the crossroads between metabolic and neurodegenerative disorders.
Blood-Based Lateral-Flow Immunoassays Dipstick Test for Damaged Mitochondrial Electron Transport Chain in Pyruvate Treated Rats with Combined Blast Exposure and Hemorrhagic Shock.
Gangliosides and Cholesterol: Dual Regulators of Neuronal Membrane Framework in Autism Spectrum Disorder.
Multiplatform Lipid Analysis of the Brain of Aging Mice by Mass Spectrometry.
The Supramolecular Architecture of Mitochondrial Complex I in the Rat Brain Is Altered by Alzheimer's-Like Cerebral Amyloidosis.
Gene Expression Profiling in the Cortex of Fabp4 Knockout Mice.
The Essential Role of Sphingolipids in TRPC5 Ion Channel Localization and Functionality within Lipid Rafts.
Impact of fatty acids on glutamate-related gene expression in the hippocampus: Focus on lauric acid.
Mitochondrial Alterations, Oxidative Stress, and Therapeutic Implications in Alzheimer's Disease: A Narrative Review.
Optimization of permeabilized brain tissue preparation to improve the analysis of mitochondrial oxidative capacities in specific subregions of the rat brain.
Neutral sphingomyelinase 2: A promising drug target for CNS disease.
Lipin phosphatidic acid phosphatases: Structure, function, regulation, and disease association.
Exploring the interplay of glucose metabolism, insulin resistance, and neurodegenerative pathologies: insights from streptozotocin and hypoglycaemic in vitro models.
Time Course of Mitochondrial Antioxidant Markers in a Preclinical Model of Severe Penetrating Traumatic Brain Injury.
The role of astrocyte metabolic reprogramming in ischemic stroke (Review).
Influence of alpha-synuclein on glucose metabolism in Alzheimer's disease continuum: Analyses of α-synuclein seed amplification assay and FDG-PET.
Decanoic acid-enriched ketogenic diet in refractory epilepsy.
Neurodegeneration in Autism: A Study of Clusterin, Very Long-Chain Fatty Acids, and Carnitine.
Development of an Oxylipin Library Using Liquid Chromatography-Ion Mobility Quadrupole Time-of-Flight: Application to Mouse Brain Tissue.

Mol Genet Metab. 2025 Feb 04. pii: S1096-7192(25)00041-1. [Epub ahead of print]144(3): 109050

The ELOVL proteins: Very and ultra long-chain fatty acids at the crossroads between metabolic and neurodegenerative disorders.

Enza Ferrero, Frédéric M Vaz, David Cheillan, Alfredo Brusco, Cecilia Marelli.

  In lipid metabolism, the fatty acid (FA) elongation system synthesises a wide array of FAs, crucial for various biological functions. The role of this system is to lengthen FA carbon chains to produce FAs with ≥C16, and notably, very long-chain FAs (VLCFAs, C24-C26) and ultra long-chain FAs (ULCFAs, C28 to ≥C36). Elongation occurs in the endoplasmic reticulum (ER) through the actions of a complex of four ER-embedded enzymes, which includes the ELOVL proteins. Together with desaturases that introduce double bonds, these processes significantly increase the variety of FAs. VLCFAs and ULCFAs are required for the biosynthesis of complex lipids, notably glycero(phospho)lipids, ether(phospho)lipids and sphingolipids. The FA elongation system is therefore fundamental for membrane biogenesis and lipid homeostasis, and also for signalling pathways associated with inflammation and cell proliferation. This review focuses on the elongase enzymes, encoded by the ELOVL genes, which catalyze the first and rate-limiting step of the FA elongation cycle. We summarize the physiological roles of the elongase system, with emphasis on the less-characterized ULCFAs, their biological functions, and the functional tools, biomarkers and lipidomic studies used to study them. Additionally, we discuss how ELOVL enzyme defects contribute to disorders at the intersection of metabolic and neurodegenerative conditions, driven by disrupted lipid metabolism and misfolded enzymes in the ER and Golgi.

Keywords:  ELOVL; Elongase system; Metabolic disorders; Neurodegenerative disorders; Ultra long-chain fatty acids (ULCFA); Very long-chain fatty acids (VLCFA)

DOI:  https://doi.org/10.1016/j.ymgme.2025.109050
J Clin Med. 2025 Jan 24. pii: 754. [Epub ahead of print]14(3):

Blood-Based Lateral-Flow Immunoassays Dipstick Test for Damaged Mitochondrial Electron Transport Chain in Pyruvate Treated Rats with Combined Blast Exposure and Hemorrhagic Shock.

Evans Okonkwo, Biswajit Saha, Geetaram Sahu, Alakesh Bera, Pushpa Sharma.

  Blast trauma presents a unique challenge due to its complex mechanism of injury, which impacts the brain and other vital organs through overpressure waves and internal bleeding. Severe blood loss leads to an inadequate oxygen supply and insufficient fuel delivery to cells, impairing ATP production by mitochondria-essential for cell survival. While clinical symptoms of metabolic disruption are evident soon after injury, the molecular, cellular, and systemic damage persists for days to years post-injury. Current challenges in treating traumatic brain injury (TBI) stem from (1) the lack of early blood-based biomarkers for detecting metabolic failure and mitochondrial damage and (2) the limited success of mitochondrial-targeted therapeutic strategies. Objectives: To identify blood-based mitochondrial biomarkers for evaluating the severity of brain injuries and to investigate therapeutic strategies targeting mitochondria. Methods: A preclinical rat model subjected to blast exposure, with or without hemorrhagic shock (HS), followed by resuscitation was utilized. Blood samples were obtained at baseline (T0), post-injury (T60), and at the conclusion of the experiment (T180), and analyzed using a validated dipstick assay to measure mitochondrial enzyme activity. Results: Blast and HS injuries led to a significant decrease in the activity of mitochondrial enzymes, including complex I, complex IV, and the pyruvate dehydrogenase complex (PDH), compared to baseline (p < 0.05). Concurrently, blood lactate concentrations were significantly elevated (p < 0.001). An inverse correlation was observed between mitochondrial enzyme dysfunction and blood lactate levels (p < 0.05). Treatment with sodium pyruvate post-injury restored complex I, complex IV, and PDH activity to near-baseline levels, corrected hyperlactatemia, and reduced reactive oxygen species (ROS) production by mitochondria. Conclusions: Serial monitoring of blood mitochondrial enzyme activity, such as complex I, complex IV, and PDH, may serve as a valuable tool for prognostication and guiding the use of mitochondrial-targeted therapies. Additionally, mitochondrial enzyme assays in blood samples can provide insights into the global redox status, potentially paving the way for novel therapeutic interventions in TBI.

Keywords:  PDH; blast injury; complex IV; enzyme activity; hemorrhagic shock; mitochondrial complex I; plasma lactate; sodium pyruvate resuscitation

DOI:  https://doi.org/10.3390/jcm14030754
Int J Mol Sci. 2025 Feb 04. pii: 1322. [Epub ahead of print]26(3):

Gangliosides and Cholesterol: Dual Regulators of Neuronal Membrane Framework in Autism Spectrum Disorder.

Borna Puljko, Marija Štracak, Svjetlana Kalanj-Bognar, Ivana Todorić Laidlaw, Kristina Mlinac-Jerkovic.

  Autism spectrum disorder (ASD) is a neurodevelopmental disorder with heterogeneous clinical presentation. Diagnosing ASD is complex, and the criteria for diagnosis, as well as the term ASD, have changed during the last decades. Diagnosis is made based on observation and accomplishment of specific diagnostic criteria, while a particular biomarker of ASD does not yet exist. However, studies universally report a disequilibrium in membrane lipid content, pointing to a unique neurolipid signature of ASD. This review sheds light on the possible role of cholesterol and gangliosides, complex membrane glycosphingolipids, in the development of ASD. In addition to maintaining membrane integrity, neuronal signaling, and synaptic plasticity, these lipids play a role in neurotransmitter release and calcium signaling. Evidence linking ASD to lipidome changes includes low cholesterol levels, unusual ganglioside levels, and unique metabolic profiles. ASD symptoms may be mitigated with therapeutic interventions targeting the lipid composition of membranes. However, restoring membrane equilibrium in the central nervous system remains a challenge. This review underscores the need for comprehensive research into lipid metabolism to uncover practical insights into ASD etiology and treatment as lipidomics emerges as a major area in ASD research.

Keywords:  autistic disorder; glycosphingolipids; lipid rafts; lipidome; sphingolipids

DOI:  https://doi.org/10.3390/ijms26031322
J Proteome Res. 2025 Feb 08.

Multiplatform Lipid Analysis of the Brain of Aging Mice by Mass Spectrometry.

Punyatoya Panda, Christina R Ferreira, Bruce R Cooper, Allison J Schaser, Uma K Aryal.

  Lipids are critical to brain structure and function, accounting for approximately 50% of its dry weight. However, the impact of aging on brain lipids remains poorly characterized. To address this, here we applied three complementary mass spectrometry techniques: multiple reaction monitoring (MRM) profiling, untargeted liquid chromatography tandem mass spectrometry (LC-MS/MS), and desorption electrospray ionization-MS imaging (DESI-MSI). We used brains from mice of three age groups: adult (3-4 months), middle-aged (10 months), and old (19-21 months). Phospholipids such as phosphatidylcholine, phosphatidylethanolamine, and phosphatidylglycerol were more abundant, while phosphatidylinositol and phosphatidylserine were reduced in old mice compared to adults or middle-aged mice. Key lipids such as polyunsaturated fatty acids, including DHA, AA, HexCer, SHexCer, and SM, were among the most abundant lipids in aged brains. DESI-MSI revealed spatial lipid distribution patterns consistent with findings from MRM profiling and LC-MS/MS. Integration of lipidomic data with the recently published proteomics data from the same tissues highlighted changes in proteins and phosphorylation levels of several proteins associated with Cer, HexCer, FA, PI, SM, and SHexCer metabolism, aligning with the multiplatform lipid surveillance. These findings shed insight into age-dependent brain lipid changes and their potential contribution to age-related cognitive decline.

Keywords:  DESI imaging; aging; proteomics; targeted lipidomics; untargeted lipidomics

DOI:  https://doi.org/10.1021/acs.jproteome.4c00688
J Neurochem. 2025 Feb;169(2): e70017

The Supramolecular Architecture of Mitochondrial Complex I in the Rat Brain Is Altered by Alzheimer's-Like Cerebral Amyloidosis.

Gisela V Novack, Pablo Galeano, Lucas A Defelipe, Lorenzo Campanelli, Karen S Campuzano, Cecilia Rotondaro, Eduardo M Castaño, Sonia Do Carmo, A Claudio Cuello, María M García-Alai, Laura Morelli.

  Mitochondrial respiratory complexes are organized into supercomplexes (SC) to regulate electron flow and mitigate oxidative stress. Alterations in SC organization in the brain may affect energy expenditure, oxidative stress, and neuronal survival. In this report, we investigated the amount, activity and organization of mitochondrial complex I (CI) in the hippocampus of 12-month-old McGill-R-Thy1-APP transgenic (Tg) rats, an animal model of Alzheimer's-like cerebral amyloidosis. By means of BN-PAGE, we found that the organization of SC did not differ between genotypes, but a lower abundance of SC was detected in Tg compared to wild-type (WT) rats. Using a more sensitive technique (2-D electrophoresis followed by Western blot), higher levels of free CI and a decrease in the relative abundance of assembled CI in SC (I-III2 and I-III2-IV) were observed in Tg rats. In-gel activity assays showed that the total activity of CI (CI + SC-CI) is lower in Tg compared to WT, while Tg samples show a significant decrease in SC-CI-associated activity. This alteration in CI assembly was associated with nitro-oxidative stress and changes in mitochondrial fusion-fission parameters. To assess CI composition, we applied LC-MS/MS to the isolated CI from BN-PAGE and found that 11 of 45 subunits described in mammals were found to be less abundant in Tg. We examined the levels of the nuclear-derived NDUFA9 subunit, which is critical for CI assembly, and found higher levels in the cytoplasmic fraction and lower levels in the mitochondrial fraction in Tg, suggesting that brain amyloidosis affects the import of CI subunits from the cytosol to the mitochondria, destabilizing the SC. This is the first report to characterize the types, abundance and activity of SC in the hippocampus of an animal model of cerebral amyloidosis, providing additional experimental evidence for the molecular mechanisms underlying the brain bioenergetic deficit characteristic of Alzheimer's disease.

Keywords:  OXPHOS; mitochondria; native electrophoresis; neurodegeneration; nitroxidative stress; supercomplexes

DOI:  https://doi.org/10.1111/jnc.70017
Neuropsychopharmacol Rep. 2025 Mar;45(1): e70006

Gene Expression Profiling in the Cortex of Fabp4 Knockout Mice.

Hinako Kirikae, Xiaofeng He, Tetsuo Ohnishi, Hirofumi Miyazaki, Takeo Yoshikawa, Yuji Owada, Motoko Maekawa.

   AIMS: Fatty acid binding protein 4, adipocyte (Fabp4), is well known for its role in peripheral lipid metabolism, but its potential role in brain function remains largely unexplored. This study aimed to investigate Fabp4 expression in the adult mouse brain and explore gene expression changes in Fabp4 knockout (KO) mice to assess its potential impact on brain function.
METHODS: We conducted in situ hybridization to assess Fabp4 expression in key brain regions of adult mice. In parallel, differential gene expression analysis using RNA-seq was conducted in the prefrontal cortex of Fabp4 KO mice to identify genes affected by Fabp4 deficiency.
RESULTS: No Fabp4 expression was detected in the brains of mice, suggesting a lack of direct involvement in the central nervous system. However, Fabp4 KO mice exhibited significant changes in gene expression in the brain, with 31 genes upregulated and 30 downregulated. Downregulated genes were linked to histone methylation and metabolic processes, while upregulated ones were associated with synaptic organization.
CONCLUSION: Although Fabp4 is not expressed in the brain, its deficiency leads to substantial changes in gene expression, likely mediated by peripheral metabolic pathways and epigenetic regulation. These changes may explain the previously observed autism-like behaviors and increased dendritic spine density in Fabp4 KO mice. This study sheds light on the role of systemic lipid metabolism in neurodevelopmental disorders such as autism spectrum disorder (ASD) and highlights epigenetic mechanisms as potential mediators of these effects.

Keywords:  Fabp4 knockout (KO) mice; RNA‐seq; autism spectrum disorder; epigenetic gene expression; synaptic gene expression

DOI:  https://doi.org/10.1002/npr2.70006
Pharmacol Res. 2025 Feb 07. pii: S1043-6618(25)00073-8. [Epub ahead of print] 107648

The Essential Role of Sphingolipids in TRPC5 Ion Channel Localization and Functionality within Lipid Rafts.

Junliang Wan, Zhenying Hu, Huaiyi Zhu, Jingyi Li, Ziyuan Zheng, Zhitao Deng, Junyan Lu, Yu Chen, Gui-Lan Chen, Bo Zeng, Jin Zhang, Jingjing Duan.

  Sphingolipids are critical components of cellular membranes that play a pivotal role in modulating ion channel function by forming lipid rafts that stabilize and localize these channels. These lipids regulate membrane fluidity and protein-lipid interactions, directly influencing ion channel activity, trafficking, and signaling pathways essential for maintaining cellular homeostasis. Despite their fundamental role, the impact of sphingolipids on ion channel functionality, particularly within the nervous system, remains insufficiently understood. This study addresses this gap by examining the influence of sphingolipids on transient receptor potential canonical 5 (TRPC5), a key brain ion channel involved in sensory transduction and linked to conditions such as obesity, anxiety, and postpartum depression when disrupted. In this study, we demonstrate that TRPC5 is localized within lipid rafts. Inhibition of sphingolipid synthesis through myrioncin (Myr), the sphingomyelin synthase 2 inhibitor Ly93, or D,L-erythro-PDMP hydrochloride (PMDP) significantly disrupts TRPC5 localization at the plasma membrane. Treatment with lipid raft disruptors methyl-β-cyclodextrin (MCD) or sphingomyelin phosphodiesterase 3 (SMPD3), in conjunction with sphingolipid synthesis inhibitors, led to decreased TRPC5-mediated calcium flux and currents. This highlights the critical importance of TRPC5 localization in lipid rafts for its functionality. Furthermore, LC-MS/MS-based sphingolipidomics has shown that a balanced sphingolipid profile is crucial for channel function. Alterations in sphingolipid metabolism, especially the deficiency of sphingomyelin and glycosphingolipids, may primarily disrupt lipid raft structure. Interactions between amino acid residues with phenyl ring side chains and lipids at the inner and outer plasma membrane edges serve as 'fixators', anchoring TRPC5 channels within lipid rafts. Given the structural similarities among TRP channels, we propose that sphingolipid metabolic homeostasis may universally influence TRP channel activity, potentially explaining diverse neurological disorder phenotypes associated with sphingolipid metabolism disruptions.

Keywords:  Sphingolipids; TRPC5; ion channel; lipid metabolism; lipid raft

DOI:  https://doi.org/10.1016/j.phrs.2025.107648
Neurosci Lett. 2025 Feb 07. pii: S0304-3940(25)00040-0. [Epub ahead of print]850 138152

Impact of fatty acids on glutamate-related gene expression in the hippocampus: Focus on lauric acid.

Laura Romero-Muñoz, Ana Belén Sanz-Martos, Nuria Del Olmo, Beatriz Merino, Mariano Ruiz-Gayo, Victoria Cano.

  Excessive dietary fat consumption has been linked to impairments in synaptic plasticity in the hippocampus (HIP), a brain region crucial for learning and memory that relies on balanced glutamatergic neurotransmission. This study investigates the acute effects of three fatty acids (FAs)-lauric acid (LA), palmitic acid (PA), and oleic acid (OA)-on glutamate (GLU)-related gene expression in the HIP of male and female young mice. Hippocampal slices were treated with FAs, and mRNA levels of genes involved in GLU transport, GLU-glutamine (GLN) cycling, and GLU receptor subunit encoding were quantified using RT-PCR. FA treatment reduced mRNA levels of enzymes involved in the conversion of GLU to GLN (glutamine synthetase; GS), GABA (glutamate decarboxylase 1; GAD67), and α-ketoglutarate (glutamate pyruvate transaminase 2; AAT2). Additionally, the expression of glutamine transporters (SNAT1, SNAT2, SNAT3), the astrocytic GLU transporter GLT-1, and the NMDA receptor subunit NMDA2a was also reduced. These effects were most pronounced with LA. Notably, while the HIP showed similar sensitivity to fatty acids across sexes, overall gene expression levels were lower in females. These findings highlight the acute susceptibility of hippocampal GLU-related pathways to FA exposure, particularly LA, suggesting potential risks of high-LA diets on cognitive function. Further research is needed to explore the long-term consequences of dietary fat on hippocampal health and its sex-specific effects.

Keywords:  Dietary fatty acids; Glutamate neurotransmission; Glutamate-glutamine cycle; Hippocampus; Sex-differences

DOI:  https://doi.org/10.1016/j.neulet.2025.138152
Cells. 2025 Feb 06. pii: 229. [Epub ahead of print]14(3):

Mitochondrial Alterations, Oxidative Stress, and Therapeutic Implications in Alzheimer's Disease: A Narrative Review.

Erica Spina, Riccardo Rocco Ferrari, Elisa Pellegrini, Mauro Colombo, Tino Emanuele Poloni, Antonio Guaita, Annalisa Davin.

  The relationship between aging, mitochondrial dysfunction, neurodegeneration, and the onset of Alzheimer's disease (AD) is a complex area of study. Aging is the primary risk factor for AD, and it is associated with a decline in mitochondrial function. This mitochondrial dysfunction is believed to contribute to the neurodegenerative processes observed in AD. Neurodegeneration in AD is characterized by the progressive loss of synapses and neurons, particularly in regions of the brain involved in memory and cognition. It is hypothesized that mitochondrial dysfunction plays a pivotal role by disrupting cellular energy metabolism and increasing the production of reactive oxygen species (ROS), which can damage cellular components and exacerbate neuronal loss. Despite extensive research, the precise molecular pathways linking mitochondrial dysfunction to AD pathology are not fully understood. Various hypotheses have been proposed, including the mitochondrial cascade hypothesis, which suggests that mitochondrial dysfunction is an early event in AD pathogenesis that triggers a cascade of cellular events leading to neurodegeneration. With this narrative review, we aim to summarize some specific issues in the literature on mitochondria and their involvement in AD onset, with a focus on the development of therapeutical strategies targeting the mitochondria environment and their potential application for the treatment of AD itself.

Keywords:  Alzheimer’s disease; aging; mitochondria; mitochondrial dysfunction

DOI:  https://doi.org/10.3390/cells14030229
J Neurosci Methods. 2025 Feb 05. pii: S0165-0270(25)00028-7. [Epub ahead of print] 110387

Optimization of permeabilized brain tissue preparation to improve the analysis of mitochondrial oxidative capacities in specific subregions of the rat brain.

Léa Dorémus, Emilie Dugast, Arnaud Delafenêtre, Morgane Delouche, Thomas Aupy, Olivier Bernard, Stéphane Sebille, Nathalie Thiriet, Jérôme Piquereau.

   BACKGROUND: As the major energy producer of cerebral tissue, mitochondria play key roles in brain physiology and physiopathology. Yet, the fine details of the functioning of mitochondrial oxidative phosphorylation in this organ are still scattered with grey area. This is partly due to the heterogeneity of this tissue that challenges our abilities to study specific cerebral subregions. In the last decades, cerebral mitochondria have largely been studied as a single entity by isolating mitochondria from large sections of brain. Given the evidence that these organelles must adapt to brain areas functions, it seems crucial to develop technologies enabling study of the mitochondria in given subregions.
NEW METHOD: A few years ago, a method allowing the investigation of mitochondrial functions in permeabilized brain subregions have been proposed by Holloway's team. Although this protocol represented a significant advance, we propose improvements in the tissue permeabilization procedure and in the conditions for measuring oxidative capacity.
RESULTS AND COMPARISON WITH EXISTING METHODS: The present study demonstrates that adjustments enabled obtention of higher respiration values than Holloway's protocol and might allow the detection of slight mitochondrial alterations. In a second part of this study, we showed that cortex, striatum, hippocampus and cerebellum displayed similar maximal oxidative capacities (under pyruvate, malate and succinate) while complex IV-driven respiration is significantly lower in cerebellum compared to cortex. These observations were supported by the measurement of citrate synthase and cytochrome oxidase activities.
CONCLUSION: The developed procedure improves the investigations of mitochondrial electron transfer chain in specific cerebral regions.

Keywords:  cerebral subregions; mitochondrial functions; mitochondrial oxidative capacities; permeabilized tissue

DOI:  https://doi.org/10.1016/j.jneumeth.2025.110387
Adv Pharmacol. 2025 ;pii: S1054-3589(24)00047-4. [Epub ahead of print]102 65-101

Neutral sphingomyelinase 2: A promising drug target for CNS disease.

Meixiang Huang, Matthew Stremlau, Jason Zavras, Cristina Zivko, Ajit G Thomas, Peter Pietri, Vasiliki Machairaki, Barbara S Slusher.

  Neutral sphingomyelinase 2 (nSMase2), encoded by the SMPD3 gene, is a pivotal enzyme in sphingolipid metabolism, hydrolyzing sphingomyelin to produce ceramide, a bioactive lipid involved in apoptosis, inflammation, membrane structure, and extracellular vesicle (EV) biogenesis. nSMase2 is abundantly expressed in the central nervous system (CNS), particularly in neurons, and its dysregulation is implicated in pathologies such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), prion diseases, and neuroviral diseases. In this review, we discuss the critical role of nSMase2 in the CNS and its involvement in neurological as well as non-neurological diseases. We explore the enzyme's functions in sphingolipid metabolism, its regulatory mechanisms, and the implications of its dysregulation in disease pathogenesis. The chapter highlights the therapeutic potential of pharmacologically targeting nSMase2 with small molecule inhibitors and emphasizes the need for further research to optimize inhibitor specificity and efficacy for clinical applications. By understanding the multifaceted roles of nSMase2, we aim to provide insights into novel therapeutic strategies for treating complex diseases associated with its dysregulation.

Keywords:  Alzheimer’s disease (AD); Amyotrophic lateral sclerosis (ALS); Central nervous system; Ceramide; Extracellular vesicles (EVs); Neuroviral infections; Parkinson’s disease (PD); Prion diseases; SMPD3; Sphingomyelin; nSMase2

DOI:  https://doi.org/10.1016/bs.apha.2024.10.015
Adv Biol Regul. 2025 Feb 10. pii: S2212-4926(25)00009-0. [Epub ahead of print] 101082

Lipin phosphatidic acid phosphatases: Structure, function, regulation, and disease association.

Franceine S Welcome, Taisha C M Elizaire, Michael V Airola.

Lipids play essential roles as structural barriers in cell membranes, long-term energy storage, and as signaling molecules. One class of enzymes involved in lipid synthesis are lipins. Lipins are magnesium-dependent phosphatidic acid phosphatases that produce diacylglycerol, playing key roles in TAG synthesis, de novo phospholipid synthesis and metabolism. Here, we review recent advances on the structure, function, and regulation of lipins with a particular focus on the structural impacts of missense mutations associated with rhabdomyolysis, Majeed syndrome and neuropathies. Structural insights reveal that while some disease-associated mutations directly disrupt catalysis, many missense mutations are not near the active site, but still play a key role in PAP activity. With the resolved crystal structure of a lipin homolog Tt Pah2, AlphaFold, and AlphaMissense it has become increasingly possible to predict the pathogenicity and structural contributions of individual residues and mutations. Going forward, this structural information can be used to predict and understand new mutations as they arise.

DOI: https://doi.org/10.1016/j.jbior.2025.101082
J Neural Transm (Vienna). 2025 Feb 11.

Exploring the interplay of glucose metabolism, insulin resistance, and neurodegenerative pathologies: insights from streptozotocin and hypoglycaemic in vitro models.

Edna Grünblatt, Cristine Marie Yde Ohki, G Angelika Schmitt-Böhrer, Peter Riederer, Susanne Walitza.

  Neurodegenerative diseases raise public health concerns. Recent evidence indicates that Alzheimer's disease (AD) sufferers will triple by 2050. The rising incidence of dementia diagnoses raises concerns about the socio-economical and emotional impact of this uncurable illness, which reduces quality of life through cognitive decline. Although genetic and environmental factors may contribute to its aetiology, neuropathological mechanisms underlying these disorders are still under investigation. One is brain insulin resistance (BIR), which has been associated with clinical cognitive dysfunction and linked to mitochondrial dysfunction, neurogenesis deficits, and cell death. Not limited to neurodegeneration, these phenotypes have been associated with other neuropsychiatric disorders. Streptozotocin (STZ), a diabetes-causing drug that targets pancreatic β-cells, may imitate BIR in suitable models. From patients' neuroimaging to in vitro approaches, scientists have been striving to understand the pathophysiology of such disorders at the behavioural, molecular, and cellular levels. Although animal models are useful for studying insulin resistance's systemic effects, in vitro phenotypic research represents an alternative to study molecular and cellular aspects. STZ and hypoglycaemia-like scenarios have been successful for studying neurodegenerative disorders in primary cell culture (e.g., neuroblastoma cells) and patient-specific neural cell lines derived from pluripotent stem cells (iPSCs). Intriguingly, STZ treatment or hypoglycaemia-like conditions in a dish were able to induce AD pathological characteristics such Aβ plaque deposition and Tau protein hyperphosphorylation. Such approaches have shown potential in understanding molecular and cellular implications of metabolic changes in neuropsychiatric disorders, according to this review. Furthermore, these models may help identify novel treatment targets.

Keywords:  Alzheimer’s disease; Astrocytoma; Brain insulin resistance; HT22; Hypoglycaemia; In vitro; N2A; Neuroblastoma; Neuropsychiatric disorders; PC12; Primary cells; SH-SY5Y; SK-N-MC; Streptozotocin; iPSC

DOI:  https://doi.org/10.1007/s00702-025-02891-6
Int J Mol Sci. 2025 Jan 22. pii: 906. [Epub ahead of print]26(3):

Time Course of Mitochondrial Antioxidant Markers in a Preclinical Model of Severe Penetrating Traumatic Brain Injury.

Sudeep Musyaju, Hiren R Modi, Deborah A Shear, Anke H Scultetus, Jignesh D Pandya.

  Traumatic brain injury (TBI) results from external mechanical forces exerted on the brain, triggering secondary injuries due to cellular excitotoxicity. A key indicator of damage is mitochondrial dysfunction, which is associated with elevated free radicals and disrupted redox balance following TBI. However, the temporal changes in mitochondrial redox homeostasis after penetrating TBI (PTBI) have not been thoroughly examined. This study aimed to investigate redox alterations from 30 min to two-weeks post-injury in adult male Sprague Dawley rats that experienced either PTBI or a Sham craniectomy. Redox parameters were measured at several points: 30 min, 3 h, 6 h, 24 h, 3 d, 7 d, and 14 d post-injury. Mitochondrial samples from the injury core and perilesional areas exhibited significant elevations in protein modifications including 3-nitrotyrosine (3-NT) and protein carbonyl (PC) adducts (14-53%, vs. Sham). In parallel, antioxidants such as glutathione, NADPH, peroxiredoxin-3 (PRX-3), thioredoxin-2 (TRX-2), and superoxide dismutase 2 (SOD2) were significantly depleted (20-80%, vs. Sham). In contrast, catalase (CAT) expression showed a significant increase (45-75%, vs. Sham). These findings indicate a notable imbalance in redox parameters over the two-week post-PTBI period suggesting that the therapeutic window to employ antioxidant therapy extends well beyond 24 h post-TBI.

Keywords:  antioxidants; free radicals; mitochondrial dysfunction; oxidative stress; penetrating traumatic brain injury; time course

DOI:  https://doi.org/10.3390/ijms26030906
Int J Mol Med. 2025 03;pii: 49. [Epub ahead of print]55(3):

The role of astrocyte metabolic reprogramming in ischemic stroke (Review).

Weixin Chen, Tangyou Mao, Rui Ma, Yuxuan Xiong, Ran Han, Le Wang.

  Ischemic stroke, a leading cause of disability and mortality worldwide, is characterized by the sudden loss of blood flow in specific area of the brain. Intravenous thrombolysis with recombinant tissue plasminogen activator is the only approved pharmacological treatment for acute ischemic stroke; however, the aforementioned treatment has significant clinical limitations, thus there is an urgent need for the development of novel mechanisms and therapeutic strategies for ischemic stroke. Astrocytes, abundant and versatile cells in the central nervous system, offer crucial support to neurons nutritionally, structurally and physically. They also contribute to blood‑brain barrier formation and regulate neuronal extracellular ion concentrations. Accumulated evidence has revealed the involvement of astrocytes in the regulation of host neurotransmitter metabolism, immune response and tissue repair, and different metabolic characteristics of astrocytes can contribute to the process and development of ischemic stroke, suggesting that targeted regulation of astrocyte metabolic reprogramming may contribute to the treatment and prognosis of ischemic stroke. In the present review, the current understanding of the multifaceted mechanisms of astrocyte metabolic reprogramming in ischemic stroke, along with its regulatory factors and pathways, as well as the strategies to promote its polarization balance, which hold promise for astrocyte immunometabolism‑targeted therapies in the treatment of ischemic stroke, were summarized.

Keywords:  astrocyte; immunometabolism; ischemic stroke; metabolic reprogramming; strategies

DOI:  https://doi.org/10.3892/ijmm.2025.5490
Alzheimers Dement. 2025 Feb;21(2): e14571

Influence of alpha-synuclein on glucose metabolism in Alzheimer's disease continuum: Analyses of α-synuclein seed amplification assay and FDG-PET.

Alzheimer's Disease Neuroimaging Initiative

   INTRODUCTION: We investigated the association between alpha-synuclein (α-syn) pathology and brain glucose metabolism across the cognitive spectrum of Alzheimer's disease (AD) co-pathologies.
METHODS: Fluorodeoxyglucose positron emission tomography (FDG-PET) data from 829 Alzheimer's Disease Neuroimaging Initiative participants (648 cognitively impaired [CI], 181 unimpaired [CU]) were compared between α-syn seed amplification assay (SAA) positive and negative groups. Interactions with cerebrospinal fluid (CSF) AD biomarkers were examined.
RESULTS: SAA+ was associated with widespread hypometabolism among CI individuals, particularly in posterior cortical regions, independent of CSF amyloid and tau levels in the occipital lobes. Regional hypometabolism mediated the effect of α-syn SAA on disease severity in CI individuals, independent of CSF amyloid and tau levels. There were no influences of SAA on FDG-PET in CU individuals.
DISCUSSION: This study supports a model in which α-syn aggregation influences metabolic dysfunction, which then influences clinical disease severity, independent of AD. SAA+ could help optimize participant selection and outcome measures for clinical trials in AD.
HIGHLIGHTS: α-synuclein seed amplification positivity (SAA+) was associated with hypometabolism in cognitively impaired individuals. Hypometabolism mediated the influence of α-synuclein on disease severity. Occipital hypometabolism in SAA+ was independent of cerebrospinal fluid levels of Alzheimer's disease pathology. These findings can optimize future clinical trials targeting α-synuclein pathology.

Keywords:  Alzheimer's disease; Lewy bodies; alpha‐synuclein; amyloid beta; biomarkers; brain metabolism; cognitive impairment; fluorodeoxyglucose positron emission tomography; neurodegeneration; seed amplification assay; tau

DOI:  https://doi.org/10.1002/alz.14571
Front Neurol. 2025 ;16 1524799

Decanoic acid-enriched ketogenic diet in refractory epilepsy.

Hui Jin Shin, Seonae Ryu, NaRae Lee, Eunjoo Lee, Ara Ko, Hoon-Chul Kang, Joon Soo Lee, Se Hee Kim, Heung Dong Kim.

   Objective: To assess the anti-seizure efficacy and safety of a C10-enriched medium-chain triglyceride (MCT) ketogenic diet (KD) compared with the classic KD in pediatric patients with refractory epilepsy.
Methods: This 16-week, open-label, randomized, controlled, crossover pilot study was conducted at Severance Children's Hospital, Seoul, South Korea, between August 2022 and September 2023. Fifteen pediatric patients with refractory epilepsy were enrolled and received classic KD and C10-enriched KD for 8 weeks each. The study compared seizure reduction rate, tolerability, and safety of the two diets.
Results: Fifteen patients were enrolled. Patients were divided into 2 groups depending on the type of KD initiated. Ten patients completed the trial. Initial treatment with the C10-enriched KD resulted in seizure reduction in all five patients, with two becoming seizure-free. Initial treatment with classic KD was effective in two out of five patients. Upon crossover, those initially on C10-enriched KD maintained their seizure reduction, while patients initially on the classic KD showed additional seizure reduction when switched to C10-enriched KD. Adverse effects included transient hypoglycemia, metabolic acidosis, hypercalciuria, and gastrointestinal symptoms, all of which were manageable.
Discussion: The C10-enriched KD demonstrated comparable efficacy and tolerability to the classic KD, offering a promising option for patients with refractory epilepsy who do not respond adequately to the classic KD alone. This study, the first to directly compare a C10-enriched KD with a classic KD, highlights the potential synergistic effects of decanoic acid.

Keywords:  Decanoic acid; epilepsy; ketogenic diet; refractory; seizure

DOI:  https://doi.org/10.3389/fneur.2025.1524799
J Mol Neurosci. 2025 Feb 11. 75(1): 18

Neurodegeneration in Autism: A Study of Clusterin, Very Long-Chain Fatty Acids, and Carnitine.

Esra Yurumez, Merve Cikili-Uytun, Banu Kaymak, Ozlem Dogan, Humeyra Hilal Ozturk, Beyza Nur Baysar-Kanoglu, Didem Behice Oztop.

  The clinical identification of regression phenomena in ASD lacks specific biological or laboratory criteria and is often based on family history and highly subjective observations by clinicians. The present study aimed to investigate the potential role of plasma clusterin (CLU), very long-chain fatty acids (VLCFA), and carnitine as biomarkers of neurodegeneration in children with autism spectrum disorder (ASD) with and without regression. By exploring these biomarkers, we sought to provide insights into mitochondrial dysfunction, glial activation, and lipid metabolism, which may contribute to the pathophysiology of ASD and aid in the early diagnosis and intervention of regression phenomena in ASD. Ninety children aged 2-6 years were included: 30 with autism spectrum disorder (ASD), 30 with regressive ASD, and 30 healthy controls. Psychiatric assessments were conducted using DSM-5 criteria, CARS, ABC, RBS-R, and ASSQ scales. Regression in ASD was evaluated retrospectively using a modified ADI-R questionnaire. Fasting blood samples were collected, and plasma clusterin (CLU), VLCFA, and carnitine levels were measured. Statistical analyses were performed using MANOVA to assess the effect of group differences on dependent biochemical variables. Serum clusterin and carnitine levels showed no significant differences between groups. However, C22 VLCFA levels were significantly higher in both autism groups compared to controls (p = 0.04), with post hoc analysis indicating the difference between the non-regressive and control groups (p = 0.02). Serum carnitine was positively correlated with stereotypic behaviors subscale scores (r = 0.37, p = 0.004) and total scores (r = 0.35, p = 0.006) of RBS-R. Our study provides insights into the complexities of biomarker research in autism spectrum disorder (ASD), highlighting the challenges in identifying consistent biological markers for regression and non-regression phenotypes. Although no significant findings were observed, further biomarker studies are essential to distinguish possible endophenotypes, improve early diagnosis, and uncover potential therapeutic targets in ASD.

Keywords:  Autism spectrum disorders; Carnitine; Clusterin; Fatty acids; Neurodegeneration

DOI:  https://doi.org/10.1007/s12031-024-02303-6
Anal Chem. 2025 Feb 09.

Development of an Oxylipin Library Using Liquid Chromatography-Ion Mobility Quadrupole Time-of-Flight: Application to Mouse Brain Tissue.

Maria Moran-Garrido, Ameer Y Taha, Ángel Gaudioso, Maria Dolores Ledesma, Coral Barbas.

Oxylipins are bioactive lipid mediators derived from polyunsaturated fatty acids (PUFAs) that play crucial roles in physiological and pathological processes. The analysis and identification of oxylipins are challenging due to the numerous isomeric forms. Ion mobility (IM), which separates ions based on their spatial configuration, combined with liquid chromatography (LC) and mass spectrometry (MS), has been proven effective for separating isomeric compounds. In this study, we developed an extensive oxylipin library containing information on retention time (RT), m/z, and CCS values for 74 oxylipin standards using LC-IM-QTOF-MS in positive and negative ionization modes. The oxylipins in the library were grouped into 15 isomer categories to evaluate the efficacy of IM in isomeric separation. Various adducts were investigated, including protonated, deprotonated, and sodiated forms. The ΔCCS% for more than 1000 isomeric pairs was calculated, revealing that 30% of these exhibited a ΔCCS% greater than 2%. Positive ionization mode demonstrated superior separation capabilities, with 274 isomer pairs achieving baseline separation (ΔCCS% >  4%). Sodium adducts significantly improved isomer separation. With the inclusion of LC separation, only nine oxylipins coeluted, forming six different isomeric pairs. CCS values for the adducts [M+Na]+ and [M+2Na-H]+ separated three of these isomeric pairs. The CCS values were compared to experimental libraries, confirming the high reproducibility of CCS measurements, with average errors below 2%. Applying this library to mouse brain samples, 19 different oxylipins were identified by matching RT, m/z, and CCS values. Coeluting isomers, 9- and 13-HODE, 8- and 12-HETE, and 15-oxo-ETE and 14(15)-EpETrE, were successfully separated and identified using drift time separation.

DOI: https://doi.org/10.1021/acs.analchem.4c06265