bims-medebr 2025-05-25 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–05–25
twenty-six papers selected by
Regina F. Fernández, Johns Hopkins University

Dysregulated astrocyte cholesterol synthesis in Huntington's disease: A potential intersection with other cellular dysfunctions.
Reduced cholesterol alters the biophysical properties of repaired myelin.
High-Fat Diet-Induced Excessive Accumulation of Cerebral Cholesterol Esters and Microglial Dysfunction Exacerbate Alzheimer's Disease Pathology in APPNL-G-F mice.
What Does Iron Mean to an Oligodendrocyte?
Glut1 Deficiency Syndrome: Novel Pathomechanisms, Current Concepts, and Challenges.
De novo serine biosynthesis is protective in mitochondrial disease.
The Role of Fatty Acid Binding Protein 7 in Neurological Diseases.
Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer's disease.
Single-Cell RNA and Transcriptome Sequencing to Analyze the Role of Lactate Metabolism in Traumatic Brain Injury Astrocytes.
Dissecting Metabolic Control of Behaviors and Physiology During Aging in Drosophila.
Dysregulation of Monounsaturated Fatty Acids is Related to α-Synuclein in Multiple System Atrophy.
Intervention Role of APOE in CNS Diseases: APOE Actions and APOE Neurogenesis Capability.
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of 13C-labelled glucose metabolism.
SIRT3 is required for the protective function of ketogenic diet on neural inflammation and neuropathic pain.
Bis-Allylic Deuterated Docosahexaenoic Acid-Esterified Phospholipids Resist In Vivo Peroxidation in Rat Brain.
Hypercholesterolemia, oxidative stress, and low-grade inflammation: a potentially dangerous scenario to blood-brain barrier.
Relationship Between Cerebral Glucose Metabolism and Neurodevelopmental Outcomes in Very-Low-Birth-Weight Infants without Structural Abnormalities.
Nervonic acid, a long chain monounsaturated fatty acid, improves mitochondrial function in adrenomyeloneuropathy fibroblasts.
Astrocyte Fabp7 modulates nocturnal seizure threshold and activity-dependent gene expression in mouse brain.
Integrative metabolomics and transcriptomics analysis of hippocampus reveals taurine metabolism and sphingolipid metabolism dysregulation associated with sleep deprivation-induced memory impairment.
In situ imaging study of targeted iron and metabolically related molecules in tumors and brain tissues using MALDI-MS imaging.
Nuclear SREBP2 condensates regulate the transcriptional activation of lipogenic genes and cholesterol homeostasis.
ABHD18 degrades cardiolipin by stepwise hydrolysis of fatty acids.
Author Correction: A human brain map of mitochondrial respiratory capacity and diversity.
The role of genetic defects in carnitine-associated hepatic encephalopathy: a review of literature.
Alpha-synuclein aggregates trigger cardiolipin externalization and mitophagy.

J Huntingtons Dis. 2025 May 21. 18796397251336192

Dysregulated astrocyte cholesterol synthesis in Huntington's disease: A potential intersection with other cellular dysfunctions.

Marta Valenza.

  Astrocytes are key elements for synapse development and function. Several astrocytic dysfunctions contribute to the pathophysiology of various neurodegenerative disorders, including Huntington's disease (HD), an autosomal-dominant neurodegenerative disorder that is characterized by motor and cognitive defects with behavioral/psychiatric disturbances. One dysfunction in HD related to astrocytes is reduced cholesterol synthesis, leading to a decreased availability of local cholesterol for synaptic activity. This review describes the specific role of astrocytes in the brain local cholesterol synthesis and presents evidence supporting a defective astrocyte-neuron cholesterol crosstalk in HD, by focusing on SREBP-2, the transcription factor that regulates the majority of genes involved in the cholesterol biosynthetic pathway. The emerging coordination of SREBP-2 with other physiological processes, such as energy metabolism, autophagy, and Sonic Hedgehog signaling, is also discussed. Finally, this review intends to stimulate future research directions to explore whether the impairment of astrocytic SREBP-2-mediated cholesterol synthesis in HD associates with other cellular dysfunctions in the disease.

Keywords:  SREBP-2; Sonic Hedgehog; astrocyte; autophagy; cholesterol; energy metabolism; synapse

DOI:  https://doi.org/10.1177/18796397251336192
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 May 20. pii: S1388-1981(25)00045-9. [Epub ahead of print] 159637

Reduced cholesterol alters the biophysical properties of repaired myelin.

Estephanie L Nottar Escobar, Nishama De Silva Mohotti, Mara Manolescu, Anika Radadiya, Prajnaparamita Dhar, Meredith D Hartley.

  The myelin sheath is a lipid-rich membrane that ensheathes axons and is required for healthy and efficient signal transduction. Myelin is damaged in neurological diseases like multiple sclerosis, but remyelination can occur through the action of oligodendrocyte precursor cells (OPCs), which differentiate into mature oligodendrocytes that wrap axons to form repaired myelin. In this study, a genetic-based mouse model of demyelination was used, which features near-complete demyelination followed by robust remyelination in the brain. Lipid mass spectrometry on isolated myelin from the remyelinated brain revealed a decrease in the percent mole fraction of cholesterol when compared to healthy myelin. Biophysical studies on monomolecular lipid films formed using myelin lipid extracts from repaired myelin showed changes in the surface behavior of the lipid films, compared to the healthy myelin. Films formed using the remyelinated lipid extracts resulted in lower surface pressures and lower compressional moduli when compared to healthy controls, suggesting that repaired myelin membranes have lower lateral molecular packing within the lipid film. Synthetically prepared model membranes, based on the major lipid compositions of the healthy and diseased extracts, revealed that changes in cholesterol levels were the primary contributor to the changes in biophysical properties. Supplementation of the diseased lipid extracts with cholesterol led to a robust improvement in membrane surface pressures and compressibility. Together, these results suggest that high cholesterol levels are required for myelin membrane stability and that reduced cholesterol in repaired myelin may have a profound impact on the biophysical properties of the myelin membrane.

Keywords:  Cholesterol; Lipid monolayers; Lipidomics; Myelin; Surface pressure

DOI:  https://doi.org/10.1016/j.bbalip.2025.159637
Mol Neurobiol. 2025 May 17.

High-Fat Diet-Induced Excessive Accumulation of Cerebral Cholesterol Esters and Microglial Dysfunction Exacerbate Alzheimer's Disease Pathology in APPNL-G-F mice.

Shuhan Yang, Hirofumi Miyazaki, Tunyanat Wannakul, Eiko Amo, Takaomi Saido, Takashi Saito, Hiroki Sasaguri, Motoko Maekawa, Yuji Owada.

  Epidemiological studies have identified high-fat diet (HFD)-induced obesity as a risk factor for Alzheimer's disease (AD), yet the underlying molecular mechanisms remain inadequately elucidated. Microglia, the brain's innate immune cells, are pivotal in AD brain by engulfing β-amyloid (Aβ) peptides and compacting poorly consolidated Aβ plaques. Microglia are highly susceptible to the metabolic milieu; however, it is unclear how long-term HFD alters the lipid environment and influences microglial phenotype in AD brains. In this study, APPNL-G-F knock-in AD model mice were fed an HFD for 9-27 weeks and subsequently analyzed for Aβ pathology and microglial function. Our findings indicated that HFD intake accelerated Aβ deposition, attenuated the recruitment of microglia to the plaques and impaired their phagocytic activity, while also promoting the accumulation of intracellular lipid droplets (LDs). Lipidomic analyses revealed that HFD, in synergy with AD pathology, increased the proportion of cholesterol esters in the cerebral cortex. In vitro, oleic acid-a major HFD constituent-similarly diminished the phagocytic capacity of MG6 microglia and induced LDs accumulation, along with downregulation of gene sets of cholesterol efflux, phagocytosis and engulfment. Overall, these findings implied that HFD-induced perturbation in brain cholesterol homeostasis may compromise microglial activation and expedite AD progression in APPNL-G-F mice.

Keywords:  Alzheimer’s disease; High-fat diet; Lipid droplet; Lipid metabolism; Microglial function

DOI:  https://doi.org/10.1007/s12035-025-05052-8
Glia. 2025 May 22.

What Does Iron Mean to an Oligodendrocyte?

Quinn W Wade, James R Connor.

  Iron is essential for life and plays a key role in multiple fundamental cellular functions. The brain has the highest rate of energy consumption, and within the brain, oligodendrocytes have the highest level of oxidative metabolism per volume. Oligodendrocytes also stain the strongest for iron. The high requirement for iron is related to an oligodendrocyte's primary function to produce the myelin sheath, which requires iron as a cofactor. In addition to the high-energy demands that accompany the production of such dense and extensive membranous sheaths, iron is also required for lipid synthesis. Although the involvement of iron in oligodendrocyte functioning is clear, how iron is specifically acquired and utilized by oligodendrocytes is not completely understood. The purpose of this review is to provide a complete and thorough overview of the role of iron in oligodendrocytes. Here, we discuss in detail what is currently known about key iron transport proteins that participate in the balance of iron in oligodendrocytes. Understanding how oligodendrocytes utilize iron is beneficial in understanding dysmyelinating diseases, and the knowledge could be utilized to develop treatment options.

Keywords:  H‐ferritin; iron; myelin; oligodendrocytes; transferrin

DOI:  https://doi.org/10.1002/glia.70043
J Inherit Metab Dis. 2025 May;48(3): e70044

Glut1 Deficiency Syndrome: Novel Pathomechanisms, Current Concepts, and Challenges.

Joerg Klepper.

  Glut1 Deficiency Syndrome (Glut1DS) has emerged as a treatable, but complex entity. Increasing data on pathogenic mechanisms, phenotype, genotype, and ketogenic dietary therapies (KDT) are available, as summarized in this review. Many challenges remain: novel symptoms emerge and vary with age. In Glut1DS, KDT in pregnancy and the clinical features in neonates and adults are poorly understood. KDT are ineffective in some patients for reasons yet unknown. Research reaches beyond the concept of brain energy depletion by impaired GLUT1-mediated glucose transfer across the blood-brain barrier. Novel concepts investigate alternative substrates, transport mechanisms, and metabolic interactions of different brain cell types. Future, yet currently unavailable prospects are neonatal screening for Glut1DS, reliable biomarkers, predictors for outcome, and alternative therapies, along with and beyond KDT.

Keywords:  De Vivo disease; GLUT1; Glut1 Deficiency Syndrome; Glut1DS; SLC2A1; hypoglycorrhachia; ketogenic dietary therapies; treatable

DOI:  https://doi.org/10.1002/jimd.70044
Cell Rep. 2025 May 15. pii: S2211-1247(25)00481-4. [Epub ahead of print]44(5): 115710

De novo serine biosynthesis is protective in mitochondrial disease.

Christopher B Jackson, Anastasiia Marmyleva, Geoffray Monteuuis, Ryan Awadhpersad, Takayuki Mito, Nicola Zamboni, Takashi Tatsuta, Amy E Vincent, Liya Wang, Nahid A Khan, Thomas Langer, Christopher J Carroll, Anu Suomalainen.

  The importance of serine as a metabolic regulator is well known for tumors and is also gaining attention in degenerative diseases. Recent data indicate that de novo serine biosynthesis is an integral component of the metabolic response to mitochondrial disease, but the roles of the response have remained unknown. Here, we report that glucose-driven de novo serine biosynthesis maintains metabolic homeostasis in energetic stress. Pharmacological inhibition of the rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), aggravated mitochondrial muscle disease, suppressed oxidative phosphorylation and mitochondrial translation, altered whole-cell lipid profiles, and enhanced the mitochondrial integrated stress response (ISRmt) in vivo in skeletal muscle and in cultured cells. Our evidence indicates that de novo serine biosynthesis is essential to maintain mitochondrial respiration, redox balance, and cellular lipid homeostasis in skeletal muscle with mitochondrial dysfunction. Our evidence implies that interventions activating de novo serine synthesis may protect against mitochondrial failure in skeletal muscle.

Keywords:  CP: Metabolism; de novo serine synthesis; mitochondrial disease; mitochondrial integrated stress response; mitochondrial translation; tissue specificity; treatment

DOI:  https://doi.org/10.1016/j.celrep.2025.115710
Mol Neurobiol. 2025 May 22.

The Role of Fatty Acid Binding Protein 7 in Neurological Diseases.

Yingxi Chen, Jiarui Liu, Yurou He, Yang Lü, Weihua Yu.

  Fatty acid binding protein 7 (FABP7) is a pivotal cytoplasmic protein involved in the transport and metabolism of fatty acids, with critical functions in the nervous system. This review highlights recent advances in understanding the role and mechanisms of FABP7 in neurological diseases. It begins with an overview of FABP7's distribution and expression in the nervous system, emphasizing its involvement in essential biological processes such as lipid metabolism, energy regulation, synaptic transmission, cell growth, and neuroinflammation. This review also explores FABP7's associations with major neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), schizophrenia, and depression, shedding light on its dual roles in neuroprotection and neurodegeneration. These findings position FABP7 as a promising target for novel therapeutic strategies. By unraveling its precise mechanisms and contributions to both neural health and disease, future research on FABP7 has the potential to revolutionize treatments for neurological disorders, offering innovative directions for therapeutic development.

Keywords:  Energy homeostasis; Fatty acid binding protein 7; Lipid metabolism; Neuroinflammation; Neurological disorders; Synaptic transmission

DOI:  https://doi.org/10.1007/s12035-025-05071-5
Immunity. 2025 May 14. pii: S1074-7613(25)00192-X. [Epub ahead of print]

Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer's disease.

Priya Prakash, Palak Manchanda, Evi Paouri, Kanchan Bisht, Kaushik Sharma, Jitika Rajpoot, Victoria Wendt, Ahad Hossain, Prageeth R Wijewardhane, Caitlin E Randolph, Yihao Chen, Sarah Stanko, Nadia Gasmi, Anxhela Gjojdeshi, Sophie Card, Jonathan Fine, Krupal P Jethava, Matthew G Clark, Bin Dong, Seohee Ma, Alexis Crockett, Elizabeth A Thayer, Marlo Nicolas, Ryann Davis, Dhruv Hardikar, Daniela Allende, Richard A Prayson, Chi Zhang, Dimitrios Davalos, Gaurav Chopra.

  Microglial phagocytosis genes have been linked to increased risk for Alzheimer's disease (AD), but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here, we showed that microglia formed lipid droplets (LDs) upon amyloid-β (Aβ) exposure and that LD loads increased with proximity to amyloid plaques in brains from individuals with AD and the 5xFAD mouse model. LD-laden microglia exhibited defects in Aβ phagocytosis, and unbiased lipidomic analyses identified a parallel decrease in free fatty acids (FFAs) and increase in triacylglycerols (TGs) as the key metabolic transition underlying LD formation. Diacylglycerol O-acyltransferase 2 (DGAT2)-a key enzyme that converts FFAs to TGs-promoted microglial LD formation and was increased in mouse 5xFAD and human AD brains. Pharmacologically targeting DGAT2 improved microglial uptake of Aβ and reduced plaque load and neuronal damage in 5xFAD mice. These findings identify a lipid-mediated mechanism underlying microglial dysfunction that could become a therapeutic target for AD.

Keywords:  Alzheimer’s disease; DGAT2; amyloid; lipid droplets; lipidomics; lipids; metabolism; microglia; neurodegeneration; phagocytosis

DOI:  https://doi.org/10.1016/j.immuni.2025.04.029
Brain Behav. 2025 May;15(5): e70428

Single-Cell RNA and Transcriptome Sequencing to Analyze the Role of Lactate Metabolism in Traumatic Brain Injury Astrocytes.

Zhang Bu, Yuqian Zhou, Feng Xu, Shan Xu.

   PURPOSE: After traumatic brain injury (TBI), ischemia and hypoxia of brain tissue, glucose undergoes anaerobic fermentation, leading to a large accumulation of lactic acid. Our aim was to explore the role of lactate metabolism in brain cells after TBI.
METHOD: In scRNA-seq dataset, 10-week-old male C57BL/6 J mice were randomized to undergo mild fluid percussion injury or sham surgery, and we analyzed frontal cortex tissue during the acute (24 h) and subacute (7 days) phases of TBI at single-cell resolution. Cell cycle phases were evaluated, and principal component analysis was performed. Cell populations were identified and visualized using the UMAP downscaling technique. Differentially expressed genes (DEGs) were analyzed using the "FindAllMarkers" algorithm. In addition, the set of genes related to lactate metabolism was evaluated using the AUCell score. GO and KEGG enrichment analyses were performed to investigate the functional pathways of DEGs in astrocytes in the acute and subacute phases of TBI.
RESULTS: A total of 13 cell populations were distinguished, including neurons, astrocytes, and oligodendrocyte progenitors. The number of neurons, astrocytes, and endothelial cells was reduced in the TBI group compared with the sham group. During the acute phase of TBI, enhanced interactions between brain-associated cells, especially astrocytes and oligodendrocyte precursor cells, were observed. Several signaling pathways, including EGF, CSF, MIF inflammatory factors as well as PSAP and PTN neurotrophic factor signaling were significantly enhanced after TBI. Lactate metabolism scores were elevated in the TBI group, especially in astrocytes. During the subacute phase, the frequency of intercellular communication increased but its intensity decreased. Astrocytes and oligodendrocyte precursor cells remained at high levels during both phases. PSAP signaling was closely associated with the subacute phase of TBI. Subsequently, NADH:ubiquinone oxidoreductase subunit B9 (Ndufb9) and cytochrome c oxidase subunit 8A (Cox8a) were identified as key players in lactate metabolism associated with TBI. Ndufb9 and Cox8a showed a consistent upward trend in brain tissue following TBI with transcriptomic data.
CONCLUSION: Lactate metabolism genes play an important role in TBI. These findings provide new insights into the cellular and molecular mechanisms following TBI.

Keywords:  astrocytes; lactate metabolism; traumatic brain injury

DOI:  https://doi.org/10.1002/brb3.70428
Res Sq. 2025 May 09. pii: rs.3.rs-6550812. [Epub ahead of print]

Dissecting Metabolic Control of Behaviors and Physiology During Aging in Drosophila.

Elizabeth S Pasam, Kishore Madamanchi, Girish C Melkani.

  Aging disrupts physiological and behavioral homeostasis, largely driven by one-carbon metabolism, mitochondrial dysfunction, energy sensing, and metabolic imbalance. To elucidate the roles of conserved metabolic, energy sensing, and mitochondrial genes in age-related decline, we employed genetic manipulations in vivo using Drosophila melanogaster models, in a cell-autonomous and non-cell-autonomous manner. By using panneuronal and indirect flight muscle (IFM)- specific drivers, we assessed the impact of gene knockdown or overexpression on sleep-circadian rhythms, locomotion, and lipid metabolism in a cell-autonomous and non-cell-autonomous manner to address bidirectional neuro-muscle communications. Knockdown of genes such as SdhD, Marf, and Gnmt leads to decrease in flight performance especially in 6 weeks with both the drivers. Which demonstrates cell-autonomous and non-cell autonomous effects of these genes. Negative geotaxis with panneuronal knockdown of Adsl, Gnmt, SdhD, Marf genes showed reduced locomotor performance in age-dependent manner consolidating their non-cell autonomous role and neuro-muscular interaction. Whereas mAcon1, LSD2, Ampkα, Ald, Adsl genes showed reduced flight performance with only IFM specific driver emphasizing the cell-autonomous role. Panneuronal knockdown of Ald, GlyP, mAcon1, and Gnmt genes showed increased total sleep, reduced activity, while Adsl and Ogdh knockdown led to sleep fragmentation, in a mid-age suggests cell autonomous impact. Functional analysis of AMPK signaling via overexpression and knockdown of Ampkα, as well as expression of the yeast ortholog SNF1A and its kinase-dead mutant, revealed kinase-dependent, age- and tissue-specific modulation of sleep and activity rhythms. Lipid analysis showed that panneuronal overexpression of Ampkα altered lipid droplet number and size in the brain, indicating disrupted lipid homeostasis during aging. These findings establish Ampkα as a central regulator of behavioral and metabolic aging, linking neuronal energy sensing, motor function, and lipid dynamics, and offer mechanistic insights into tissue-specific metabolic regulation with potential relevance for interventions targeting age-related decline and neurodegeneration.

Keywords:  Aging; circadian rhythm; lipid metabolism; mitochondrial dysfunction; sleep fragmentation

DOI:  https://doi.org/10.21203/rs.3.rs-6550812/v1
Mov Disord. 2025 May 23.

Dysregulation of Monounsaturated Fatty Acids is Related to α-Synuclein in Multiple System Atrophy.

Finula I Isik, YuHong Fu, Russell Pickford, Qi Cheng, Yue Yang, Simon J G Lewis, Nicolas Dzamko, Glenda M Halliday, Woojin Scott Kim.

   BACKGROUND: Multiple system atrophy (MSA) is a neurodegenerative disease pathologically characterized by the presence of glial cytoplasmic inclusions (GCI) composed of α-synuclein aggregates. In Parkinson's disease, increases in monounsaturated fatty acids (MUFA) in phospholipid membranes promote α-synuclein binding, aggregation, and toxicity, and the inhibition of stearoyl-CoA desaturase (SCD), the enzyme responsible for synthesizing MUFA, alleviates α-synuclein toxicity. However, little is known about phospholipid MUFA or SCD in the context of MSA pathology.
OBJECTIVES: To determine whether phospholipid MUFA and SCD levels are altered in MSA brain and related to α-synuclein pathology.
METHODS: Phospholipid MUFA levels in the disease-affected motor cortex white matter (MWM) and disease-unaffected superior occipital cortex (SOC) of postmortem MSA and control brain were analyzed using liquid chromatography-mass spectrometry. Brain GCI, α-synuclein, and SCD were analyzed using immunofluorescence, Western blotting, and quantitative polymerase chain reaction (qPCR). Serum SCD was analyzed using ELISA.
RESULTS: MUFA in phosphatidic acid, phosphatidylcholine, and phosphatidylethanolamine were elevated in MSA MWM compared with control MWM by 3.9%, 8.8%, and 9.5%, respectively, whereas none were altered in SOC. MUFA were strongly associated with α-synuclein only in MWM. SCD mRNA and protein expression were decreased only in MSA MWM compared with control MWM.
CONCLUSIONS: These findings suggest a prevalence of MUFA dysregulation in specific regions of MSA brain, resulting in MUFA levels remaining high despite decreases in SCD expression. Our study has provided new insights into an unrecognized pathway in MSA and opened a new area of research for better understanding MSA pathogenesis. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords:  monounsaturated fatty acids; multiple system atrophy; phospholipid; stearoyl‐CoA desaturase; α‐synuclein

DOI:  https://doi.org/10.1002/mds.30248
Mol Neurobiol. 2025 May 22.

Intervention Role of APOE in CNS Diseases: APOE Actions and APOE Neurogenesis Capability.

Wenhua Li, Suya Ma, Min Li.

  Neurogenesis is a biological process in which new neurons are generated from neural stem cells (NSCs) in specific neural niches in the brain. Impaired neurogenesis, characterized by the progressive loss of neurons, leads to cognitive and motor disabilities and is a hallmark of central nervous system (CNS) diseases. Conversely, enhancing neurogenesis has been shown to alleviate the symptoms of CNS diseases. Apolipoprotein E (APOE) is a protein that plays various biological roles in CNS diseases. Emerging research indicates that APOE is involved in adult neurogenesis, which is crucial for maintaining the neural progenitor pool in the dentate gyrus (DG) and synaptic activity. Therefore, APOE could be a therapeutic target for promoting neurogenesis in the treatment and intervention of CNS diseases. In this context, we present a comprehensive overview of the clinical evidence supporting the role of APOE in CNS diseases on the basis of a meta-analysis. We also discuss the neurogenic potential of APOE, which has significant implications not only for understanding the biological underpinnings of neurological diseases but also for developing novel treatment strategies for CNS diseases.

Keywords:   APOE ; Central nervous system diseases; Meta-analysis; Neurogenesis

DOI:  https://doi.org/10.1007/s12035-025-05028-8
Nat Metab. 2025 May 19.

Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of 13C-labelled glucose metabolism.

CRUK Rosetta Grand Challenge Consortium

Transcriptomic studies have attempted to classify glioblastoma (GB) into subtypes that predict survival and have different therapeutic vulnerabilities1-3. Here we identified three metabolic subtypes: glycolytic, oxidative and a mix of glycolytic and oxidative, using mass spectrometry imaging of rapidly excised tumour sections from two patients with GB who were infused with [U-13C]glucose and from spatial transcriptomic analysis of contiguous sections. The phenotypes are not correlated with microenvironmental features, including proliferation rate, immune cell infiltration and vascularization, are retained when patient-derived cells are grown in vitro or as orthotopically implanted xenografts and are robust to changes in oxygen concentration, demonstrating their cell-intrinsic nature. The spatial extent of the regions occupied by cells displaying these distinct metabolic phenotypes is large enough to be detected using clinically applicable metabolic imaging techniques. A limitation of the study is that it is based on only two patient tumours, albeit on multiple sections, and therefore represents a proof-of-concept study.

DOI: https://doi.org/10.1038/s42255-025-01293-y
Int J Biol Sci. 2025 ;21(7): 3011-3029

SIRT3 is required for the protective function of ketogenic diet on neural inflammation and neuropathic pain.

Mengqiu Deng, Yuanyuan Fang, Yan Chu, Ruifeng Ding, Xiaoyi Fan, Huawei Wei, Honghao Song, Guowei Jiang, Hailing Zhang, Chaofeng Han, Hongbin Yuan.

  Chronic neuroinflammation is a key pathological feature of neuropathic pain. The ketogenic diet (KD) has demonstrated potential to reduce neuronal excitability and alleviate inflammation in epilepsy, yet its effects and precise mechanisms in neuropathic pain remain elusive. We first observed that β-hydroxybutyrate (BHB), a key metabolite induced by KD, was reduced in mice following neuropathic pain induced by chronic constriction injury (CCI). Subsequently, we demonstrated that KD effectively alleviated CCI-induced thermal hyperalgesia and mechanical allodynia, while mitigating neuroinflammation through reduced microglial activation and pro-inflammatory cytokine levels. BHB reduced reactive oxygen species (ROS) production, which coincided with enhanced mitochondrial membrane potential in microglia, thereby attenuating microglia-mediated inflammatory responses. Both in vivo and in vitro experiments revealed KD-induced upregulation of uncoupling protein 2 (UCP2), sirtuin 3 (SIRT3) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) in the spinal dorsal horn. Importantly, SIRT3 deficiency abolished KD's protective effects against neuropathic pain and reduced BHB levels, potentially attributable to diminished expression of hepatic ketone body synthases and spinal ketone body-utilizing enzymes. These findings highlight SIRT3 as a promising therapeutic target for neuropathic pain within the ketogenic diet paradigm, providing a foundation for novel therapeutic strategies.

Keywords:  ketogenic diet; microglia; neuropathic pain; sirtuin 3; β-hydroxybutyrate

DOI:  https://doi.org/10.7150/ijbs.110921
J Am Chem Soc. 2025 May 23.

Bis-Allylic Deuterated Docosahexaenoic Acid-Esterified Phospholipids Resist In Vivo Peroxidation in Rat Brain.

Secilia Garza, Genevieve James, Hui Gyu Park, Paul R S Baker, Martin-Paul Agbaga, Vicki Ea, Mikhail S Shchepinov, J Thomas Brenna.

The human central nervous system simultaneously has the most highly unsaturated fatty acids (HUFAs) and the highest metabolic rate among body tissue. Up to 1% of consumed O2 is converted to reactive oxygen species (ROS) that cause unregulated damage to HUFA-rich membrane phospholipids (PLs). Docosahexaenoic acid (DHA) is the brain's most unsaturated and abundant HUFA. Reinforcing the ROS-labile bis-allylic positions with deuterium (D-DHA) protects against oxidative damage in vitro and in vivo. We developed an LC-MS/MS method to detect ambient levels of nascent oxidation products of DHA and D-DHA containing PLs in vivo in rat brain lipid extracts. Multiple reaction monitoring (MRM)-triggered mass spectra confirmed D-DHA incorporation in D-DHA-fed rat brain PLs. DHA-PL nascent oxidation products add 2 O, consistent with known peroxidation reactions. In contrast, D-DHA oxidation is primarily detected as a single O addition, consistent with epoxidation. D-DHA-PL showed 20%-30% lower overall oxidation compared to DHA-PL. Our data are consistent with a mechanism of action whereby D-DHA blocks excess lipid peroxidation, leading to lower overall membrane damage. D-DHA is a unique therapeutic approach against neurodegenerative diseases where ROS-driven oxidation is implicated.

DOI: https://doi.org/10.1021/jacs.4c17871
Metab Brain Dis. 2025 May 17. 40(5): 205

Hypercholesterolemia, oxidative stress, and low-grade inflammation: a potentially dangerous scenario to blood-brain barrier.

Hémelin Resende Farias, Lílian Corrêa Costa-Beber, Fátima Theresinha Costa Rodrigues Guma, Jade de Oliveira.

  For more than a century, hypercholesterolemia has been linked to atherosclerotic cardiovascular disease. Notably, this metabolic condition has also been pointed out as a risk factor for neurodegenerative diseases, such as Alzheimer's disease (AD). Oxidative stress seems to be the connective factor between hypercholesterolemia and cardio and neurological disorders. By disturbing redox homeostasis, hypercholesterolemia impairs nitric oxide (NO) availability, an essential vasoprotective element, and jeopardizes endothelial function and selective permeability. The central nervous system (CNS) is partially protected from peripheral insults due to an arrangement between endothelial cells, astrocytes, microglia, and pericytes that form the blood-brain barrier (BBB). The endothelial dysfunction related to hypercholesterolemia increases the risk of developing cardiovascular diseases and also initiates BBB breakdown, which is a cause of brain damage characterized by neuroinflammation, oxidative stress, mitochondrial dysfunction, and, ultimately, neuronal and synaptic impairment. In this regard, we reviewed the mechanisms by which hypercholesterolemia-induced oxidative stress affects peripheral vessels, BBB, and leads to memory deficits. Finally, we suggest oxidative stress as the missing link between hypercholesterolemia and dementia.

Keywords:  Cholesterol; Dementia; Endothelial dysfunction; Inflammation; Mild cognitive impairment; Oxidative stress

DOI:  https://doi.org/10.1007/s11011-025-01620-y
Nucl Med Mol Imaging. 2025 Jun;59(3): 174-184

Relationship Between Cerebral Glucose Metabolism and Neurodevelopmental Outcomes in Very-Low-Birth-Weight Infants without Structural Abnormalities.

Jae Hyun Park, Jimin Yuei, Soyoung Lee, Jungsu S Oh, Kyoung Sook Won, Hae Won Kim.

   Purpose: Very-low-birth-weight (VLBW) infants are more likely to have poor neurodevelopmental outcomes, even if structural abnormalities are not observed during brain magnetic resonance imaging (MRI). The purpose of the present study was to determine whether cerebral glucose metabolism is correlated with neurodevelopmental outcomes in VLBW infants without structural abnormalities.
Methods: Twenty-seven VLBW infants (birth weight < 1,500 g) without structural abnormalities were prospectively enrolled. All infants underwent F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) examinations at term-equivalent ages, and the regional glucose metabolic ratios were calculated. Neurodevelopmental outcomes were assessed using the Mental Development Index (MDI) and the Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development-II at a corrected age of 18-24 months. Poor neurodevelopmental outcomes were defined as an MDI or PDI score < 85.
Results: The glucose metabolic ratio in the right central region of the brain was significantly correlated with the MDI score (r = 0.505, p = 0.007). The glucose metabolic ratios in the right central region and right insula in the poor-neurodevelopmental-outcome group were significantly lower than those in the good-neurodevelopmental-outcome group (1.03 ± 0.02 vs. 1.08 ± 0.04, p = 0.004, and 1.08 ± 0.05 vs. 1.13 ± 0.05, p = 0.018, respectively). Furthermore, the right central region and insula exhibited large extent of metabolic connectivity in infants with good neurodevelopmental outcome than that in infants with poor neurodevelopmental outcome.
Conclusions: Cerebral glucose metabolism was correlated with the neurodevelopmental outcomes of VLBW infants at a corrected age of 18-24 months.
Supplementary Information: The online version contains supplementary material available at 10.1007/s13139-024-00893-y.

Keywords:  F-18 FDG; Neurodevelopmental outcome; Positron emission tomography; Very-low-birth-weight infant

DOI:  https://doi.org/10.1007/s13139-024-00893-y
Br J Pharmacol. 2025 May 22.

Nervonic acid, a long chain monounsaturated fatty acid, improves mitochondrial function in adrenomyeloneuropathy fibroblasts.

Chenxu Li, Marcia R Terluk, Reena V Kartha.

   BACKGROUND AND PURPOSE: Nervonic acid plays a vital role in maintaining normal brain and neuronal function. Nervonic acid has gained increasing attention because of its potential neuroprotective and anti-inflammatory properties. Nonetheless, the beneficial effects of nervonic acid are yet to be fully investigated. Adrenomyeloneuropathy (AMN), a type of X-linked adrenoleukodystrophy (ALD), is a progressive inherited metabolic disease characterised by accumulation of saturated very long-chain fatty acids (VLCFAs) in plasma and tissues, leading to increasing oxidative stress, mitochondrial dysfunction, neuroinflammation, cognitive dysfunction and disability. We previously found that nervonic acid can biochemically reverse the accumulation of saturated VLCFAs and increase cellular ATP production in ALD. Here, we investigated nervonic acid as a potential therapy for ALD by assessing its impact on mitochondrial function.
EXPERIMENTAL APPROACH: We assessed the effect of nervonic acid on cellular bioenergetics and oxidative stress in AMN patient-derived fibroblasts. We employed Seahorse real-time cell metabolic analysis and imaging of cells treated with increasing concentrations of nervonic acid. Normal dermal fibroblasts served as the healthy control.
KEY RESULTS: AMN cells demonstrate significantly impaired basal respiration, ATP production, maximal respiration and spare respiratory capacity compared to healthy fibroblasts. These mitochondrial respiration parameters significantly improved on treatment with nervonic acid in a concentration-dependent manner. Nervonic acid treatment also significantly reduced mitochondria-derived and total cellular reactive oxygen species, indicating mitigation of total oxidative stress.
CONCLUSION AND IMPLICATIONS: Our findings indicate a new mechanism of action for nervonic acid in ALD and other mitochondrial dysfunction-associated diseases. This can also indirectly prevent downstream inflammation, thus altering disease progression.

Keywords:  X‐linked adrenoleukodystrophy; adrenomyeloneuropathy; metabolic disorder; mitochondrial function; monounsaturated fatty acid; nervonic acid; oxidative stress

DOI:  https://doi.org/10.1111/bph.70044
PNAS Nexus. 2025 May;4(5): pgaf146

Astrocyte Fabp7 modulates nocturnal seizure threshold and activity-dependent gene expression in mouse brain.

Micah Lefton, Carlos C Flores, Yuji Owada, Christopher J Davis, Thomas N Ferraro, Yool Lee, Wheaton L Schroeder, Jason R Gerstner.

  Epileptic seizures often track with time of day and/or changes in vigilance state; however, specific molecular and cellular mechanisms driving the ictal and temporal associations are lacking. Astrocytes are a type of glial cell known to modulate neuronal excitability and circadian rhythms. These cells also abundantly express fatty acid-binding protein 7 (Fabp7), a clock-driven molecule necessary for normal sleep regulation, lipid signaling, and gene transcription. To determine whether Fabp7 influences time-of-day-dependent seizure susceptibility, we tested male C57/BL6N wild-type (WT) and Fabp7 knockout (KO) mice using electroshock seizure threshold. Compared with WT mice, Fabp7 KO mice exhibited markedly higher general- and maximal-electroshock seizure thresholds (GESTs and MESTs, respectively) during the dark phase, but not the light phase. We used RNA-seq to determine the role of Fabp7 in activity-dependent gene expression in nocturnal seizures and compared genome-wide mRNA expression in cortical/hippocampal tissue collected from WT-MEST and Fabp7 KO-MEST mice with WT-SHAM and Fabp7 KO-SHAM mice during the dark period. Whereas significant differential expression of immediate early genes was observed in WT-MEST compared with WT-SHAM, this effect was blocked in the Fabp7 KO-MEST versus Fabp7 KO-SHAM. Gene ontology and pathway analysis of all groups revealed significant overlap between WT-MEST:WT-SHAM and Fabp7 KO-SHAM:WT-SHAM comparisons, suggesting basal mRNA levels of core molecular and cellular mechanisms in the brain of Fabp7 KO approximate postictal WT brain. Together, these data suggest that Fabp7 regulates time-of-day-dependent neural excitability and that neural activity likely interacts with astrocyte Fabp7-mediated signaling cascades to influence activity-dependent gene expression.

Keywords:  blbp; circadian; excitability; glia; transcription

DOI:  https://doi.org/10.1093/pnasnexus/pgaf146
Brain Res Bull. 2025 May 21. pii: S0361-9230(25)00209-6. [Epub ahead of print] 111397

Integrative metabolomics and transcriptomics analysis of hippocampus reveals taurine metabolism and sphingolipid metabolism dysregulation associated with sleep deprivation-induced memory impairment.

Ting Chen, Junke Jia, Chenyi Gao, Qi Zhong, Lijuan Tang, Xiaokai Sui, Shuang Li, Chang Chen, Zongze Zhang.

  Sleep plays a crucial role in restoring and repairing the body, consolidating memory, regulating emotions, maintaining metabolic and so on. Sleep deprivation is known to impair cognitive functions. In this study, we investigated the mechanisms underlying memory impairment induced by sleep deprivation through a combined metabolomic and transcriptomic analysis of hippocampus. Eight-week-old mice were selected as the study subjects and the sleep deprivation chamber was used to establish a sleep deprivation (SD) model. Novel object recognition tests (NOR), and Y-maze tests were used to assess the behavioral outcomes in mice. The hippocampus were extracted and studied using the untargeted metabolomics or transcriptomics high-throughput sequencing method. An integrative analysis was conducted to elucidate the metabolic and genetic changes. Behavioral tests showed that SD group exhibited memory impairment. Metabolomic analysis identified 84 differentially expressed metabolites (DEMs), including 12 under the positive ion mode and 72 under the negative ion mode. The analysis revealed that sleep deprivation caused abnormalities in several metabolic pathways, with particularly pronounced effects observed in glycerophospholipid metabolism, linoieic acid metabolism, alanine, aspartate, glutamate metabolism, taurine and hypotaurine metabolism, and purine metabolism. While transcriptomic analysis releaved 97 differentially expressed genes (DEGs) (51 were down-regulated and 46 were up-regulated DEGs). Integrative analysis of the metabolomic and transcriptomic identified profiles showed that sleep deprivation may regulate taurine and hypotaurine metabolism and sphingolipid metabolism, there by influencing memory. Our results prompt severe metabolic disturbances occur in the hippocampus with SD in mice, which can provide a basis for the mechanism research.

Keywords:  Hippocampus; Memory; Metabolites; Sleep deprivation; Transcriptomics

DOI:  https://doi.org/10.1016/j.brainresbull.2025.111397
Talanta. 2025 May 15. pii: S0039-9140(25)00792-1. [Epub ahead of print]295 128302

In situ imaging study of targeted iron and metabolically related molecules in tumors and brain tissues using MALDI-MS imaging.

Kang Han, Xintong Shi, Heng Zhang, Xiaofang Jin, Qiaoya Zhao, Xingyao Li, Tong Zhang, Yajing Xie, Li Duan, Yan-Zhong Chang.

  Iron is one of the essential trace elements required for maintaining life, and it participates in several physiological activities. Comprehensive direct targeting of iron in tissue slices will be more conducive to exploring the physiological processes of iron metabolism disorders. In this study, we introduce a novel matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) methodology designed to map iron distribution comprehensively across tumor tissues and specific brain regions. We selected the reactive matrix based on iron chelating agents to promote the covalent charge labeling of oxygen and iron, which solved the problem of the low detection limit of metal elements when using MSI. Our research expands beyond iron mapping to include the simultaneous detection of molecules associated with energy metabolism in tumor tissues, lipid molecules related to myelin in demyelination models, and both neurotransmitter and lipid molecules in Parkinson's disease (PD) models. This multifaceted approach has unveiled the potential roles of iron in tumor progression and the pathogenesis of neurodegenerative diseases, providing novel insights into its functions during pathological processes.

Keywords:  Iron chelators; Iron mapping; Iron metabolism; MALDI-MSI

DOI:  https://doi.org/10.1016/j.talanta.2025.128302
Nat Metab. 2025 May 20.

Nuclear SREBP2 condensates regulate the transcriptional activation of lipogenic genes and cholesterol homeostasis.

Mengqiang Xu, Shi-You Jiang, Shuocheng Tang, Meimei Zhu, Yueer Hu, Juewan Li, Jizhi Yan, Chenyang Qin, Dongxia Tan, Yang An, Yuxiu Qu, Bao-Liang Song, Hanhui Ma, Wei Qi.

The precursor of sterol regulatory element-binding protein-2 (SREBP2) is a membrane-bound transcription factor regulating cholesterol biosynthesis. Under cholesterol-deficient conditions, mature SREBP2 is released from membrane-bound precursors through proteolytic cleavage and enters the nucleus. However, regulation of the transcriptional activity of nuclear SREBP2 (nSREBP2) is poorly understood. In the present study, we reported that nSREBP2 forms nuclear condensates through its amino-terminal, intrinsically disordered region (IDR) and works together with transcription coactivators, partly on superenhancers, for the transcriptional activation of SREBP2 target genes. Substitution of a conserved phenylalanine by alanine within the IDR abolishes the formation of nSREBP2 condensates and reduces its transcriptional activity. This can be effectively rescued by fusion with a phase separation driving FUS-IDR. Knock-in of the phenylalanine-to-alanine substitution in male mice compromises feeding-induced nSREBP2 activity and lowers hepatic and circulating cholesterol levels, underscoring the functional significance of nSREBP2 condensates. Together, the present study reveals that nuclear condensates driven by nSREBP2 N-terminal IDR facilitate the efficient activation of lipogenic genes and play an important role in cholesterol homeostasis.

DOI: https://doi.org/10.1038/s42255-025-01291-0
J Biol Chem. 2025 May 14. pii: S0021-9258(25)02087-3. [Epub ahead of print] 110237

ABHD18 degrades cardiolipin by stepwise hydrolysis of fatty acids.

Mindong Ren, Shiyu Chen, Miriam L Greenberg, Michael Schlame.

  Cardiolipin (CL), the signature phospholipid of mitochondria, carries four fatty acids that are remodeled after de novo synthesis. In yeast, remodeling is accomplished by the joint action of Cld1, a lipase that removes a fatty acid from CL, and Taz1, a transacylase that transfers a fatty acid from another phospholipid to monolyso-CL. While taz1 homologues have been identified in all eukaryotes, cld1 homologues have remained obscure. Here we demonstrate that ABHD18, a highly conserved protein of plants, animals, and humans, is functionally homologous to Cld1. Knockdown of Abhd18 decreased the concentration of monolyso-CL in murine, Taz-knockout myoblasts. Inactivation of Abhd18 in Drosophila substantially increased the abundance of CL. Abhd18 inactivation also reversed the increase in the rate of CL degradation, as measured with 13C isotopes, and the accumulation of deacylated CLs, such as monolyso-CL and dilyso-CL, in TAZ-deficient flies. CL species with more than 5 double bonds were resistant to ABHD18. Our data demonstrate that ABHD18 is the elusive lipase that hydrolyzes CL in mice and flies and presumably in other organisms. Rather than removing just one fatty acid, we show that ABHD18 deacylates CL further. Thus, ABHD18 catalyzes the breakdown of CL whereas TAZ protects CL from degradation.

Keywords:  cardiolipin; lipase; lysophospholipid; mitochondria; phospholipid turnover; tafazzin

DOI:  https://doi.org/10.1016/j.jbc.2025.110237
Nature. 2025 May 22.

Author Correction: A human brain map of mitochondrial respiratory capacity and diversity.

Eugene V Mosharov, Ayelet M Rosenberg, Anna S Monzel, Corey A Osto, Linsey Stiles, Gorazd B Rosoklija, Andrew J Dwork, Snehal Bindra, Alex Junker, Ya Zhang, Masashi Fujita, Madeline B Mariani, Mihran Bakalian, David Sulzer, Philip L De Jager, Vilas Menon, Orian S Shirihai, J John Mann, Mark D Underwood, Maura Boldrini, Michel Thiebaut de Schotten, Martin Picard.

DOI: https://doi.org/10.1038/s41586-025-09081-0
Gastroenterol Hepatol Bed Bench. 2024 ;17(4): 357-378

The role of genetic defects in carnitine-associated hepatic encephalopathy: a review of literature.

Ali Kheirandish, Reza Shah Hosseini, Shirin Yaghoobpoor, Ashkan Bahrami, Alireza Aghajani, Mobina Fathi, Milad Alipour, Ameneh Zarebidoki, Ashraf Mohamadkhani.

Hepatic encephalopathy (HE) is a serious neurological disorder characterized by brain dysfunction due to liver failure which occurs as a result of chronic or acute liver disease. HE can manifest with various neurological or psychiatric symptoms ranging from excessive sleepiness and sleep disorders to coma. HE is a serious disorder that in acute conditions can even lead to the death of the patient due to cerebral edema. Carnitine acts as a vital component in facilitating the transport of long-chain fatty acids into the mitochondria, thereby enabling their oxidation for the generation of energy. Carnitine additionally assumes a crucial role in the functionality of the brain. Carnitine deficiency is associated with various types of inherited disorders related to low levels of carnitine. A strong correlation exists between the insufficiency of carnitine and the occurrence of HE. If a deficiency of carnitine is identified through clinical symptoms or laboratory results in patients with liver dysfunction, treatment with carnitine replacement therapy is recommended. Thus, the administration of acetyl-L-carnitine in patients with HE can improve their mental and psychological conditions. In the present study, we provide an overview of the molecular and cellular mechanisms underlying HE. Our aim in this review has been genetic investigation of HE and genetic mutations to the causes of this neurological condition, which include carnitine deficiency, hyperammonemia, and etc. Finally, we discuss the genetic mutations that lead to carnitine deficiency as well as hyperammonemia and are associated with this neurological disease, together with the future treatment of this disease based on carnitine therapy. More studies soon will help early diagnosis (before poor prognosis) based on clinical observations, genetic tests, prenatal diagnosis, and new treatment strategies. Hepatic encephalopathy, Carnitine, Ammonia, Genetic, Treatment.

DOI: https://doi.org/10.22037/ghfbb.v17i4.2960
Autophagy Rep. 2024 ;3(1): 2314361

Alpha-synuclein aggregates trigger cardiolipin externalization and mitophagy.

Rebeca Martín-Jiménez, Olivier Lurette, Etienne Hebert-Chatelain.

  Accumulation of Lewy bodies in dopaminergic neurons is associated to Parkinson disease (PD). The main component of Lewy bodies appears to be aggregates of alpha-synuclein (α-syn). Several mutations of the gene encoding this protein promote its aggregation. Thus, clustering of α-syn is considered a central event in the onset of PD. An old theory also postulates that mitochondrial dysfunction represents another cause of PD pathogenesis. However, the impact of α-syn aggregates on mitochondria remains poorly understood considering the technical difficulties to discriminate between the different forms of α-syn. In this punctum, we describe our recent work in which we used a newly developed optogenetic tool to control the aggregation of α-syn and examine the impact on mitochondria. This work revealed that α-syn aggregates dynamically interact with mitochondria, triggering their depolarization and leading to cardiolipin translocation to the surface of mitochondria and mitophagy. Abbreviations: α-syn: alpha-synuclein; BNIP3L: BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like; FUNDC1: FUN14 domain-containing protein 1; IMM: inner mitochondrial membrane; LIPA: light-induced protein aggregation; OMM: outer mitochondrial membrane; PD: Parkinson disease; SNc: substantia nigra par compacta.

Keywords:  Lewy bodies; PLSCR3; mitochondrial fission; mitochondrial membrane potential; parkinson disease; selective autophagy; ubiquitin

DOI:  https://doi.org/10.1080/27694127.2024.2314361