bims-medebr 2025-12-14 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–12–14
28 papers selected by
Regina F. Fernández, Johns Hopkins University

NAD⁺ Reduction in Glutamatergic Neurons Induces Lipid Catabolism and Neuroinflammation in the Brain via SARM1.
Temporal Dynamics of CNS Cholesterol Esters Correlate with Demyelination and Remyelination.
The role of lipid metabolism in neuronal senescence.
Neuronal fatty acid oxidation fuels memory after intensive learning in Drosophila.
Microglia-derived APOE2 improves remyelination even in the presence of endogenous APOE4.
Altered Glut4, IRAP, and Brain Insulin Signaling in a Mouse Model of Epilepsy and Contributions to Glucose Transport in Neurons and Astrocytes.
An Alternative Metabolic Pathway of Glucose Oxidation Induced by Mitochondrial Complex I Inhibition: Serinogenesis and Folate Cycling.
Validation of Dynamic Deuterium Metabolic Imaging (DMI) for the Measurement of Cerebral Metabolic Rates of Glucose in Rat.
Structural transport and inhibition mechanism of the mitochondrial pyruvate carrier.
The Neurochemical Landscape of Oligodendrocyte Physiology: From Myelination to Metabolic and Synaptic Modulation.
Deficiency of the Tangier Disease Gene Abca1 Is Associated With Microglial Defects in Mice.
Enhanced lipid metabolism serves as a metabolic vulnerability to polyunsaturated fatty acids in glioblastoma.
Mitochondrial Transplantation Increases Bioenergetics and Neurite Outgrowth in Healthy and P301Ltau-Expressing SH-SY5Y Cells.
Dysregulated metabolism of ceramides and glycosphingolipids in Parkinson's Disease.
Three mammalian VDAC isoforms distinctly regulate mitochondrial function and proteome to maintain cell metabolism.
Metabolic costs and trade-offs of hypermetabolism in human motor neurons with ATP synthase deficiency.
The astrocytic engine: Na+,K+-ATPase at the nexus of brain function and malfunction.
Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment.
Medium-chain triglycerides and ketogenic diet prevent alterations of the gut microbiome in transgenic Alzheimer's disease mice.
RetSat Knockout Mitigates Hypoxia-Induced Microglial Activation by Enhancing Lipid Droplets Degradation.
Brain glucose extraction is fixed at 10% despite twofold variability in resting cerebral blood flow in healthy humans.
Multimodal mass spectrometry imaging for plaque- and region-specific neurolipidomics in Alzheimer's disease mouse models.
Dynamic changes in mitochondria support phenotypic flexibility of microglia.
NPD1/GPR37 signaling protects against painful traumatic brain injury and comorbidities by regulating demyelination, glial responses, and neuroinflammation in the mouse brain.
The Quantum Brain: The Untold Story of Docosahexaenoic Acid's Role in Brain Evolution, Biophysics, and Cognition.
Astrocytic LCN2 drives neuronal dysfunction in epilepsy by suppressing tunnel nanotube-mediated mitochondrial transfer via NLRP3 inflammasome activation.
Multimodal MR imaging for quantification of brain lipid in mice at 9.4T.
HK1 and HK2 Beyond Glycolysis: Mitochondrial Interactions and Dual Roles in Metabolism and Cell Fate.

Adv Sci (Weinh). 2025 Dec 12. e09950

NAD⁺ Reduction in Glutamatergic Neurons Induces Lipid Catabolism and Neuroinflammation in the Brain via SARM1.

Zhen-Xian Niou, Sen Yang, Andrea Enriquez, Nino A Espinas, Anoosha Sri, Caliel D Hines, Jason M Tennessen, Chia-Shan Wu, Jui-Yen Huang, Hui-Chen Lu.

  NAD⁺ homeostasis is vital for neuronal health, as demonstrated by the opposing roles of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), a NAD⁺-synthesizing enzyme, and sterile alpha and TIR motif-containing protein 1 (SARM1), a NAD⁺ hydrolase. Neurodegenerative insults that decrease NMNAT2 activate SARM1, leading to axon loss. To understand how the NMNAT2-SARM1 axis influences brain energy metabolism, multi-omics approaches are used to investigate the metabolic changes resulting from neuronal NMNAT2 loss. Loss of NMNAT2 in glutamatergic neurons leads to a significant metabolic shift in the cerebral cortex from glucose to lipid catabolism, reduced lipid abundance, and pronounced neurodegenerative phenotypes and motor behavioral deficits. These metabolic disturbances are accompanied by altered glial expression of enzymes regulating glucose and lipid metabolism, enhanced inflammatory signaling, and disrupted astrocytic transcriptomic profiles related to cholesterol synthesis and immune activation. Notably, SARM1 deletion in NMNAT2-deficient mice restored lipid metabolism, astrocyte transcriptomic profiles, and mitigated neurodegeneration and motor behaviors. These findings suggest that neuronal NAD⁺ depletion triggers maladaptive, SARM1-dependent metabolic reprogramming, shifting energy use from glucose to lipids, which in turn promotes inflammation and neurodegeneration.

Keywords:  NMNAT2, SARM1; energy metabolism; inflammation; lipids; neurodegeneration

DOI:  https://doi.org/10.1002/advs.202509950
ACS Chem Neurosci. 2025 Dec 09.

Temporal Dynamics of CNS Cholesterol Esters Correlate with Demyelination and Remyelination.

Nishama De Silva Mohotti, Jenna M Williams, Rashmi Binjawadagi, Hiroko Kobayashi, Disni Dedunupitiya, Jack M Petersen, Alana Garcia, Meredith D Hartley.

  Elevated cholesterol ester levels have been observed in the CNS of patients with neurological diseases; yet, the source of cholesterol ester accumulation and whether it is directly linked to demyelination remain undefined. This study investigates the temporal dynamics of cholesterol esters using the Plp1-iCKO-Myrf mouse model, which features distinct phases of demyelination and remyelination. Our findings reveal that cholesterol ester levels increased with demyelination in both the brain and spinal cord. In the brain, cholesterol esters declined to normal levels during remyelination, whereas cholesterol esters remained elevated in the spinal cord, which had limited remyelination. Expression of acetyl-CoA-acyltransferase 1 (ACAT1) and lecithin-cholesterol acyltransferase (LCAT) were elevated during demyelination, implying the potential involvement of both proteins in the formation of cholesterol esters. Colocalization studies revealed that ACAT1 is predominantly expressed by microglia and LCAT is predominantly expressed by astrocytes during demyelination, highlighting the active roles of glial cells in cholesterol ester metabolism. In addition, we showed that administering the remyelinating drug, Sob-AM2, effectively reduced the level of cholesterol ester accumulation in the brain during demyelination, underscoring the potential that manipulating cholesterol ester regulatory pathways may offer for restoring cholesterol homeostasis and promoting remyelination in demyelinating diseases.

Keywords:  ACAT1; Demyelination; LCAT; astrocytes; brain; cholesterol ester; lipid droplets; microglia; remyelination; spinal cord; thyroid hormone agonists

DOI:  https://doi.org/10.1021/acschemneuro.5c00703
FEBS Open Bio. 2025 Dec 12.

The role of lipid metabolism in neuronal senescence.

Dikaia Tsagkari, Eleftheria Panagiotidou, Nektarios Tavernarakis.

  Senescence is a complex cellular state characterised by irreversible growth arrest and metabolic reprogramming. In neurons, senescence has been mainly observed in the context of ageing and age-related neurodegeneration. Lipid metabolism plays a critical role in cellular homeostasis, with emerging evidence suggesting that alterations in lipid species, including fatty acids, cholesterol, sphingolipids and phospholipids, fundamentally drive or contribute to the senescent phenotype in both neuronal and non-neuronal cells in the brain. Namely, changes in lipid species levels result in the accumulation of lipid droplets (LDs), leading to dysregulation of membrane dynamics, and in turn to the production of bioactive lipid mediators, which collectively shape the senescence-associated secretory phenotype (SASP) in the brain. In this review, we describe the cell type-specific patterns of lipid dysregulation in neurons, astrocytes, microglia and other glial cells during senescence, highlighting the role of key lipid species and their association with senescence markers and phenotypes. Furthermore, we discuss the bidirectional relationship between lipid metabolism and mitochondrial dysfunction in cellular senescence. We also examine the molecular mechanisms through which lipid metabolic pathways can orchestrate neural senescence and their contribution to ageing and age-related neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Finally, we review emerging therapeutic strategies targeting lipid metabolic pathways to modulate neural senescence and potentially ameliorate age-associated brain pathology.

Keywords:  ageing; autophagy; lipid metabolism; mitochondria; neurodegeneration; neuronal cells; senescence

DOI:  https://doi.org/10.1002/2211-5463.70181
Nat Metab. 2025 Dec 10.

Neuronal fatty acid oxidation fuels memory after intensive learning in Drosophila.

Alice Pavlowsky, Bryon Silva, Ruchira Basu, Amandine Correia Delecourt, David Geny, Lydia Danglot, Pierre-Yves Plaçais, Thomas Preat.

Metabolic flexibility allows cells to adapt to different fuel sources, which is particularly important for cells with high metabolic demands1-3. In contrast, neurons, which are major energy consumers, are considered to rely essentially on glucose and its derivatives to support their metabolism. Here, using Drosophila melanogaster, we show that memory formed after intensive massed training is dependent on mitochondrial fatty acid (FA) β-oxidation to produce ATP in neurons of the mushroom body (MB), a major integrative centre in insect brains. We identify cortex glia as the provider of lipids to sustain the usage of FAs for this type of memory. Furthermore, we demonstrate that massed training is associated with mitochondria network remodelling in the soma of MB neurons, resulting in increased mitochondrial size. Artificially increasing mitochondria size in adult MB neurons increases ATP production in their soma and, at the behavioural level, strikingly results in improved memory performance after massed training. These findings challenge the prevailing view that neurons are unable to use FAs for energy production, revealing, on the contrary, that in vivo neuronal FA oxidation has an essential role in cognitive function, including memory formation.

DOI: https://doi.org/10.1038/s42255-025-01416-5
J Neuroinflammation. 2025 Dec 11.

Microglia-derived APOE2 improves remyelination even in the presence of endogenous APOE4.

Georgia L Nolt, Lesley R Golden, Shealee P Thorpe, Jessica L Funnell, Isaiah O Stephens, Gabriela Hernandez, Steven M MacLean, Chloe C Lucido, Chesney R Brock, Akhil V Pallerla, Darcy R Adreon, Holden C Williams, Josh M Morganti, Lance A Johnson.

  Demyelination occurs with aging and is exacerbated in neurodegenerative diseases. During demyelination, microglia upregulate expression of APOE, the gene encoding for the brain's primary lipid transport protein apolipoprotein E (ApoE), which also mediates microglial engulfment and elimination of myelin debris. Compared to the E3 allele of APOE, the E2 allele decreases risk for Alzheimer's disease (AD), while the E4 allele increases AD risk and is associated with an increased severity and progression of multiple sclerosis. Previous work shows that mice expressing E2 exhibit improved microglial function and remyelination compared to mice expressing E4. However, whether microglial-derived APOE is responsible for driving these differences following demyelination, and if microglia-selective expression of E2 is sufficient to provide protection, is unknown. We sought to determine if microglia-specific replacement of the E4 allele with E2 can rescue myelin loss and promote remyelination, even in the presence of continued E4 expression by other central nervous system (CNS) cells. Using a novel APOE allelic "switch" model in which we can induce a replacement of E4 with E2 exclusively in microglia, we characterize the glial cell response and lipid profile of mice that underwent either lysophosphatidylcholine (LPC) or cuprizone (CPZ)-induced demyelination and subsequent remyelination. We found that although alterations to the brain lipid profile were subtle, microglial E2 replacement significantly improved remyelination, lessened microgliosis, and decreased astrocytic lipid droplet load following CPZ-remyelination. Our results indicate that microglia-specific E2 expression, in the presence of continued E4 expression, may provide protection against myelin loss via both cell-autonomous and non-autonomous immunometabolic mechanisms.

Keywords:  Apolipoprotein E; Brain; Gliosis; Lipid metabolism; Microglia; Myelination

DOI:  https://doi.org/10.1186/s12974-025-03639-5
J Neurochem. 2025 Dec;169(12): e70320

Altered Glut4, IRAP, and Brain Insulin Signaling in a Mouse Model of Epilepsy and Contributions to Glucose Transport in Neurons and Astrocytes.

Weizhi Xu, Elliott S Neal, Nicholas Barlow, Philip Thompson, Karin Borges.

  There is evidence that glucose transport is impaired between seizures, which can promote seizure generation. In addition to glucose transporters Glut1 and Glut3, Glut4 is also found in the brain. Glut4 translocation is regulated by insulin signaling in peripheral tissues and insulin-regulated aminopeptidase (IRAP), but remains poorly understood in the brain. This study aimed to characterize the expression of Glut1, Glut3, Glut4, and key regulators of Glut4 trafficking in the chronic stage of the mouse pilocarpine epilepsy model. Roles of Glut4 and IRAP in glucose uptake were investigated in cultured neurons versus astrocytes. Western blot, RT-qPCR, and immunohistochemistry were used to investigate the expression of Glut1, Glut3, Glut4, IRAP, and insulin signaling genes in the chronic stage of the mouse pilocarpine model in the hippocampus and cortex between seizures. Contributions of Glut4 and IRAP to 3H-2-deoxyglucose uptake were quantified in primary mouse neurons and astrocytes. In the hippocampus during the chronic stage of the model, Glut1 and IRAP expression was unaltered, Glut3 decreased, but Glut4 2.5-fold increased with Glut4 and IRAP being specifically upregulated in GFAP+ astrocytes. Insulin signaling appeared altered, with reduced expression of key pathway genes and changed phospho-AktSer473 and -AMPKαThr172 levels. Although systemically injected insulin did not activate brain insulin signaling, insulin and neurotransmitters stimulated glucose transport into cultured neurons and astrocytes by 15%-50%. This was largely mediated by Glut4, despite its relatively low expression in these cells. Notably, in neurons but not in astrocytes, IRAP inhibitors further enhanced this stimulated transport by an additional 15% via Glut4-mediated uptake. This is the first report showing increased astrocytic Glut4 expression in a rodent epilepsy model. Along with the finding of significant contributions of Glut4 and IRAP to glucose uptake in neurons, our work points to IRAP inhibitors as new pharmacological approaches improving neuronal energy supply to prevent seizure generation in epilepsy.

Keywords:  astrocyte; glucose transporter 4; insulin regulated aminopeptidase; pilocarpine model

DOI:  https://doi.org/10.1111/jnc.70320
Int J Mol Sci. 2025 Nov 24. pii: 11349. [Epub ahead of print]26(23):

An Alternative Metabolic Pathway of Glucose Oxidation Induced by Mitochondrial Complex I Inhibition: Serinogenesis and Folate Cycling.

Roman Abrosimov, Ankush Borlepawar, Parvana Hajieva, Bernd Moosmann.

  Inhibition of respiratory chain complex I (NADH dehydrogenase) is a widely encountered biochemical consequence of drug intoxication and a primary consequence of mtDNA mutations and other mitochondrial defects. In an organ-selective form, it is also deployed as antidiabetic pharmacological treatment. Complex I inhibition evokes a pronounced metabolic reprogramming of uncertain purposefulness, as in several cases, anabolism appears to be fostered in a state of bioenergetic shortage. A hallmark of complex I inhibition is the enhanced biosynthesis of serine, usually accompanied by an induction of folate-converting enzymes. Here, we have revisited the differential transcriptional induction of these metabolic pathways in three published models of selective complex I inhibition: MPP-treated neuronal cells, methionine-restricted rats, and patient fibroblasts harboring an NDUFS2 mutation. We find that in a coupled fashion, serinogenesis and circular folate cycling provide an unrecognized alternative pathway of complete glucose oxidation that is mostly dependent on NADP instead of the canonic NAD cofactor (NADP:NAD ≈ 2:1) and thus evades the shortage of oxidized NAD produced by complex I inhibition. In contrast, serine utilization for anabolic purposes and C1-folate provision for S-adenosyl-methionine production and transsulfuration cannot explain the observed transcriptional patterns, while C1-folate provision for purine biosynthesis did occur in some models, albeit not universally. We conclude that catabolic glucose oxidation to CO2, linked with NADPH production for indirect downstream respiration through fatty acid cycling, is the general purpose of the remarkably strong induction of serinogenesis after complex I inhibition.

Keywords:  NADPH-FADH2 axis; Parkinson’s disease; fatty acid cycling; futile cycle; glycolytic inhibition; metabolic reprogramming; metformin; mitochondrial disease; oxidative stress

DOI:  https://doi.org/10.3390/ijms262311349
NMR Biomed. 2026 Jan;39(1): e70194

Validation of Dynamic Deuterium Metabolic Imaging (DMI) for the Measurement of Cerebral Metabolic Rates of Glucose in Rat.

Claudius S Mathy, Monique A Thomas, Graeme F Mason, Robin A de Graaf, Henk M De Feyter.

  Deuterium metabolic imaging (DMI) is an innovative technique in which 2H magnetic resonance spectroscopic imaging (MRSI) is utilized to determine the metabolic activity of administered 2H-labeled substrates. As such it can be viewed as the 2H counterpart to more traditional 13C labeling methods that can be considered the gold standard for metabolic mapping in vivo. To ensure reliable findings from dynamic 2H MRSI experiments about absolute metabolic flux rates after administration of a 2H-labeled substrate it is essential to take into account 2H-specific aspects, namely 2H label losses and kinetic isotopy effects (KIEs). Here, a modified version of a 13C-based metabolic model for glucose metabolism in rat brain was developed to address these 2H-related effects, tested for 2H MRSI data acquired during infusion of [6,6'-2H2]-glucose, and validated by comparison with indirect 1H-[13C] MRSI data acquired during infusion of [1-13C]-glucose. The flux rates for glucose consumption (CMRgl = 0.57 ± 0.08 μmol/min/g) and the TCA cycle (Vtca = 1.24 ± 0.14 μmol/min/g) derived from the 2H MRSI data and using the updated metabolic model were in excellent agreement with the estimates based on 13C data (CMRgl = 0.59 ± 0.14 μmol/min/g and Vtca = 1.24 ± 0.32 μmol/min/g). The successful validation of dynamic 2H MRSI for absolute flux rate determination forms the basis for future quantitative study of metabolic disorders in vivo.

Keywords:  MRS; deuterium metabolic imaging (DMI); metabolic modeling

DOI:  https://doi.org/10.1002/nbm.70194
Trends Biochem Sci. 2025 Dec 05. pii: S0968-0004(25)00266-X. [Epub ahead of print]

Structural transport and inhibition mechanism of the mitochondrial pyruvate carrier.

Denis Lacabanne, Jonathan J Ruprecht, Maximilian Sichrovsky, Lucy R Forrest, Vanessa Leone, Sotiria Tavoulari, Edmund R S Kunji.

  The mitochondrial pyruvate carrier (MPC), of the SLC54 family of solute carriers, has a critical role in eukaryotic energy metabolism by transporting pyruvate, the end-product of glycolysis, into the mitochondrial matrix. Recently, structures of the human MPC1/MPC2 and MPC1L/MPC2 heterodimers in the outward-open, occluded, and inward-open states have been determined by cryo-electron microscopy (cryo-EM) and by AlphaFold modeling. In this review we discuss the membrane orientation, substrate binding site properties, and structural features of the alternating access mechanism of the carrier, as well as the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state. These structural studies will support drug development efforts for the treatment of diabetes mellitus, neurodegeneration, metabolic dysfunction-associated steatotic liver disease (MASLD), and some types of cancers.

Keywords:  alternating access transport mechanism; membrane protein structure; mitochondrion; solute carrier family SLC54; structure-based drug design; sugar and energy metabolism

DOI:  https://doi.org/10.1016/j.tibs.2025.11.002
J Neurochem. 2025 Dec;169(12): e70318

The Neurochemical Landscape of Oligodendrocyte Physiology: From Myelination to Metabolic and Synaptic Modulation.

Jorge Correale.

  Oligodendrocytes, traditionally recognized for their role in axonal myelination, are increasingly appreciated as metabolically dynamic and functionally diverse cells integral to central nervous system (CNS) homeostasis. This review delineates the evolving neurochemical landscape of oligodendrocyte physiology, emphasizing their roles beyond myelin production. We explore key processes including lipid metabolism, metabolic coupling with neurons, ion buffering, neurotransmitter signaling, and synaptic modulation. Oligodendrocytes preferentially utilize aerobic glycolysis and support axonal energy metabolism via the export of lactate and phosphocreatine, maintaining ATP levels even in the absence of mitochondria within the myelin sheath. Their capacity for regional and transcriptional heterogeneity allows adaptive responses to local microenvironments and neuronal activity. Lipid biosynthesis and storage mechanisms are intricately regulated through mTORC1, SREBPs, and lipophagy, enabling rapid membrane expansion, and structural integrity during myelination. Furthermore, oligodendrocytes modulate the periaxonal milieu via potassium buffering, pH regulation, and osmotic balance, primarily through Kir channels, carbonic anhydrases, and aquaporins. They also express a wide array of neurotransmitter receptors, enabling bidirectional communication with neurons and activity-dependent modulation of maturation and plasticity. Intracellular signaling pathways such as PI3K/Akt/mTOR, MAPK/ERK, and Wnt/β-catenin orchestrate the integration of metabolic and transcriptional programs. Collectively, these findings redefine oligodendrocytes as active participants in CNS physiology, contributing to neuronal health, circuit plasticity, and responses to injury or disease.

Keywords:  ionic and osmotic buffering; lipid metabolism; metabolic coupling; myelination; oligodendrocytes

DOI:  https://doi.org/10.1111/jnc.70318
Int J Dev Neurosci. 2025 Dec;85(8): e70074

Deficiency of the Tangier Disease Gene Abca1 Is Associated With Microglial Defects in Mice.

Tomas Celis, Oriana Ramírez-Herrera, Myrna Barraza, Susan Calfunao, Fujiko Saavedra, Patricia Romo-Toledo, Dolores Busso, Nicolas Santander.

  Microglia, the resident macrophages of the central nervous system, are a diverse population that develop during embryonic and postnatal stages in the mouse. Several signalling pathways are involved in their specification and maturation, but other types of cues might be involved, including lipid metabolism. Here, we evaluated the effect of the inactivation of two main cholesterol transporters in mice, ABCA1 and SR-B1, on microglial development. Using public datasets, we showed that both transporters are expressed in microglia and are differentially regulated in neurodegeneration models. Inactivation of either transporter was associated with distinct effects on microglial density and/or morphology at different developmental stages and in different brain regions. These studies suggest that microglia require appropriate lipid transport to support their homeostatic identity and could implicate this process in neurodegenerative diseases.

Keywords:  ABCA1; SR‐B1; cholesterol; microglia

DOI:  https://doi.org/10.1002/jdn.70074
JCI Insight. 2025 Dec 09. pii: e191465. [Epub ahead of print]

Enhanced lipid metabolism serves as a metabolic vulnerability to polyunsaturated fatty acids in glioblastoma.

Shiva Kant, Yi Zhao, Pravin Kesarwani, Kumari Alka, Jacob F Oyeniyi, Ghulam Mohammad, Nadia Ashrafi, Stewart F Graham, C Ryan Miller, Prakash Chinnaiyan.

  Enhanced lipid metabolism, which involves the active import, storage, and utilization of fatty acids from the tumor microenvironment, plays a contributory role in malignant glioma transformation; thereby, serving as an important gain of function. In this work, through studies initially designed to understand and reconcile possible mechanisms underlying the anti-tumor activity of a high-fat ketogenic diet, we discovered that this phenotype of enhanced lipid metabolism observed in glioblastoma may also serve as a metabolic vulnerability to diet modification. Specifically, exogenous polyunsaturated fatty acids (PUFA) demonstrate the unique ability of short-circuiting lipid homeostasis in glioblastoma cells. This leads to lipolysis-mediated lipid droplet breakdown, an accumulation of intracellular free fatty acids, and lipid peroxidation-mediated cytotoxicity, which was potentiated when combined with radiation therapy. Leveraging this data, we formulated a PUFA-rich modified diet that does not require carbohydrate restriction, which would likely improve long-term adherence when compared to a ketogenic diet. The modified PUFA-rich diet demonstrated both anti-tumor activity and potent synergy when combined with radiation therapy in mouse glioblastoma models. Collectively, this work offers both a mechanistic understanding and a potentially translatable approach of targeting this metabolic phenotype in glioblastoma through diet modification and/or nutritional supplementation that may be readily integrated into clinical practice.

Keywords:  Brain cancer; Metabolism; Metabolomics; Neuroscience; Oncology; Radiation therapy

DOI:  https://doi.org/10.1172/jci.insight.191465
Mol Neurobiol. 2025 Dec 10. 63(1): 279

Mitochondrial Transplantation Increases Bioenergetics and Neurite Outgrowth in Healthy and P301Ltau-Expressing SH-SY5Y Cells.

Aline Broeglin, Aurélien Riou, Andreas Papassotiropoulos, Anne Eckert, Amandine Grimm.

  Tauopathies are neurodegenerative diseases characterized by the abnormal accumulation of tau protein in neurons, leading to cognitive impairment. A common feature of these disorders is mitochondrial dysfunction, which leads to bioenergetic deficits and contributes to neuronal cell death. As neurons have high energy demands, impaired mitochondrial function directly affects their viability and function. Thus, mitochondria represent an attractive target for neuroprotective strategies in tauopathies. Mitochondrial transplantation (MT) is an emerging therapeutic approach to restoring cellular bioenergetics. Although MT has shown promise in various models of brain diseases, its efficacy has not been evaluated in the context of tau-induced mitochondrial dysfunction. This study examines the impact of MT on healthy cells and in a cellular model of tauopathy. Mitochondria were freshly isolated from astrocytic cells and transplanted into healthy SH-SY5Y neuroblastoma cells and SH-SY5Y cells overexpressing the P301L tau mutation, for 24 and 48 h. Our results demonstrate that MT enhances cell viability, ATP production, mitochondrial membrane potential, and respiration in both healthy and tau-mutant SH-SY5Y cells. In addition, MT reduced mitochondrial superoxide anion levels and promoted neurite outgrowth in both cell lines. Key bioenergetic outcomes were recapitulated in neurons derived from induced pluripotent stem cells (iPSCs) carrying the P301L tau mutation. These findings suggest that MT might be a promising therapeutic strategy to counteract mitochondrial deficits in tauopathies. Importantly, this approach positions mitochondria not as a target but as the therapeutic agent itself. Further studies are warranted to advance MT toward in vivo applications in tau-related neurodegenerative disorders.

Keywords:  Bioenergetic; Mitochondria; Neurites; P301Ltau mutation; Tauopathies; Transplantation

DOI:  https://doi.org/10.1007/s12035-025-05604-y
J Lipid Res. 2025 Dec 05. pii: S0022-2275(25)00218-4. [Epub ahead of print] 100955

Dysregulated metabolism of ceramides and glycosphingolipids in Parkinson's Disease.

Yu-Fong Peng, Szu-Ju Chen, Jeng-Lin Li, Chin-Hsien Lin, Ching-Hua Kuo.

   BACKGROUND: Alterations in sphingolipid metabolism have been implicated in the pathogenesis of Parkinson's disease (PD), yet findings regarding peripheral sphingolipid changes remain inconsistent. This study aimed to elucidate the metabolic profiles of plasma ceramides and glycosphingolipids (GSLs) in PD patients.
METHODS: We recruited 250 PD patients and 250 age- and sex-matched neurologically healthy controls. Plasma ceramide and GSL species were quantified using liquid chromatography‒tandem mass spectrometry, complemented by a meta-analysis of the gene expression levels of relevant enzymes in the substantia nigra obtained from Gene Expression Omnibus.
RESULTS: A total of 119 sphingolipids were analyzed. Significant differences in plasma sphingolipid species were observed, including increased GSLs and decreased dihydroceramides. Incorporation of 38 significantly altered sphingolipid species enabled discrimination of PD patients from controls with an AUC of 0.80 (P < 0.0001). Notable alterations in lipid ratios were detected, with increases in the monohexosylceramide-to-ceramide ratio, as well as the monosialodihexosylganglioside-to-dihexosylceramide and trihexosylceramide-to-dihexosylceramide ratios. We also observed a higher ceramide-to-dihydroceramide ratio and shifts in ceramide characteristics, reflecting changes in ceramide synthesis pathway. Supporting these findings, meta-analysis revealed changes in expression of relevant enzymes, including decreased expression of lysosomal hydrolases, such as β-glucocerebrosidase and α-galactosidase, reinforcing the impaired GSL degradation and alteration in ceramide synthesis observed in PD.
CONCLUSION: Our results suggest that altered peripheral ceramide and GSL profiles can discriminate PD from controls. Moreover, we highlight disrupted GSL and ceramide metabolism in PD patients, emphasizing the need for further research to explore the implications of these metabolic disturbances in PD pathogenesis.

Keywords:  GBA1; GLA; Parkinson’s disease; ceramides; globotriaosylceramides; glucosylceramides; glycosphingolipids; lactosylceramides; monosialodihexosylganglioside; sphingolipids

DOI:  https://doi.org/10.1016/j.jlr.2025.100955
J Biol Chem. 2025 Dec 05. pii: S0021-9258(25)02861-3. [Epub ahead of print] 111009

Three mammalian VDAC isoforms distinctly regulate mitochondrial function and proteome to maintain cell metabolism.

Megha Rajendran, William M Rosencrans, Nina A Bautista, Wendy Fitzgerald, Diana Huynh, Bethel G Beyene, Baiyi Quan, Jennifer D Petersen, Julie Hwang, Tsui-Fen Chou, Sergey M Bezrukov, Tatiana K Rostovtseva.

  The Voltage Dependent Anion Channel (VDAC) is the most ubiquitous protein in the mitochondrial outer membrane. This channel facilitates the flux of water-soluble metabolites and ions like calcium across the mitochondrial outer membrane. Beyond this canonical role, VDAC has been implicated, through interactions with protein partners, in several cellular processes such as apoptosis, calcium signaling, and lipid metabolism. There are three VDAC isoforms in mammalian cells, VDAC1, VDAC2, and VDAC3, with varying tissue-specific expression profiles. From a biophysical standpoint, all three isoforms conduct metabolites and ions with similar efficiency. However, isoform knockouts (KOs) in mice lead to distinct phenotypes, which may be due to differences in VDAC isoform interactions with partner proteins. To understand the functional role of each VDAC isoform within a single cell type, we created functional KOs of each isoform in HeLa cells and performed a comparative study of their metabolic activity and proteomics. We found that each isoform KO alters the proteome differently, with VDAC3 KO dramatically downregulating key members of the electron transport chain (ETC) while shifting the mitochondria into a glutamine-dependent state. Importantly, this unexpected dependence of mitochondrial function on the VDAC3 isoform is not compensated for by the more ubiquitously expressed VDAC1 and VDAC2 isoforms. In contrast, VDAC2 KO did not affect respiration but upregulated ETC components and decreased key enzymes in the glutamine metabolic pathway. VDAC1 KO specifically reduced glycolytic activity linked to decreased hexokinase localization to mitochondria. These results reveal non-redundant roles of VDAC isoforms in cancer cell metabolic adaptability.

Keywords:  CRISPR/Cas9 gene knockout; metabolic regulation; mitochondrial respiratory chain complex; proteomics; voltage-dependent anion channel

DOI:  https://doi.org/10.1016/j.jbc.2025.111009
Commun Biol. 2025 Dec 11. 8(1): 1759

Metabolic costs and trade-offs of hypermetabolism in human motor neurons with ATP synthase deficiency.

Rubén Torregrosa-Muñumer, Jeremi Turkia, Rumeysa Ermiş, Jouni Kvist, Sandra Harjuhaahto, Jana Pennonen, Ville Hietakangas, Emil Ylikallio, Henna Tyynismaa.

Hypermetabolism, a futile cycle of energy production and consumption, has been proposed as an adaptative response to deficiencies in mitochondrial oxidative phosphorylation. However, the cellular costs of hypermetabolism remain largely unknown. Here we studied the consequences of hypermetabolism in human motor neurons harboring a heteroplasmic mutation in MT-ATP6, which impairs ATP synthase assembly. Respirometry, metabolomics, and proteomics analyses of the motor neurons showed that elevated ATP production rates were accompanied with increased demand for acetyl-Coenzyme A (acetyl-CoA) and depleted pantothenate (vitamin B5), and the proteome was remodeled to support the metabolic adaptation. Mitochondrial membrane potential and coupling efficiency remained stable, and the therapeutic agent avanafil did not affect metabolite levels. However, a redistribution of acetyl-CoA usage resulted in metabolic trade-offs, including reduced histone acetylation and altered maintenance of the neurotransmitter acetylcholine, revealing potential vulnerabilities in motor neurons. These findings advance the understanding of cellular metabolic consequences imposed by hypermetabolic conditions.

DOI: https://doi.org/10.1038/s42003-025-09149-7
Am J Physiol Cell Physiol. 2025 Dec 09.

The astrocytic engine: Na+,K+-ATPase at the nexus of brain function and malfunction.

Alexei Verkhatsky, Line Mathilde Brostrup Hansen, Christian Staehr, Vladimir V Matchkov.

  Astrocytes are fundamental for brain homeostasis and act as dynamic signaling elements within the central nervous system. By maintaining ionic balance, neurotransmitter turnover, and metabolic support, they sustain neuronal excitability and network stability. Ionic excitability of astrocytes is mediated primarily by fluctuations of intracellular Na+, K+, Ca2+, and Cl- ions. Central to these processes is the Na+,K+-ATPase, which maintains transmembrane Na+ and K+ gradients, driving secondary active transport, including uptake of neurotransmitters such as glutamate, GABA, and their precursors glutamine and L-serine. Astrocytic Na+ changes rapidly coordinate neuronal activity with glial homeostasis via NMDA receptor signaling, whereas K+ clearance is primarily mediated by the Na+,K+-ATPase α+ isoform, preventing neuronal hyperexcitability. The Na+,K+-ATPase also contributes to neurovascular coupling, linking synaptic activity to local vasodilation through Ca2+- and K+-dependent signaling in astrocytic endfeet. Beyond ion transport, the Na+,K+-ATPase serves as a signaling hub, engaging intracellular kinase signaling pathways, including Src and PI3K kinases, thereby modulating astrocyte morphology, metabolism, and stress responses. Dysfunctions of astrocytic Na+,K+- ATPase isoforms are implicated in multiple neuronal pathologies, including seizures, familial hemiplegic migraine, neurodegeneration, and neuroinflammatory disorders. These pathologies reflect primarily loss-of-function mechanisms, altered ion homeostasis, and reactive oxygen species or inflammatory signaling. Understanding the isoform- and cell-type-specific functions of the Na+,K+-ATPase across the neurovascular unit will be crucial for future development of targeted therapies aimed to restore ion homeostasis and signaling in the diseased brain.

Keywords:  Astrocyte; Brain homeostasis; Ionic homeostasis; K+-ATPase; Na+; Neuroinflammation; Neurovascular coupling

DOI:  https://doi.org/10.1152/ajpcell.00814.2025
Nat Commun. 2025 Dec 12. 16(1): 11104

Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment.

Alicia N Pietramale, Xhoela Bame, Megan E Doty, Kiera E Schwarz, Robert A Hill.

Microglia continually surveil the brain allowing for rapid detection of tissue damage or infection. Microglial metabolism is linked to tissue homeostasis, yet how mitochondria are subcellularly partitioned in microglia and dynamically reorganize during surveillance, injury responses, and phagocytic engulfment in the intact brain are not known. Here, we performed intravital imaging and ultrastructural analyses of microglia mitochondria in mice and human tissue, revealing that microglial processes diverge in their mitochondrial content, with some containing multiple mitochondria while others are completely void. Microtubules and hexokinase 2 mirror this uneven mitochondrial distribution indicating that these cytoskeletal and metabolic components are linked to mitochondrial organization in microglia. Microglial processes that engage in minute-to-minute surveillance typically do not have mitochondria. Moreover, unlike process surveillance, mitochondrial motility does not change with animal anesthesia. Likewise, the processes that acutely chemoattract to a lesion site or initially engage with a neuron undergoing programmed cell death do not contain mitochondria. Rather, microglia mitochondria have a delayed arrival into the responding cell processes. Thus, there is subcellular heterogeneity of mitochondrial partitioning. Moreover, microglial processes that surveil and acutely respond to damage do not contain mitochondria.

DOI: https://doi.org/10.1038/s41467-025-66708-6
Commun Biol. 2025 Dec 07.

Medium-chain triglycerides and ketogenic diet prevent alterations of the gut microbiome in transgenic Alzheimer's disease mice.

Paule E H M'Bra, Isaura Suárez-Uribe, Mariano Avino, Evelyne Ng Kwan Lim, Marian Mayhue, Philippe Balthazar, Anne Aumont, Karine Prévost, Eric Massé, Karl J L Fernandes.

The systemic mechanisms underlying the benefits of ketogenic interventions on cognition in Alzheimer's disease (AD) are understudied. Interventions involving a carbohydrate-free high-fat ketogenic diet (KD) or dietary supplementation with medium-chain triglycerides (MCT) both improve cognition in AD mouse models, yet with opposing effects on circulating ketones levels, peripheral insulin sensitivity and inflammation. Since the gut microbiome regulates systemic metabolism and inflammation and is altered by aging and disease, we investigated how it is affected in mice subjected to MCT and KD. At early stages of pathology, AD mice exhibited substantially reduced richness and distinct composition of gut microbiome species. Administration of MCT or KD for 1-month increased microbiome diversity, restoring the levels of more than 50% of the bacteria altered in AD mice and inducing novel alterations. Both diets increased levels of short-chain fatty acid-producing bacteria, such as Lachnospiraceae, which directly correlated with improved hippocampal dendritic spine density. Interestingly, longer term administration of KD increased the obesity-associated Firmicutes/Bacteroidota ratio and bodyweight in AD but not WT mice, suggesting that AD-associated metabolic defects should be considered when designing such intervention. We conclude that MCT and KD may influence AD central and peripheral defects in part via modulation of the gut microbiome.

DOI: https://doi.org/10.1038/s42003-025-09171-9
Glia. 2026 Feb;74(2): e70118

RetSat Knockout Mitigates Hypoxia-Induced Microglial Activation by Enhancing Lipid Droplets Degradation.

Wenyu Hu, Shuoshuo Li, Wenjun Shi, Ping Zhang, Xue Zhang, Ying Liu, Xin Zhou, Peng Shi, Junliang Yuan, Zengqiang Yuan, Jinbo Cheng.

  Exposure to hypoxic environments leads to neurological dysfunction, with recent studies implicating microglia-derived neuroinflammation involved in hypoxia-induced neuronal impairment. However, the underlying pathological mechanisms remain largely unclear. Lipid-droplet-accumulating microglia (LDAM) have been linked to age-related and genetic forms of neurodegeneration, prompting the investigation of their role in hypoxia-induced neuronal impairment. In this study, we observed that hypoxia induced lipid droplets accumulation in microglia, accompanied by increased levels of RETSAT, an enzyme involved in lipid metabolism regulation. Conditional knockout of RETSAT in microglia decreased lipid droplets accumulation and alleviates hypoxia-induced microglial-derived neuroinflammation and oxidative stress, both in vitro and in vivo. Our biological studies indicate that the beneficial effects of RETSAT knockout on lipid droplets degradation are primarily mediated through enhanced activity of hormone-sensitive lipase (HSL). Furthermore, we found that the hypoxic adaptation-related RETSAT mutation Q247R promotes microglia lipolysis under hypoxic conditions. These findings suggest that RetSat is a potential therapeutic target for the prevention and treatment of hypoxia-induced microglial activation.

Keywords:  HSL; RetSat; hypoxia; lipid droplets; microglia activation

DOI:  https://doi.org/10.1002/glia.70118
J Cereb Blood Flow Metab. 2025 Dec 07. 271678X251400247

Brain glucose extraction is fixed at 10% despite twofold variability in resting cerebral blood flow in healthy humans.

Jennifer S Duffy, Hannah G Caldwell, Ryan L Hoiland, Connor A Howe, Kurt J Smith, Anthony R Bain, David B MacLeod, Philip N Ainslie, Travis D Gibbons.

  In the resting, non-stimulated brain, metabolic demands are met exclusively by the delivery and extraction of glucose and oxygen at an ~6:1 ratio. Amongst healthy people at rest, there is marked variability in resting global cerebral blood flow (CBF) yet remarkably stable concentrations of circulating glucose and oxygen. Thus, we would expect interindividual variability in resting CBF to be inversely related to oxygen and glucose extraction, maintaining oxidative glucose metabolism. Herein, we investigated the fundamental relationship between CBF and substrate extraction in 75 healthy adults (27.3 ± 4.8 years) with resting measures of CBF and cross-brain concentrations of oxygen and glucose. We observed that the marked interindividual variability in CBF (<500 to >1200 mL/min) is inversely related to oxygen extraction (R2 = 0.85, p = 0.005) but not glucose extraction (R2 = 0.30, p = 0.273). The metabolic rates of oxygen and glucose (CMRO2 and CMRglc) are both directly correlated with CBF. However, there was a 1.6-fold greater slope for CMRglc-CBF, compared to CMRO2-CBF (p = 0.040). These findings indicate that the resting brain extracts more oxygen when delivery is low, maintaining stable CMRO2 and ATP production. Despite glucose being the primary oxidized substrate, the brain's ability to adjust its extraction is limited, making CMRglc more dependent on delivery.

Keywords:  Cerebral metabolism; aerobic glycolysis; arteriovenous; cerebral blood flow; glucose extraction; oxygen extraction

DOI:  https://doi.org/10.1177/0271678X251400247
Nat Commun. 2025 Dec 09. 16(1): 10969

Multimodal mass spectrometry imaging for plaque- and region-specific neurolipidomics in Alzheimer's disease mouse models.

Timothy J Trinklein, Stanislav S Rubakhin, Samuel Okyem, Seth W Croslow, Marisa Asadian, K R Sabitha, Orly Lazarov, Fan Lam, Jonathan V Sweedler.

The progressive accumulation of amyloid beta (Aβ) plaques is a hallmark of Alzheimer's disease (AD). However, the biochemical mechanisms of their formation and the consequences associated with plaque formation remain elusive. In female 5xFAD and APPNL-G-F mice, we map region-specific, plaque-associated lipids with large molecular coverage including isomers. We describe a multimodal framework that integrates matrix assisted laser desorption/ionization with laser-induced postionization (MALDI-2) mass spectrometry imaging, trapped ion mobility spectrometry, and fluorescence microscopy. Our approach improves detectability and spatial-chemical resolution. We couple these measurements with a computational pipeline for multimodal image coregistration and discovery of plaque-altered lipids. Here, we show the lipids in and around Aβ plaques are highly heterogeneous. Integration of our data with existing spatial transcriptomics data suggests that region-specific accumulation of simple gangliosides is likely driven by lysosomal degradation of complex species. Together, this work provides a generalizable framework to understand lipid alterations within the Aβ plaque microenvironment.

DOI: https://doi.org/10.1038/s41467-025-65956-w
Nat Commun. 2025 Dec 12. 16(1): 11103

Dynamic changes in mitochondria support phenotypic flexibility of microglia.

Katherine Espinoza, Ari W Schaler, Daniel T Gray, Arielle R Sass, Adrian Escobar, Kamilia Moore, Megan E Yu, Casandra G Chamorro, Lindsay M De Biase.

Microglial capacity to adapt to tissue needs is a hallmark feature of these cells. New studies show that mitochondria critically regulate the phenotypic adaptability of macrophages. To determine whether these organelles play similar roles in shaping microglial phenotypes, we generated transgenic mouse crosses to accurately visualize and manipulate microglial mitochondria. We find that brain-region differences in microglial attributes and responses to aging are accompanied by regional differences in mitochondrial mass and aging-associated mitochondrial remodeling. Microglial mitochondria are also altered within hours of LPS injections and microglial expression of inflammation-, trophic-, and phagocytosis-relevant genes is strongly correlated with expression of mitochondria-relevant genes. Finally, direct genetic manipulation of microglial mitochondria alters microglial morphology and leads to brain-region specific effects on microglial gene expression. Overall, this study advances our understanding of microglial mitochondria and supports the idea that mitochondria influence basal microglial phenotypes and phenotypic remodeling that takes place over hours to months.

DOI: https://doi.org/10.1038/s41467-025-66709-5
Brain Behav Immun. 2025 Dec 10. pii: S0889-1591(25)00461-1. [Epub ahead of print] 106219

NPD1/GPR37 signaling protects against painful traumatic brain injury and comorbidities by regulating demyelination, glial responses, and neuroinflammation in the mouse brain.

Junli Zhao, Runda Li, Yuqing Wang, Sharat Chandra, Vivian Zhang, Haichen Wang, Ru-Rong Ji.

  Traumatic brain injury (TBI) often leads to neuropathic pain and a range of comorbidities, including post-traumatic stress disorder (PTSD), cognitive decline and depression. Neuroprotectin D1 (NPD1), a lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid (DHA), exhibits neuroprotective properties; however, the distinct roles of NPD1 and DHA in mitigating TBI-induced deficits remain unclear. In a mouse model of closed-head TBI, transient neuropathic pain lasting less than two weeks was observed, characterized by periorbital and cutaneous mechanical allodynia/hyperalgesia, motor deficits, and cognitive impairment. Peri-surgical administration of NPD1 (500 ng/mouse), but not DHA (500 µg/mouse), effectively prevented mechanical hypersensitivity, motor deficits, and cognitive impairment. NPD1 treatment also attenuated TBI-induced microgliosis, astrogliosis, and demyelination in the sensory cortex and hippocampus. RNA sequencing revealed that NPD1 suppressed neuroinflammatory responses and normalized the alteration of PTSD-related genes (e.g., Fkbp5). The antinociceptive effects of NPD1 were abolished in Gpr37-/- mice. Moreover, swimming-induced stress prolonged TBI-evoked pain, and NPD1 prevented this transition from acute to chronic pain in wild-type but not Gpr37-/- mice. Chronic pain was accompanied by depression- and anxiety-like behaviors, both of which were mitigated by NPD1 via GPR37. In addition, NPD1 post-treatment attenuated stress/TBI-induced chronic pain and comorbidities. Together, these findings identify the NPD1/GPR37 signaling axis as a key protective mechanism that modulates glial responses, demyelination, and neuroinflammation, offering a promising therapeutic target for TBI-associated pain and neuropsychiatric comorbidities.

Keywords:  Cognitive impairment; Demyelination; Depression; GPR37; Glial reaction; Neuroinflammation; Neuroprotectin D1 (NPD1); PTSD; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.bbi.2025.106219
Int J Mol Sci. 2025 Nov 28. pii: 11542. [Epub ahead of print]26(23):

The Quantum Brain: The Untold Story of Docosahexaenoic Acid's Role in Brain Evolution, Biophysics, and Cognition.

Michael A Crawford, Lawrence A Horn, Thomas Brenna, Catherine Leigh Broadhurst, Simon C Dyall, Mark Johnson, Walter F Schmidt, Andrew J Sinclair, Manahel Thabet, Yiqun Wang.

  Docosahexaenoic acid (DHA), the dominant polyunsaturated fatty acid in photoreceptors, neurons, and synapses, is usually described as a passive structural membrane constituent. We propose a different view: DHA is a quantum-electronically active molecule whose conjugated double-bond system creates an electron-rich matrix that couples with proteins to form quantum "clouds" and high-speed signaling central to recognition, recall, and cognition. Integrating evidence from molecular evolution, biophysics, and neuroscience, we argue that, as the original chromophore, DHA's unique properties enabled the emergence of the nervous system and continue to provide the electronic substrate for cognition. By suggesting that cognition depends not only on protein-based mechanisms but on DHA-mediated electron dynamics at the membrane-protein interface, this perspective reframes DHA as an active, conserved determinant of brain evolution and function.

Keywords:  Hamiltonian; Hebbian Learning; Hilbert; chromophore; conjugated double bond; docosahexaenoic acid (DHA); electron tunneling; entanglement; methylene interruption; semiconductor

DOI:  https://doi.org/10.3390/ijms262311542
Free Radic Biol Med. 2025 Dec 05. pii: S0891-5849(25)01406-6. [Epub ahead of print]244 84-106

Astrocytic LCN2 drives neuronal dysfunction in epilepsy by suppressing tunnel nanotube-mediated mitochondrial transfer via NLRP3 inflammasome activation.

Zixian Zhou, Pengcheng Zhang, Yanlin Jiang, Yingchun Xu, Fangzhou Liu, Xinyu Chen, Deng Chen, Wenfu Tang, Rujia Liao, Ling Liu.

  Epileptic seizures disrupt brain homeostasis not only by directly challenging neuronal excitability but also by impairing the intricate astrocyte-neuron cross-talk essential for metabolic support. Herein, we identify a novel pathogenic axis and a compensatory rescue mechanism that are critically interlinked. Following seizures, astrocytes initiate a protective response by forming tunneling nanotubes (TNTs) to deliver functional mitochondria to stressed neurons, thereby restoring neuronal bioenergetics. Paradoxically, this endogenous rescue pathway is suppressed by a seizure-induced, astrocyte-specific signaling cascade: the upregulation of Lipocalin-2 (LCN2) activates the NLRP3 inflammasome, triggering Gasdermin D-mediated pyroptosis and concurrently impairing TNT function. Crucially, genetic or pharmacological disruption of the LCN2/NLRP3 axis yielded dual therapeutic benefits-it robustly suppressed astrocytic pyroptosis and, unexpectedly, potentiated TNT-mediated mitochondrial transfer, leading to significant improvements in neuronal mitochondrial function and overall neurological outcomes. Our findings redefine the role of reactive astrocytes in epilepsy, revealing a single pathway that simultaneously controls an inflammatory death process and an intercellular organelle rescue system. Targeting this axis presents a promising therapeutic strategy to concurrently mitigate neuroinflammation and boost intrinsic neuroprotective mechanisms for improving post-seizure recovery.

Keywords:  Astrocyte; Epilepsy; Lipocalin-2; Mitochondrial; NOD-Like receptor protein 3; Pyroptosis

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.061
J Transl Med. 2025 Dec 12.

Multimodal MR imaging for quantification of brain lipid in mice at 9.4T.

Sunil Kumar Khokhar, Anshuman Swain, Narayan Datt Soni, Halvor Juul, Abeer Mathur, Dipak Roy, Blake Benyard, Dushyant Kumar, Ravi Prakash Reddy Nanga, Mohammad Haris, Ravinder Reddy.



Keywords:  Brain; Lipid imaging; MWF; Myelination; NOEMTR ; Repeatability; tNOE

DOI:  https://doi.org/10.1186/s12967-025-07476-1
Adv Biol (Weinh). 2025 Dec 12. e00472

HK1 and HK2 Beyond Glycolysis: Mitochondrial Interactions and Dual Roles in Metabolism and Cell Fate.

Noemi Anna Pesce, Giulia Seminara, Giuseppe Giarrusso, Marianna Flora Tomasello.

  HK1 and HK2 are increasingly recognized not only as glycolytic enzymes but also as key modulators of mitochondrial function and cell fate through dynamic interactions with VDAC. This review explores how HK-VDAC complexes support metabolic flexibility, regulate apoptosis, and coordinate glycolytic and mitochondrial activity across diverse physiological and pathological conditions. We incorporate recent reinterpretations of the Warburg effect, emphasizing how spatial and functional reorganization of HK supports proliferative metabolism beyond classical models of mitochondrial dysfunction. Importantly, the HK-VDAC interaction is dynamically regulated by post-translational modifications and signaling pathways that control its stability and mitochondrial anchoring. Disruption of these regulatory mechanisms can impair the balance between glycolytic and mitochondrial metabolism, contributing to disease progression. Emerging evidence links altered HK-VDAC interactions to the metabolic and apoptotic imbalances observed in cancer, neurodegeneration, and aging. By integrating insights from structural biology, bioenergetics, and disease models, we highlight mitochondrial HK anchoring as a central hub for metabolic adaptation and stress response.

Keywords:  HK‐VDAC; Warburg effect; aging; apoptosis; cancer; metabolism; mitochondria

DOI:  https://doi.org/10.1002/adbi.202500472