bims-medebr 2025-09-14 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–09–14
thirty-one papers selected by
Regina F. Fernández, Johns Hopkins University

Traumatic brain injury reprograms lipid droplet metabolism shaped by aging and diet in Drosophila brain.
Astrocyte-Neuron Metabolic Synergies in Neurological Homeostasis and Disease.
Interplay of Glut1 alteration and Alzheimer's disease: A narrative review on glucose transport and energy metabolism.
Alteration in hippocampal mitochondria ultrastructure and cholesterol accumulation linked to mitochondrial dysfunction in the valproic acid rat model of autism spectrum disorders.
Acyl-CoA Reductase Far1 Deficiency Impairs Ether Lipid Production and Hypomyelination in Mouse Brains.
Astrocyte Lipid Droplet Dynamics Orchestrate Neurological Disorders and Therapeutic Horizons.
Aging Effects on Lipid Metabolism in Response to Traumatic Brain Injury.
The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus.
Microglia-to-neuron signaling links APOE4 and inflammation to enhanced neuronal lipid metabolism and network activity.
Targeting mitochondrial dysfunction in Alzheimer's disease: New findings and perspectives.
Brain Metabolism of Allopregnanolone and Isoallopregnanolone in Male Rat Brain.
Altered Lipid Metabolism in CNS Demyelination and Remyelination Are Key Elements Driving Progressive MS.
Neonatal sevoflurane exposure disrupted fatty acids metabolism, leading to hypomyelination and neurological impairments.
Long-term Omega-3 Polyunsaturated Fatty Acid Supplementation Improves Meningeal Lymphatic Function During Brain Aging in Mice.
The distinct effects of metformin and imeglimin on high glucose-induced alterations in metabolic function and reactive oxygen species production in mouse Schwann cells are modulated by pemafibrate and/or fatty acid-binding proteins.
Metabolic dysregulation in Alzheimer's disease: A brain metabolomics approach.
Genetically encoded biosensors of metabolic function for the study of neurodegeneration, a review and perspective.
Beyond Support Cells: Astrocytic Autophagy as a Central Regulator of CNS Homeostasis and Neurodegenerative Diseases.
Riboflavin (Vitamin B2) Accumulation Modulates Neuronal Cellular Homeostasis in Typical Brain Development and Cerebral Palsy.
The Hypometabolic State of the Migraine Brain: Is a Ketogenic Diet the Answer?
Myristic Acid Remodels Sphingolipid Metabolism via Dual Pathways: Canonical d18-Sphingolipid Regulation and Non-Canonical d16-Sphingolipid Synthesis.
Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.
High energy consumption characterizes abnormal brain state transitions in temporal lobe epilepsy.
Comparative Analysis of Corpus Callosum Lipidome and Transcriptome in Schizophrenia and Healthy Brain.
Mitochondrial lipidome's fatty acid profile and peroxidation index are programmed tissue-specific traits.
Sphingolipid metabolism and signaling in the central nervous system: Effects on brain health.
The Role of Phospholipids in Mitochondrial Dynamics and Associated Diseases.
Lipid droplets: Open questions and conceptual advances around a unique organelle.
Novel Application of Ion Mobility Mass Spectrometry Reveals Complex Ganglioside Landscape in Diffuse Astrocytoma Peritumoral Regions.
Modulatory Action of Insulin-like Growth Factor I (IGF-I) on Cortical Activity: Entrainment of Metabolic and Brain Functions.
Complement C4b as a Key Mediator of Synaptic Loss and Cognitive Decline in Brain Aging.

PLoS One. 2025 ;20(9): e0332333

Traumatic brain injury reprograms lipid droplet metabolism shaped by aging and diet in Drosophila brain.

Stacey A Rimkus, Barry Ganetzky, David A Wassarman.

Traumatic brain injury (TBI) initiates secondary cellular damage such as mitochondrial dysfunction, oxidative stress, and neuroinflammation. In neurodegenerative disorders, these stressors are associated with accumulation of lipid droplets (LDs) - organelles that store neutral lipids to provide energy and protect cells from lipid toxicity. However, the regulation of LD metabolism following TBI remains poorly understood. Using a Drosophila melanogaster model, we investigated how TBI influences LD accumulation, particularly in relation to aging and diet, other LD modulatory factors. Confocal microscopy of fly brains at one day after injury showed increases in both LD size and number. The rise in LD number occurred only in flies fed a carbohydrate-rich diet and was absent in those given a ketogenic diet (KD) or water, suggesting that glucose availability is necessary for LD formation post-injury and potentially underlying why KD and water do not elicit the deleterious outcomes observed with carbohydrates. Lipidomic analysis of fly heads further revealed elevated levels of triacylglycerol (TG) species typically stored in LDs, indicating enhanced lipid synthesis post-injury. By seven days post-injury, LD size and number returned to baseline levels observed in uninjured flies and remained stable through 14 days post-injury. However, by 21 days post-injury, uninjured flies showed a marked increase in LD number that was not observed in injured flies, although LD size increased in both groups. These findings suggest that TBI selectively impairs age-dependent production of new LDs without affecting the growth of existing LDs. Importantly, TG levels remained elevated in heads of injured flies, indicating that the reduction in LD number was not due to limited lipid availability. Together, our findings indicate that TBI acutely induces LD formation as a protective response but chronically impairs LD biogenesis, disrupting lipid homeostasis in an age- and diet-dependent manner that may contribute to neurodegeneration.

DOI: https://doi.org/10.1371/journal.pone.0332333
Neurochem Res. 2025 Sep 09. 50(5): 293

Astrocyte-Neuron Metabolic Synergies in Neurological Homeostasis and Disease.

Jiahao Dong, Zihan Gao, Mingrui Liu, Binglu Qian, Cheng Yuan, Hui Liu, Ni Rao, Yingjiao Liu.

  Metabolic synergy between astrocytes and neurons is key to maintaining normal brain function. As the main supporting cells in the brain, astrocytes work closely with neurons through intercellular metabolic synergy networks to jointly regulate energy metabolism, lipid metabolism, synaptic transmission, and cerebral blood flow. This important synergy is often disrupted in neurological diseases such as Alzheimer's disease, Parkinson's disease, and stroke. This study systematically explores the physiological basis of this intercellular collaboration and its dysfunctional manifestations in the aforementioned diseases, and provides detailed insights into how abnormalities in specific collaborative pathways (such as impaired lactate transport, disrupted glutamate cycling, or lipid processing defects) significantly contribute to disease progression. By elucidating the molecular mechanisms underlying these collaborative impairments, this study aims to identify potential therapeutic targets, with the core strategy being to restore these critical intercellular collaborative relationships to alleviate neurological diseases.

Keywords:  Astrocyte-neuron; Intercellular collaboration; Metabolic synergy; Neurological disorders

DOI:  https://doi.org/10.1007/s11064-025-04548-y
J Alzheimers Dis. 2025 Sep 12. 13872877251377793

Interplay of Glut1 alteration and Alzheimer's disease: A narrative review on glucose transport and energy metabolism.

Sodiq Fakorede, Toheeb Ayodeji Sodiq, Abayomi Oyeyemi Ajagbe, Adewale James Adeleke, Okeoghene Marcel Edafetanure-Ibeh, Taiwo Ayomide Awobona, Abdullahi Tunde Aborode.

  Alzheimer's disease (AD) is a prevalent neurodegenerative disorder primarily affecting the aging population, characterized by progressive cognitive decline. Traditional models of AD pathogenesis, including the amyloid cascade and tau hypotheses, have not yielded definitive therapeutic breakthroughs. Emerging research suggests that metabolic dysfunction, particularly in glucose transport, plays a central role in AD progression. The glucose transporter 1 (GLUT1), which facilitates glucose entry across the blood-brain barrier, is crucial for maintaining brain energy metabolism. Studies have shown reduced GLUT1 expression in AD brains, impairing cerebral glucose uptake and contributing to neuronal dysfunction and neurodegeneration. This review synthesizes current evidence on the interplay between GLUT1 alteration and AD, highlighting how disruptions in glucose transport can exacerbate the disease's neuropathological features, including amyloid and tau pathologies. Furthermore, we explore potential therapeutic strategies aimed at restoring GLUT1 function, such as gene therapy, ketogenic diets, and small molecules that enhance GLUT1 expression. These approaches may offer promising avenues to mitigate the metabolic dysfunction driving AD and improve patient outcomes. This work underscores the importance of integrating metabolic insights into AD research to develop innovative therapeutic targets and interventions.

Keywords:  Alzheimer's disease; GLUT1; brain energy metabolism; glucose transport; neurodegeneration

DOI:  https://doi.org/10.1177/13872877251377793
Psychopharmacology (Berl). 2025 Sep 10.

Alteration in hippocampal mitochondria ultrastructure and cholesterol accumulation linked to mitochondrial dysfunction in the valproic acid rat model of autism spectrum disorders.

Paula D Prince, Martín G Codagnone, Javier A W Opezzo, Juan S Adán Areán, Christian Höcht, Nathalie Arnal, Silvia Alvarez, Sandra Zárate, Analía Reinés.

   RATIONALE: Autism spectrum disorders (ASD) are a group of neurodevelopmental and multifactorial conditions with cognitive manifestations. The valproic acid (VPA) rat model is a well-validated model that successfully reproduces the behavioral and neuroanatomical alterations of ASD. Previous studies found atypical brain connectivity and metabolic patterns in VPA animals: local glucose hypermetabolism in the prefrontal cortex, with no metabolic changes in the hippocampus.
AIM: This study aimed to explore mitochondrial structural features, lipid content, and functionality in the hippocampus and cerebral cortex in the VPA model.
METHODS: On embryonic day 10.5, pregnant Wistar rats were injected with VPA (450 mg/kg) or saline solution. In the hippocampus and cerebral cortex of male offspring (postnatal day 35), the mitochondrial structure was evaluated by transmission electron microscopy, oxidized/reduced glutathione was determined by high-performance liquid chromatography, mitochondrial membrane cholesterol, and phospholipids were determined by thin-layer chromatography, and oxygen consumption and ATP synthesis were measured in isolated mitochondria.
RESULTS: Mitochondrial increased oxygen consumption and decreased ATP production, increased oxidized/reduced glutathione, cholesterol accumulation in mitochondrial membrane and altered mitochondrial structure were found in the hippocampus of VPA animals. All parameters were preserved in the cerebral cortex of VPA rats.
CONCLUSIONS: These findings reveal brain region-specific mitochondrial structural and functional alterations in VPA-treated animals, with preserved mitochondria in regions with high glucose demand and impaired mitochondria in metabolically normal areas. Moreover, cholesterol accumulation in hippocampal mitochondrial membranes is a potential cause of mitochondrial dysfunction, contributing to a prooxidant state.

Keywords:  Autism spectrum disorders; Brain connectivity; Hippocampus; Mitochondria; Mitochondrial lipid profile; Prefrontal cortex; Valproic acid

DOI:  https://doi.org/10.1007/s00213-025-06899-4
Mol Cell Biol. 2025 Sep 11. 1-16

Acyl-CoA Reductase Far1 Deficiency Impairs Ether Lipid Production and Hypomyelination in Mouse Brains.

Tenga Takahashi, Kento Otsuka, Takayuki Sassa, Akio Kihara.

  Mammalian cell membranes contain ether lipids, which include an alkyl chain derived from a fatty alcohol that is produced by fatty acyl-CoA reductases (FARs). There are two mammalian FAR genes, FAR1 and FAR2, and mutations in FAR1 cause the peroxisomal fatty acyl-CoA reductase 1 disorder (PFCRD), which is accompanied by various symptoms, including neurological disorders. To date, the contributions of FAR1 and FAR2 to brain ether lipid production and the molecular mechanism of PFCRD have remained unknown. To investigate these, we analyzed knockout (KO) mice of Far1 and Far2. In the brain, the expression levels of Far1 were higher than those of Far2, and Far1 was widely expressed. Lipidomic analyses showed that the quantity of ether lipids ethanolamine-plasmalogens was reduced in Far1 KO mice, with a complementary increase in diacyl-type phosphatidylethanolamines, but not in Far2 KO mice. Electron microscope analysis of the corpus callosum revealed reductions in the percentage of myelinated axons and myelin thickness in Far1 KO mice relative to WT mice. In conclusion, FAR1 is the major FAR isozyme involved in ether lipid synthesis in the brain, and its deficiency causes hypomyelination. We speculate that this hypomyelination is one of the causes of the neurological symptoms of PFCRD.

Keywords:  Ether lipid; FAR1; fatty acyl-CoA reductase; myelin; plasmalogen

DOI:  https://doi.org/10.1080/10985549.2025.2548234
Small Sci. 2025 Sep;5(9): 2500152

Astrocyte Lipid Droplet Dynamics Orchestrate Neurological Disorders and Therapeutic Horizons.

Jiani Zhong, Yanyi Peng, Lingyue Zhang, Bo Xiao, Mengqi Zhang.

  Astrocytes, the predominant glial cells in the central nervous system (CNS), play a pivotal role in maintaining neuronal homeostasis and function. Accumulating evidence suggests that astrocytic dysfunction is closely associated with the pathogenesis of various neurological disorders, including neurodegenerative diseases, ischemic stroke (IS), epilepsy, and glioma. Lipid droplets (LDs), ubiquitous intracellular lipid storage organelles, exhibit metabolic abnormalities that are commonly observed in these neurological conditions, particularly in astrocytes, where LD metabolic dysregulation may serve as a critical link between glial dysfunction and neuronal damage. However, a systematic understanding of the regulatory mechanisms governing LD metabolism in astrocytes and their relationship to the pathogenesis of neurological diseases remains elusive. This article reviews the biology and pathology of astrocytes and summarizes the characteristics, regulatory factors, and abnormalities of LD metabolism in astrocytes, highlighting its association with neurodegenerative diseases, stroke, epilepsy, and glioma. Finally, we propose future research directions, emphasizing the need for integrative multiomics approaches and innovative regulatory technologies to elucidate the role of astrocytic LD metabolism in neurological disorders. Understanding the dysregulation of LD metabolism in astrocytes may provide novel insights into disease etiology and facilitate the development of glial-targeted diagnostic and therapeutic strategies.

Keywords:  astrocytes; lipid droplets; metabolism; neurological disorders; pathogenesis; therapeutics

DOI:  https://doi.org/10.1002/smsc.202500152
J Neurochem. 2025 Sep;169(9): e70227

Aging Effects on Lipid Metabolism in Response to Traumatic Brain Injury.

Regina F Fernandez, Paulina Weglarczyk, Shaghayegh Zokaei, Suzette Huguenin, Joseph Scafidi, Jessica M Ellis, Susanna Scafidi.

  Traumatic brain injury (TBI) is highly prevalent among very young and older adults, with poorer outcomes and longer recovery in aged individuals. The brain is a lipid-rich organ and high rates of membrane remodeling occur during recovery, yet remain poorly delineated, especially in aged. To determine the impact of age on lipid metabolism during TBI recovery, TBI was induced by control cortical impact in 3 (young) and 20 (aged) month-old mice. The ipsilateral cortex was harvested at 1-, 3-, 7-, and 28-day post injury (dpi) for analysis of gene expression, membrane lipidomics, total lipid fatty acid profile, and intermediates of fatty acid β-oxidation, acylcarnitines. Lipid metabolizing genes were largely downregulated in response to TBI in young mice, yet remained unchanged or were increased in aged mice, resulting in significantly higher expression in aged compared to young. TBI increased acylcarnitines by a robust ~3-fold in both young and aged cohorts acutely following injury and restored to sham levels by day 28. Phospholipidome compositional analysis reveals largest changes in the aged mice at 28 dpi. Aged mice phospholipid profiles shifted towards higher mono- and di- unsaturated and lower saturated and highly polyunsaturated species. Phospholipids with 4 unsaturated bonds, predicted to contain arachidonic acid, tended to increase post-TBI, whereas species containing 6 unsaturated bonds, predicted to contain docosahexaenoic acid (DHA) steadily declined during recovery. Total fatty acid analysis confirmed decreased DHA at 28 dpi in aged mice and more severely after TBI. In summary, TBI in aged led to a loss of transcriptional repression, more profound phospholipid change, earlier upregulation of acylcarnitines, and significant decrease in brain DHA content. Together, these data suggest that TBI occurrence in aging, compared to young, has less impact on gene expression of lipid metabolic genes but greater impact on lipid content.

Keywords:  acylcarnitines; aging; lipid metabolism; membrane biology; traumatic brain injury

DOI:  https://doi.org/10.1111/jnc.70227
Neurobiol Dis. 2025 Sep 04. pii: S0969-9961(25)00301-8. [Epub ahead of print]215 107084

The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus.

L Daniel Estrella, Xiaoke Xu, Collin White, Jane E Manganaro, Lexi Sheldon, Trey Farmer, Kelly L Stauch.

  Amongst the major histopathological hallmarks in Alzheimer's disease are intracellular neurofibrillary tangles consisting of hyperphosphorylated and aggregated Tau, synaptic dysfunction, and synapse loss. We have previously shown evidence of synaptic mitochondrial dysfunction in a mouse model of Tauopathy that overexpresses human Tau (hTau). Here, we questioned whether the levels or activity of Parkin, an E3 ubiquitin ligase involved in mitophagy, can influence Tau-induced synaptic mitochondrial dysfunction. Here, we generated novel mouse strains by crossing hTau mice with either Parkin knockout mice or mice expressing mutant Parkin (ParkinW402A, shown to lead to constitutively active Parkin in vitro). We found that Parkin levels are increased in synaptic mitochondria isolates from hTau compared to WT mice, suggesting increased mitophagy; while ParkinW402A surprisingly led to decreased levels of Parkin in hTau mice. Furthermore, we showed that absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction; however, ParkinW402A did not show functional rescuing effects. When compared to WT, proteomic analyses of synaptosomes demonstrated that hTau mice display protein changes that predict alterations to pathways related to mitochondrial metabolism, synaptic long-term potentiation, and synaptic calcium homeostasis. Both the absence of Parkin and expression of ParkinW402A led to distinct changes in the hTau mouse synaptic proteome. Finally, we showed that Parkin-null hTau mice have higher levels of phosphorylated Tau in the hippocampal Dentate Gyrus, with no observable changes in hTau mice expressing ParkinW402A. The data presented here illustrate the protective role that Parkin plays under Tau-induced mitochondrial and proteomic alterations, particularly at the synaptic level.

Keywords:  Alzheimer's disease; Mitophagy; Parkin; ParkinW402A; Phosphorylated Tau; Synapse; Synaptic mitochondria; Tauopathy

DOI:  https://doi.org/10.1016/j.nbd.2025.107084
Proc Natl Acad Sci U S A. 2025 Sep 16. 122(37): e2516103122

Microglia-to-neuron signaling links APOE4 and inflammation to enhanced neuronal lipid metabolism and network activity.

Ana P Verduzco Espinoza, Na Na, Loraine Campanati, Priscilla Ngo, Kristin K Baldwin, Hollis T Cline.

  Microglia regulate neuronal circuit plasticity. Disrupting their homeostatic function has detrimental effects on neuronal circuit health. Neuroinflammation contributes to the onset and progression of neurodegenerative diseases, including Alzheimer's disease (AD), with several microglial activation genes linked to increased risk for these conditions. Inflammatory microglia alter neuronal excitability, inducing metabolic strain. Interestingly, expression of APOE4, the strongest genetic risk factor for AD, affects both microglial activation and neuronal excitability, highlighting the interplay between lipid metabolism, inflammation, and neuronal function. It remains unclear how microglial inflammatory state is conveyed to neurons to affect circuit function and whether APOE4 expression alters this intercellular communication. Here, we use a reductionist model of human iPSC-derived microglial and neuronal monocultures to dissect how the APOE genotype in each cell type independently contributes to microglial regulation of neuronal activity during inflammation. Conditioned media (CM) from LPS-stimulated microglia increased neuronal network activity, assessed by calcium imaging, with APOE4 microglial CM driving greater neuronal activity than APOE3 CM. Both APOE3 and APOE4 neurons increase network activity in response to CM treatments, while APOE4 neurons uniquely increase presynaptic puncta in response to APOE4 microglial CM. CM-derived exosomes from LPS-stimulated microglia can mediate increases to network activity. Finally, increased network activity is accompanied by increased lipid droplet (LD) metabolism, and blocking LD metabolism abolishes network activity. These findings illuminate how microglia-to-neuron communication drives inflammation-induced changes in neuronal circuit function, demonstrate a role for neuronal LDs in network activity, and support a potential mechanism through which APOE4 increases neuronal excitability.

Keywords:  APOE4; Alzheimer’s disease; exosomes; lipid droplets; microglia

DOI:  https://doi.org/10.1073/pnas.2516103122
Prog Neuropsychopharmacol Biol Psychiatry. 2025 Sep 09. pii: S0278-5846(25)00245-3. [Epub ahead of print] 111491

Targeting mitochondrial dysfunction in Alzheimer's disease: New findings and perspectives.

Authors Jana Hroudová, Zdeněk Fišar.

  Alterations in mitochondrial energy metabolism, impaired processes of mitochondrial dynamics and mitophagy have recently been identified as important contributors to the pathophysiology of Alzheimer's disease (AD). Genetic predispositions and defects in mitochondrial metabolism, particularly within the electron transport chain of the oxidative phosphorylation system, have been linked to the pathology of intracellular and extracellular amyloid-beta (Aβ) and tau protein. This review summarizes the current molecular background of AD and explains the relationships between genetic factors, impaired energy metabolism, and the formation of pathological proteins. It highlights altered mitochondrial dynamics, impaired mitochondrial signaling, mitophagy, neuroinflammation, and apoptosis. Based on these findings, the review discusses mitochondrial biomarkers and novel molecules targeting mitochondrial dysfunction in the pathophysiology of AD.

Keywords:  Alzheimer's disease; Amyloid beta; Energy metabolism; Mitochondria; Mitophagy

DOI:  https://doi.org/10.1016/j.pnpbp.2025.111491
Int J Mol Sci. 2025 Sep 03. pii: 8559. [Epub ahead of print]26(17):

Brain Metabolism of Allopregnanolone and Isoallopregnanolone in Male Rat Brain.

Charlotte Öfverman, Martin Hill, Maja Johansson, Torbjörn Bäckström.

  Allopregnanolone (allo) and isoallopregnanolone (isoallo) are neuroactive steroid epimers that differ in hydroxyl orientation at carbon three. Allo is a potent GABA-A receptor agonist, while isoallo acts as an antagonist, influencing brain function through their interconversion. Their metabolism varies across brain regions due to enzyme distribution, with AKR1C1-AKR1C3 active in the brain and AKR1C4 restricted to the liver. In rats, AKR1C9 (liver) and AKR1C14 (intestine) perform similar roles. Beyond AKR1Cs, HSD17Bs regulate steroid balance, with HSD17B6 active in the liver, thyroid, and lung, while HSD17B10, a mitochondrial enzyme, influences metabolism in high-energy tissues. Our current data obtained using the GC-MS/MS platform show that allo and isoallo in rats undergo significant metabolic conversion, suggesting a regulatory role in neurosteroid action. High allo levels following isoallo injection indicate brain interconversion, while isoallo clears more slowly from blood and undergoes extensive conjugation. Metabolite patterns differ between brain and plasma-allo injection leads to 5α-DHP and isoallo production, whereas isoallo treatment primarily yields allo. Human plasma contains mostly sulfate/glucuronided steroids (2.4-6% non-sulfate/glucuronided), whereas male rats exhibit much higher free steroid levels (29-56%), likely due to the absence of zona reticularis. These findings highlight tissue-specific enzymatic differences, which may impact neurosteroid regulation and CNS disorders.

Keywords:  17β-hydroxysteroid dehydrogenases; GC-MS; aldoketoreductases; allopregnanolone; brain; circulation; hippocampus; isoallopregnanolone; neuroactive steroids; rat; striatum

DOI:  https://doi.org/10.3390/ijms26178559
Int J Mol Sci. 2025 Aug 27. pii: 8314. [Epub ahead of print]26(17):

Altered Lipid Metabolism in CNS Demyelination and Remyelination Are Key Elements Driving Progressive MS.

Agata Matejuk, Szymon Matejuk, Halina Offner, Arthur A Vandenbark.

  Lipids, together with water and proteins, constitute the essential structure of cell membranes, and in the CNS, critically contribute to the production, function, and maintenance of the myelin sheath. Myelin produced by oligodendrocytes (OLs) acts as an electric insulator and assures proper conduction of information. Three major fractions of myelin lipids are cholesterol, phospholipids, and glycolipids. These lipids not only sculpt the myelin landscape as a structural support for proteins, but they also play a crucial role in molecular interactions underlying processes of protein trafficking and signal transductions. The high lipid content of myelin makes it susceptible to lipid metabolism disorders. Disorders in systemic and local lipid metabolism may lead to loss of myelin integrity and stability, and potentially to CNS demyelination seen in neurodegenerative diseases, notably progressive multiple sclerosis, for which there are few effective therapies. Precise interactions among disorders in lipid metabolism, function of oligodendrocytes, and demyelination/remyelination events, including de novo myelin formation and myelin remodeling processes, may lay the foundation for novel therapeutics for progressive MS and other demyelinating CNS conditions.

Keywords:  MS; cholesterol; demyelination; lipids; remyelination

DOI:  https://doi.org/10.3390/ijms26178314
Biomed Pharmacother. 2025 Sep 08. pii: S0753-3322(25)00689-4. [Epub ahead of print]191 118495

Neonatal sevoflurane exposure disrupted fatty acids metabolism, leading to hypomyelination and neurological impairments.

Sufang Jiang, Tianyu Cao, Jiaqi Li, Lichao Di, Xueji Wang, Zhongcong Xie, Lining Huang.

  Myelin is a lipid-rich substance that is crucial for neural function. Neonatal anesthesia has been linked to neurological impairments associated with myelination dysfunction. This study sought to evaluate whether disrupted fatty acid homeostasis is involved in the mechanism of sevoflurane developmental neurotoxicity. Sevoflurane (3 %, 2 h/day) was administered to mice from postnatal day (P) P6 to P8. Subsequently, ultra-performance liquid chromatography and RNA sequencing (RNA-seq) were used to investigate the effects of sevoflurane on long-chain fatty acid metabolism at P9. Behavioral tests and myelination development were analyzed at P50. Peroxisome proliferator-activated receptor β (PPARβ) agonist administration and docosahexaenoic acid (DHA) treatment were performed to assess their rescuing effect on sevoflurane-impaired cognition in the mice. Following neonatal exposure to sevoflurane, a number of differentially expressed genes (DEGs) were closely related to lipid metabolism. Lipidomic analysis demonstrated that concentrations of long-chain fatty acids were dramatically reduced by repeated sevoflurane exposure. Consistently, cognitive impairments and hypomyelination were observed. Furthermore, the PPARβ agonist KD3010 attenuated the adverse effects of sevoflurane exposure on cognitive function and myelination. DHA treatment mimicked the protective effects of KD3010. These data demonstrate that repeated neonatal sevoflurane exposures result in profound changes in long-chain fatty acids metabolism, hypomyelination and subsequently, neurological impairments. Sevoflurane-induced myelin impairment is associated with changes in fatty acid content and composition, which may be mediated by the PPARβ pathway. These findings highlight the pivotal role of long-chain fatty acids in neonatal sevoflurane-associated neurotoxicity and open a new window for developing therapeutic strategies for sevoflurane-associated neurodevelopmental impairments.

Keywords:  Anaesthetic neurotoxicity; Cognition; Long-chain fatty acids; Myelination; Sevoflurane

DOI:  https://doi.org/10.1016/j.biopha.2025.118495
J Lipid Res. 2025 Sep 09. pii: S0022-2275(25)00157-9. [Epub ahead of print] 100895

Long-term Omega-3 Polyunsaturated Fatty Acid Supplementation Improves Meningeal Lymphatic Function During Brain Aging in Mice.

Zhoujing Liu, Jiamin Peng, Xuemin Wang, Fei Yin, Fengjuan Su, Zhong Pei, Hongfu Wu, Chuanming Luo.

  Emerging evidence implicates that meningeal lymphatic dysfunction may contribute to the pathogenesis of brain age-related diseases, suggesting its potential as a therapeutic target for brain aging. This study investigated whether long-term Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs) supplementation could delay brain aging through meningeal lymphatic modulation. We randomly assigned C57BL/6J mice into control, low-dose, and high-dose Omega-3 PUFAs groups, and administered dietary supplementation for 12 months until reaching 24 months of age. We then assessed the anti-aging effects on brain function and further examined meningeal lymphatic performance in clearance capacity and immune regulation. Our findings demonstrate that long-term Omega-3 PUFAs supplementation increases docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) levels in the brain, reduces age-related neuronal loss, and improves motor and cognitive behaviors in aged mice. Additionally, it reduces accumulation of toxic proteins (phosphorylated tau and amyloid-β) and metabolites (NADPH, succinyl-CoA, and cAMP) in the brain and decreases immune cell infiltration (CD68+ microglia and CD3+ T cells) in the central nervous system of aged mice. Furthermore, we demonstrate that these protective effects may be mediated through preservation of the meningeal lymphatic system during aging. In conclusion, this study elucidates a novel understanding of the anti-brain-aging mechanisms of Omega-3 PUFAs.

Keywords:  Omega-3 polyunsaturated fatty acids; anti-brain aging; meningeal lymphatic system

DOI:  https://doi.org/10.1016/j.jlr.2025.100895
Front Cell Neurosci. 2025 ;19 1634262

The distinct effects of metformin and imeglimin on high glucose-induced alterations in metabolic function and reactive oxygen species production in mouse Schwann cells are modulated by pemafibrate and/or fatty acid-binding proteins.

Hiroshi Ohguro, Megumi Higashide, Nami Nishikiori, Toshifumi Ogawa, Masato Furuhashi, Tatsuya Sato, Megumi Watanabe.

   Background: Imeglimin (Ime), the first in a novel class of antidiabetic agents, has potential therapeutic effects on diabetic peripheral neuropathy (DPN). This study aimed to evaluate and compare the effects on cellular metabolic function and reactive oxygen species (ROS) levels in high glucose-treated mouse Schwann cells (SCs), an in vitro DPN model, with those of metformin (Met), a conventional antidiabetic agent known for its beneficial effects on DPN. The roles of PPARα and fatty acid-binding proteins 5 and 7 (FABP5 and FABP7), both of which have been implicated in the pathogenesis of DPN, were also investigated.
Methods: Schwann cells were treated with high glucose, Ime, Met, a selective PPARα agonist pemafibrate (Pema), or a FABP5/FABP7 inhibitor (MF6). Cell viability assays, extracellular flux analysis, and ROS production assays were performed.
Results: No significant changes in cell viability were observed with any treatment. High glucose exposure increased glycolytic reserve compared to normal glucose conditions. Ime increased mitochondrial respiratory functions, whereas Met suppressed mitochondrial respiration and enhanced glycolytic functions, with these effects being more evident under normal glucose conditions. Pema significantly increased basal glycolysis under high glucose conditions, while MF6 had no appreciable effect. Both Ime and Met reduced ROS production in high glucose-treated SCs, with Ime exhibiting a more potent effect. However, the ROS-reducing effects of Ime and Met were abolished by Pema or MF6.
Conclusion: Imeglimin exerted beneficial biological effects by enhancing the energetic state and reducing ROS production without inducing metabolic quiescence in high glucose-treated SCs. These findings suggest that Ime has therapeutic potential for DPN, although its effects may be modulated by intracellular lipid metabolism.

Keywords:  FABP5; FABP7; ROS; Schwann cells; extracellular flux analyzer; imeglimin; metformin

DOI:  https://doi.org/10.3389/fncel.2025.1634262
Alzheimers Dement. 2025 Sep;21(9): e70528

Metabolic dysregulation in Alzheimer's disease: A brain metabolomics approach.

Anke Hüls, Youran Tan, Emma Casey, Zhenjiang Li, Marla Gearing, Allan I Levey, James J Lah, Aliza P Wingo, Dean P Jones, Douglas I Walker, Thomas S Wingo, Donghai Liang.

   INTRODUCTION: This study aimed to identify specific biological pathways and molecules involved in Alzheimer's disease (AD) neuropathology.
METHODS: We conducted cutting-edge high-resolution metabolomics profiling of 162 human frontal cortex samples from the Emory Alzheimer's Disease Research Center (ADRC) brain bank with comprehensive neuropathological evaluations.
RESULTS: We identified 155 unique metabolic features and 36 pathways associated with three well-established AD neuropathology markers. Of these, 18 novel metabolites were confirmed with level 1 evidence, implicating their involvement in amino acid metabolism, lipid metabolism, carbohydrate metabolism, nucleotide metabolism, and metabolism of cofactors and vitamins in AD neuropathology. Genetic variability influenced these associations, with non-carriers of the apolipoprotein E (APOE) ε4 allele showing stronger perturbations in metabolites including glucose and adenosine 5'-diphosphoribose.
DISCUSSION: This study demonstrates the potential of high-resolution metabolomic profiling in brain tissues to elucidate molecular mechanisms underlying AD pathology. Our findings provide critical insights into metabolic dysregulation in AD and its interplay with genetic factors.
HIGHLIGHTS: This is one of the largest untargeted metabolomics studies of human brain tissue. 155 metabolic features, and 36 metabolic pathways were linked to Alzheimer's disease (AD) neuropathology. Of these, 18 unique metabolites were confirmed with level 1 evidence. Glucose and adenosine 5'-diphosphoribose identified as key metabolic alterations in AD.

Keywords:  Alzheimer's disease; amino acid metabolism; carbohydrate metabolism; high‐resolution metabolomics; lipid metabolism; metabolism of cofactors and vitamins; neuropathology; nucleotide metabolism; untargeted metabolomics

DOI:  https://doi.org/10.1002/alz.70528
Neurophotonics. 2025 Jun;12(Suppl 2): S22805

Genetically encoded biosensors of metabolic function for the study of neurodegeneration, a review and perspective.

Minglei Zhao, Saman Behboudi Tanourlouee, Sean McCracken, Philip R Williams.

  Nervous system tissue is the most metabolically active in the body and neurons are the primary consumers of oxygen and metabolites in nervous tissue. Many processes support neuronal metabolism, and dysregulation of these processes or intrinsic neuronal metabolism is often tied to neurodegenerative diseases. While many techniques are available to query metabolic function and disease (e.g. Seahorse XF, histology, immunostaining), almost all of these approaches are destructive and few offer cellular resolution. However, genetically encoded biosensors can optically measure metabolic features in any tissue with optical access. Biosensors represent an approach to non-destructively monitor metabolic components and regulatory signaling repeatedly over time in intact tissues. In this review, we discuss the application of genetically encoded biosensors that measure metabolites and metabolic processes as applied to studies of neurodegeneration.

Keywords:  genetically encoded biosensors; metabolism; neurodegeneration

DOI:  https://doi.org/10.1117/1.NPh.12.S2.S22805
Cells. 2025 Aug 29. pii: 1342. [Epub ahead of print]14(17):

Beyond Support Cells: Astrocytic Autophagy as a Central Regulator of CNS Homeostasis and Neurodegenerative Diseases.

Jung Ho Lee, Wonseok Chang, Sun Seek Min, Dae Yong Song, Hong Il Yoo.

  Autophagy is a fundamental catabolic pathway critical for maintaining cellular homeostasis in the central nervous system (CNS). While neuronal autophagy has been extensively studied, growing evidence highlights the crucial roles of astrocytic autophagy in CNS physiology and pathology. Astrocytes regulate metabolic support, redox balance, and neuroinflammatory responses. These functions are closely linked to autophagic activity. The disruption of astrocytic autophagy contributes to synaptic dysfunction, chronic inflammation, myelin impairment, and blood-brain barrier instability. Dysregulation of astrocytic autophagy has been implicated in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. This review summarizes the molecular mechanisms of autophagy in astrocytes and delineates its role in intercellular communication with neurons, microglia, oligodendrocytes, and endothelial cells. Furthermore, we will discuss current pharmacological approaches targeting astrocytic autophagy, with particular attention to repurposed agents such as rapamycin, lithium, and caloric restriction mimetics. Although promising in preclinical models, therapeutic translation is challenged by the complexity of autophagy's dual roles and cell-type specificity. A deeper understanding of astrocytic autophagy and its crosstalk with other CNS cell types may facilitate the development of targeted interventions for neurodegenerative diseases.

Keywords:  astrocyte; autophagy; neurodegenerative disease; therapeutics

DOI:  https://doi.org/10.3390/cells14171342
Neurochem Res. 2025 Sep 12. 50(5): 301

Riboflavin (Vitamin B2) Accumulation Modulates Neuronal Cellular Homeostasis in Typical Brain Development and Cerebral Palsy.

Eulália Rebeca Silva-Araújo, Eduardo Padrón-Hernández, Ana Elisa Toscano, Osmar Henrique Dos Santos Júnior, Joaci Pereira Dos Santos Júnior, Henrique José Cavalcanti Bezerra Gouveia, Adriana Soares de Carvalho, Janaína Viana de Melo, Luiz Alberto Reis Mattos-Júnior, Raul Manhães-de-Castro.

  The developing brain requires high energy demands and metabolic efforts to regulate oxidative stress and myelination. Early insults cause mitochondrial dysfunction and compromise these pathways, potentially leading to cerebral palsy (CP), a severe and incurable neurological disorder that begins in childhood. Through a rodent preclinical study, we demonstrated that vitamin B2 (riboflavin), administered at a high dose (100 mg/kg), is accumulated in healthy (B2C) or paralytic (B2CP) brains and participates in neurodevelopment. Redox homeostasis was maintained in B2C through decreased malondialdehyde and carbonyls and increased glutathione-S-transferase activity. In B2CP rodents, there was a reduction in carbonyls and increased superoxide dismutase activity. Mitochondrial morphometric analysis suggests that riboflavin treatment increases biogenesis in controls and reduces mitochondrial deformation in CP. Ultrastructural analysis revealed increased myelin sheath thickness in B2C. Additionally, myelin figure formation and mitochondrial and axonal disintegration in CP were reduced by B2. Our evidence supports vitamin B2 accumulation as a beneficial mechanism to support energy homeostasis and mitochondrial demands that occur during typical neurodevelopment or in the face of CP.

Keywords:  Bioenergetics; Mitochondria; Myelin figure; Neurodevelopment; Riboflavin

DOI:  https://doi.org/10.1007/s11064-025-04552-2
Brain Behav. 2025 Sep;15(9): e70860

The Hypometabolic State of the Migraine Brain: Is a Ketogenic Diet the Answer?

Lakshini Gunasekera, Jason C Ray, Helmut Butzkueven, Terence J O'Brien, Elspeth Hutton, Neha Kaul.

   BACKGROUND: Migraine pathophysiology involves a constellation of metabolic abnormalities. These interlinked contributory factors include mitochondrial dysfunction, an altered gut microbiome, neuroinflammation, oxidative stress, weight imbalance, and altered glucose metabolism. The ketogenic diet is an emerging therapy which may restore hypometabolism seen in chronic migraine. We describe contributions of metabolic dysfunction to chronic migraine pathophysiology and discuss the role of ketogenic diet therapy to improve cerebral metabolism.
METHODS: A literature search of articles from OVID Medline, Embase, and Cochrane Library were reviewed until May 6, 2024. A total of 50 articles were included comprising case reports, case series, observational clinical trials, and narrative review articles.
RESULTS: Migraine pathophysiology involves significant hypometabolism, seen on functional imaging studies, so therapeutics which target these underlying deficiencies may ameliorate chronic migraine symptoms. The ketogenic diet reduces migraine days, pain intensity, and acute analgesic use. Current studies are limited by small sample sizes, inconsistent methodology precluding direct comparison between studies or pooling of results, and limited longitudinal follow-up.
CONCLUSION: While there is biological plausibility to reason that a ketogenic diet could correct metabolic mismatch in people with migraine, further randomized clinical trials with larger sample sizes are required to confirm the positive results of preliminary, uncontrolled studies.

Keywords:  ketogenic diet; metabolism; migraine

DOI:  https://doi.org/10.1002/brb3.70860
Nutrients. 2025 Sep 05. pii: 2881. [Epub ahead of print]17(17):

Myristic Acid Remodels Sphingolipid Metabolism via Dual Pathways: Canonical d18-Sphingolipid Regulation and Non-Canonical d16-Sphingolipid Synthesis.

Yunfei You, Qinghe Zeng, Zhenying Hu, Yu Chen, Mengmin Zhan, Yanlu Wang, Jingjing Duan.

  Background: Myristic acid (MA), a 14-carbon saturated fatty acid, serves as a precursor for the synthesis of non-canonical d16-sphingoid bases via its activated form, C14:0-CoA. However, its broader regulatory role in sphingolipid (SL) metabolism remains poorly defined. Methods: Using HepG2 cells treated with 50 μM MA, we found that sphingolipidomic analysis revealed reprogrammed sphingolipid metabolism. Results: In the canonical d18-SL pathway, MA directs its activated product C14:0-CoA into ceramide N-acyl chains and downstream metabolites-especially d18:1-C14:0 hexosylceramide. Concurrently, in the non-canonical d16-SL pathway, MA promotes d16-SL synthesis, especially d16:1-ceramides (Cer), d16:1-hexosylceramides (HexCer), and d16:1-C14:0 lactosylceramide. MA treatment further induced a coordinated shift in cellular sphingolipid pools, characterized by a significant increase in total ceramide levels (encompassing both d16- and d18-species) alongside concurrent reductions in total sphingomyelin (SM) contents. At the gene transcriptional level, MA significantly suppressed SPTLC2 mRNA expression while markedly upregulating SMPD2 and SMPD3 mRNA levels. Conclusions: Collectively, these findings position MA as a potent regulator of sphingolipid homeostasis, orchestrating dual pathway modulation: disrupting canonical d18-SL equilibrium through the selective enrichment of N-acyl C14:0-containing SLs, and activating non-canonical d16-SL synthesis. This dual pathway regulation reveals that dietary saturated fatty acids exploit sphingolipid subnetworks to regulate lipid metabolism. The interplay between dietary fatty acids and sphingolipid metabolism still requires deeper exploration. Our findings offer preliminary insights into their roles in regulating both normal and disease-associated lipid metabolism, setting the stage for subsequent mechanistic investigations.

Keywords:  ceramides; d16-sphingolipids; myristic acid; sphingolipid metabolism

DOI:  https://doi.org/10.3390/nu17172881
Nat Metab. 2025 Sep 09.

Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.

Ran Liu, Zihan Zhang, Aye K Kyaw, Kariona A Grabińska, Hardik Shah, Hongying Shen.

The essential cofactor coenzyme A (CoASH) and its thioester derivatives (acyl-CoAs) have pivotal roles in cellular metabolism. However, the mechanism by which different acyl-CoAs are accurately partitioned into different subcellular compartments to support site-specific reactions, and the physiological impact of such compartmentalization, remain poorly understood. Here, we report an optimized liquid chromatography-mass spectrometry-based pan-chain acyl-CoA extraction and profiling method that enables a robust detection of 33 cellular and 23 mitochondrial acyl-CoAs from cultured human cells. We reveal that SLC25A16 and SLC25A42 are critical for mitochondrial import of free CoASH. This CoASH import process supports an enriched mitochondrial CoA pool and CoA-dependent pathways in the matrix, including the high-flux TCA cycle and fatty acid oxidation. Despite a small fraction of the mitochondria-localized CoA synthase COASY, de novo CoA biosynthesis is primarily cytosolic and supports cytosolic lipid anabolism. This mitochondrial acyl-CoA compartmentalization enables a spatial regulation of anabolic and energy-related catabolic processes, which promises to shed light on pathophysiology in the inborn errors of CoA metabolism.

DOI: https://doi.org/10.1038/s42255-025-01358-y
Neurobiol Dis. 2025 Sep 08. pii: S0969-9961(25)00306-7. [Epub ahead of print]215 107089

High energy consumption characterizes abnormal brain state transitions in temporal lobe epilepsy.

Sam S Javidi, Qirui Zhang, Ankeeta Ankeeta, Michael R Sperling, Joseph I Tracy.

  Temporal lobe epilepsy (TLE) patients experience shifts between non-seizing and seizing brain states, but the structural networks underlying these transitions remain undefined and poorly characterized. We detected dynamic brain states in resting-state fMRI and constructed linked structural networks utilizing multi-shell diffusion-weighted MR data. Leveraging network control theory, we interrogated the structural data for all possible brain state transitions, identifying those requiring abnormal levels of transition energy (low or high) in TLE compared to matched healthy participants (n's = 25). Results revealed three transitions requiring significantly higher energy in TLE; no abnormally low-energy transitions were observed. In HPs, transitions relied on mediator regions that did not belong to the initial source or final target brain areas. TLE transitions involved a more restricted set of source/target regions, predominantly outside the epileptogenic temporal lobe. Our findings highlight the abnormal and inefficient network mechanisms that accrue from the network entrainment inherent to TLE seizure activity. We argue these findings clarify the pathologic effects and help explain the well-known cognitive inefficiencies and other deficits found in the TLE disorder.

Keywords:  Epilepsy; Minimum energy; Network control theory; Seizure network; State transition

DOI:  https://doi.org/10.1016/j.nbd.2025.107089
Consort Psychiatr. 2025 ;6(1): 5-17

Comparative Analysis of Corpus Callosum Lipidome and Transcriptome in Schizophrenia and Healthy Brain.

Maria Osetrova, Olga Efimova, Marina Zavolskova, Elena Stekolschikova, Gleb Vladimirov, Dmitry Senko, Tatiana Zhuravleva, Anna Morozova, Yana Zorkina, Denis Andreyuk, George Kostyuk, Evgeniy Nikolaev, Philipp Khaitovich.

   BACKGROUND: Functional and structural studies of the brain highlight the importance of white matter alterations in schizophrenia. However, molecular studies of the alterations associated with the disease remain insufficient.
AIM: To study the lipidome and transcriptome composition of the corpus callosum in schizophrenia, including analyzing a larger number of biochemical lipid compounds and their spatial distribution in brain sections, and corpus callosum transcriptome data. To integrate the results of molecular approaches to create a comprehensive molecular perspective of the disease.
METHODS: A total of 8 brain tissue samples (4 from healthy controls (HC) + 4 from schizophrenia patients (SZ)) were analyzed using high-performance liquid chromatography with mass spectrometry (HPLC-MS) and RNA sequencing for transcriptome profiling. Additionally, 6 brain tissue samples (3 HC + 3 SZ) were analyzed using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI). This approach enabled the characterization of mRNA and lipids in brain tissue samples, and the spatial distribution of selected lipids within brain sections.
RESULTS: The analysis revealed a general trend of reduced lipid levels in the corpus callosum of schizophrenia patients for lipid classes measured by mass spectrometric methods. Specifically, nine lipid classes detected via HPLC-MS showed significant differences in schizophrenia samples, with seven of them having lower median intensity. The results between HPLC-MS and MALDI-MSI were highly concordant. Transcriptome analysis identified 1,202 differentially expressed genes, clustered into four functional modules, one of which was associated with lipid metabolism.
CONCLUSION: We identified a series of lipidome and transcriptome alterations in the corpus callosum of schizophrenia patients that were internally consistent and aligned well with previous findings on white matter lipidome changes in schizophrenia. These results add to the existing scope of molecular alterations associated with schizophrenia, shedding light on the biological processes potentially involved in its pathogenesis.

Keywords:  corpus callosum; lipidomics; mass spectrometry; schizophrenia; transcriptomics

DOI:  https://doi.org/10.17816/CP15491
Redox Biol. 2025 Aug 30. pii: S2213-2317(25)00363-5. [Epub ahead of print]86 103850

Mitochondrial lipidome's fatty acid profile and peroxidation index are programmed tissue-specific traits.

Natàlia Mota-Martorell, Anna Fernàndez-Bernal, Joaquim Sol, Marta Santacreu-Vilaseca, Alba Juanes-Casado, Manuel Portero-Otín, Mariona Jové, Reinald Pamplona.

  Mitochondria are dynamic systems adapted to the different cellular demands. In this context, it is hypothesized that lipids, and particularly fatty acids, are also affected by these adaptations and supported at transcriptional level. By analyzing seven mammalian organs from rats, covering the three germ layers and belonging to the four basic types of tissue, we evaluated the differences in the lipidome's fatty acid profiles, calculated fatty acid-derived parameters including susceptibility to lipid peroxidation, and estimated enzymatic activity. Then, we analyzed gene expression datasets of rat tissues to identify specific signatures supporting fatty acid profiles and extended the analysis to human datasets to evaluate shared and differential traits. Our findings demonstrate that a) mitochondrial lipotype is determined by the basic type of tissue instead of the germ layer origin; b) mitochondrial fatty acid profiles define the tissue; c) myristic acid (FA14:0) and docosapentaenoic acid n-6 (22:5n-6) act as biomarkers for global definition of the tissue mitotype; d) brain and adipose tissue mitochondria are especially resistant to lipid peroxidation; e) mitochondrial fatty acid signatures are supported at transcriptional level; and f) tissue-specific transcriptomic patterns of elongase and desaturase expression in rats are largely conserved in humans (e.g., Elovl4, Elovl7, Scd, and Fads6), although species-specific differences are observed for certain transcripts, such as Elovl2, Elovl3, and Elovl5. Our findings suggest that mitochondria share general inter-tissue features but also exhibit tissue-specific specializations in their lipid phenotype. We infer that the mitochondrial fatty acid composition and its derived peroxidation index may be programmed, tissue-specific traits.

Keywords:  Desaturases; Double bond index; Elongases; Fatty acids; Mitochondria; Peroxidation index

DOI:  https://doi.org/10.1016/j.redox.2025.103850
Neurobiol Dis. 2025 Sep 08. pii: S0969-9961(25)00303-1. [Epub ahead of print] 107086

Sphingolipid metabolism and signaling in the central nervous system: Effects on brain health.

Junhua Xiao, Gerhild van Echten-Deckert.

DOI: https://doi.org/10.1016/j.nbd.2025.107086
Front Biosci (Landmark Ed). 2025 Aug 27. 30(8): 27634

The Role of Phospholipids in Mitochondrial Dynamics and Associated Diseases.

Solenn Plouzennec, Juan Manuel Chao de la Barca, Arnaud Chevrollier.

  The bioenergetic machinery of the cell is protected and structured within two layers of mitochondrial membranes. The mitochondrial inner membrane is extremely rich in proteins, including respiratory chain complexes, substrate transport proteins, ion exchangers, and structural fusion proteins. These proteins participate directly or indirectly in shaping the membrane's curvature and facilitating its folding, as well as promoting the formation of nanotubes, and proton-rich pockets known as cristae. Recent fluorescent super-resolution images have demonstrated the strong dynamics of these events, with constant remodeling processes. The mitochondrial outer membrane itself is also highly dynamic, interacting with the endoplasmic reticulum and its environment to ensure a rapid diffusion of surface components throughout the mitochondrial networks. All these movements occur besides migration, fusion, and fission of the mitochondria themselves. These dynamic events at the level of mitochondrial membranes are primarily dependent on their unique lipid composition. In this review, we discuss the latest advances in phospholipid research, focusing on their metabolism and role in mitochondrial dynamics. This process emphasizes the importance of interactions with the endoplasmic reticulum and mitochondrial matrix enzymes, extending its relevance to lipid sources, in particular, cardiolipins and phosphatidylethanolamines at the cellular, tissue and even whole-organism level. Given the expanding array of characterized mitochondrial functions, ranging from calcium homeostasis to inflammation and cellular senescence, research in the field of mitochondrial lipids is particularly significant. As mitochondria play a central role in various pathological processes, including cancer and neurodegenerative disorders, lipid metabolism may offer promising therapeutic approaches.

Keywords:  dynamic; lipids; membrane; mitochondria; mitochondrial diseases

DOI:  https://doi.org/10.31083/FBL27634
J Cell Biol. 2025 Oct 06. pii: e202406019. [Epub ahead of print]224(10):

Lipid droplets: Open questions and conceptual advances around a unique organelle.

W Mike Henne, Emma Reynolds, William A Prinz.

Once viewed as mere lipid inclusions, the past four decades have witnessed an explosion of research into lipid droplet (LD) biogenesis and function. Pioneering cell biology, biochemical, genetics, and lipidomic studies now reveal LDs as active players in lipid metabolism and cellular homeostasis. Here, we discuss some of the major findings that defined LDs as bona fide organelles. However, despite what is known, much needs to be discovered. We highlight five enduring questions that continue to challenge the LD field and discuss a few misconceptions about this remarkable organelle.

DOI: https://doi.org/10.1083/jcb.202406019
Int J Mol Sci. 2025 Aug 29. pii: 8433. [Epub ahead of print]26(17):

Novel Application of Ion Mobility Mass Spectrometry Reveals Complex Ganglioside Landscape in Diffuse Astrocytoma Peritumoral Regions.

Raluca Ica, Mirela Sarbu, Roxana Biricioiu, Dragana Fabris, Željka Vukelić, Alina D Zamfir.

  Diffuse astrocytoma is a primary brain tumor known for its gradual and diffuse infiltration into the surrounding brain tissue. Given this characteristic, the investigation of the peritumoral region holds potential biological and clinical relevance. In this study, ion mobility spectrometry mass spectrometry (IMS MS) was optimized and applied for the first time for the analysis of gangliosides present in the peritumoral tissue of diffuse astrocytoma. Ganglioside profiling and structural characterization were conducted using high-resolution nanoelectrospray ionization (nanoESI) IMS MS, along with tandem mass spectrometry (MS/MS) via low-energy collision-induced dissociation (CID) in the negative ion mode. Using IMS MS-based separation and screening, we observed a greater diversity of ganglioside species in the peritumoral tissue than previously reported. Notably, an elevated expression was detected for several species, including GT1(d18:1/18:0), GT1(d18:1/20:0), GM2(d18:1/16:2), GD1(d18:1/16:0), GD2(d18:1/20:0), Fuc-GT3(d18:1/24:4), and Fuc-GD1(d18:1/18:2). Although preliminary, these observations prompt consideration of whether these species could be implicated in processes such as microenvironmental modulation, tumor cell infiltration and invasion, maintenance of cellular interactions, or regulation of immune responses. Additionally, their potential utility as biomarkers may merit further exploration. In the subsequent phase of the study, structural analysis using IMS MS, CID tandem MS, and fragmentation data supported the identification of GT1b(d18:1/20:0) isomer in the peritumoral tissue. However, given the exploratory nature of the study and reliance on limited sampling, further investigation across broader sample sets is necessary to extend these findings.

Keywords:  astrocytoma; biomarker; gangliosides; ion mobility mass spectrometry; peritumoral tissue

DOI:  https://doi.org/10.3390/ijms26178433
Cells. 2025 Aug 27. pii: 1325. [Epub ahead of print]14(17):

Modulatory Action of Insulin-like Growth Factor I (IGF-I) on Cortical Activity: Entrainment of Metabolic and Brain Functions.

Nuria García-Magro, Alberto Mesa-Lombardo, Ángel Nuñez.

  Insulin-like growth factor I (IGF-I) is a neurotrophic factor that regulates neurogenesis, synaptogenesis, and neuronal survival. It also enhances neuronal activity and facilitates synaptic plasticity. Additionally, IGF-I plays a critical role in the regulation of metabolism in mammals. Emerging evidence indicates that IGF-I modulates sleep architecture. The circadian integration of metabolic and neuronal systems serves to optimize energy utilization across the light/dark cycle. Current data suggest that IGF-I may be a key mediator of this integration, promoting brain activity during wakefulness, a state that coincides with increased metabolic demand. In this review, we summarize recent findings on the interplay between metabolism, IGF-I, and brain activity.

Keywords:  IGF-I; cholinergic neurons; circadian rhythms; electrocorticogram; growth hormone; orexinergic neurons; synaptic plasticity

DOI:  https://doi.org/10.3390/cells14171325
Mol Ther. 2025 Sep 09. pii: S1525-0016(25)00733-6. [Epub ahead of print]

Complement C4b as a Key Mediator of Synaptic Loss and Cognitive Decline in Brain Aging.

Yi Zheng, Ting Liu, Lunan Luo, Feiyang Li, Cheng Tang, Changling Xu, Cheng Chen, Lu Yang, Ying Xiao, Ziyan Wang, Qing Yuan, Min Zheng, Hao Li, Jing Yang.

Brain aging is a major risk factor for cognitive decline and neurodegenerative diseases, driven by synaptic loss, reduced synaptic function, and inflammation. However, the molecular mechanisms underlying these dysfunctions remain unclear. Here, we conducted comparative transcriptomic analyses of brain regions (cortex and hippocampus) and kidney tissues, a peripheral organ with documented age-related dysfunction. Our study uncovered common and tissue-specific aging molecular signatures, highlighting the complexity of aging-related gene expression dynamics. Notably, we identified complement component C4b as a key mediator linking inflammation to synaptic degeneration. Experimental modulation of C4b expression in aged neurons restored synaptic integrity and neuronal activity in vitro, while in vivo CRISPR-Cas13d-mediated suppression enhanced synaptic density and improved cognitive performance in aged mice. These findings establish C4b as a critical driver of age-associated cognitive decline and a promising therapeutic target for mitigating neurodegenerative changes.

DOI: https://doi.org/10.1016/j.ymthe.2025.09.005