bims-medebr 2026-03-08 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–03–08
eighteen papers selected by
Regina F. Fernández, Johns Hopkins University

Organelle-selective click chemistry for monitoring fatty acid metabolism at the subcellular level.
Hippocampal Bioenergetics and Metabolic Profiling Identifies Fatty Acid Oxidation as a Potential Therapeutic Target in Traumatic Brain Injury.
NMR metabolomics reveals metabolic alterations in a novel mouse model of neurodegeneration.
Mitochondrial dynamics in neurodevelopment and neurodevelopmental disorders.
Analyses of astrocyte-neuron lactate shuttle transporter levels in brain tissues from people with HIV-associated neurocognitive impairment and Alzheimer's disease.
Post-catalysis structures of mitochondrial complex I with ubiquinol-10 bound in the active site.
Plasmalogen deficiency and the Alzheimer's disease risk of apolipoprotein E4.
Mitochondrial-Derived Vesicles: An Emerging Whisperer in Neurological Disorders.
Advances in Understanding Lipid Metabolism in Oligodendrocyte Development and Neurodegenerative Diseases.
A novel therapy for pyridoxine-dependent epilepsy due to biallelic pathogenic variants in ALDH7A1: secondary mitochondrial energy deficiency and improvements of neurodevelopmental outcomes on triheptanoin treatment.
Region-specific ups and downs in mitochondrial numerical densities during Alzheimer's disease progression: A pilot study in human brains.
Reconstitution approaches for understanding cellular lipid dynamics.
MALDI-TOF mass spectrometry imaging of sulfatide lipid expression in the CNS of mice with experimental autoimmune encephalomyelitis.
Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
ACSS2 mediates prenatal alcohol exposure-related morphological and behavioral phenotypes.
β-hydroxybutyrate alleviates motor impairment and neurological damage in hypoxic-ischemic encephalopathy mice.
Omega-3 and omega-6 polyunsaturated fatty acids in neurodevelopment and prematurity: Correcting imbalances and closing the Preterm PUFA Gap.
HMGCS2-dependent β-OHB/H3K9bhb ameliorates synaptic plasticity and cognition in Alzheimer's disease.

Methods Enzymol. 2026 ;pii: S0076-6879(26)00024-8. [Epub ahead of print]727 355-371

Organelle-selective click chemistry for monitoring fatty acid metabolism at the subcellular level.

Tomonori Tamura, Seita Kawamoto, Itaru Hamachi.

  Fatty acids are vital cellular components, serving as energy sources and building blocks of membranes. Their metabolism involves multiple enzymatic processes localized to specific organelles, suggesting organelle-dependent distribution of fatty acid-containing lipids. Conventional lipidomics methods, while powerful, often lack spatiotemporal resolution due to reliance on bulk extracts or fractionation. To overcome this, we developed an organelle-selective labeling strategy combining metabolic incorporation of azide-modified fatty acids (AFAs) with organelle-directed copper-free click chemistry. Following the metabolic incorporation of azide analogs of palmitate or oleate into mammalian cells, azide-modified lipids in the endoplasmic reticulum (ER)/Golgi apparatus, mitochondria, lysosomes, and plasma membrane could be visualized and profiled through labeling with organelle-targeting clickable dyes. Distinct lipid distributions were observed among organelles, consistent with known metabolic pathways, such as enrichment of polyunsaturated lipids in mitochondria. Pulse-chase experiments enabled the tracking of interorganelle transport, particularly ER-to-mitochondria trafficking of phosphatidylcholine and phosphatidylethanolamine, and they further revealed a transient accumulation of diacylglycerol within mitochondria. Overall, this methodology enables fractionation-free, organelle-level lipidomics with high spatial and temporal resolution, providing unprecedented insights into fatty acid metabolism and offering a versatile platform for future studies of subcellular lipid dynamics. Here we describe detailed protocols for sample preparation and subsequent analyses by thin-layer chromatography and mass spectrometry.

Keywords:  Fatty acids; Interorganelle lipid transport; Lipids; Organelle-selective click reaction; Organelles; Pulse chase analysis

DOI:  https://doi.org/10.1016/bs.mie.2026.01.016
Mol Neurobiol. 2026 Feb 28. pii: 476. [Epub ahead of print]63(1):

Hippocampal Bioenergetics and Metabolic Profiling Identifies Fatty Acid Oxidation as a Potential Therapeutic Target in Traumatic Brain Injury.

Di Zhou, Mengxuan Shi, Mitchell D Kilgore, Yuwen Xiu, Yingjie Wang, Danni Wang, Thin Yadanar Sein, Charles Vidoudez, Amin Iskender, Gaby A Moyano, Lauren M Dumont, Yinghua Jiang, Prasad V G Katakam, Bo Ning, Aaron S Dumont, Xiaoying Wang, Jia Fan, Ning Liu.

  Traumatic brain injury (TBI) causes lasting neurological impairments, particularly learning and memory deficits associated with hippocampal damage. Emerging evidence suggests that hippocampal vulnerability may be linked to bioenergetic dysfunction, though its role remains poorly defined. A deeper understanding of post-TBI metabolic disturbances and their association with pathological outcomes could reveal novel therapeutic targets. In this study, we conducted functional bioenergetic assessments and multi-omics analyses on hippocampal slices using a mouse controlled cortical impact model of TBI. Seahorse analysis revealed a significant reduction in mitochondrial oxidative phosphorylation in dentate gyrus (DG) slices at day 1 (acute phase), which recovered by day 7 (subacute phase) post-TBI. Metabolomic profiling revealed acute impairments in purine nucleotide, glucose, amino acid, and fatty acid metabolism, most of which normalized by day 7. Isotope tracing indicated enhanced octanoate-derived fatty acid oxidation (FAO) in DG slices at day 7 post-TBI. Proteomics confirmed suppressed purine metabolism at day 1 across hippocampal subregions, while FAO remained preserved at day 1 and became significantly elevated by day 7, suggesting a compensatory metabolic adaptation. Administration of sodium octanoate, a medium-chain fatty acid, at 1 h post-TBI enhanced mitochondrial respiration at 24 h, reduced microglial counts at 48 h, and attenuated neurodegeneration by day 3. These findings identify FAO enhancement as a promising metabolic strategy to restore hippocampal bioenergetics and promote neuroprotection following TBI.

Keywords:  Bioenergetics dysfunction; Fatty acid oxidation; Hippocampus; Sodium octanoate; Traumatic brain injury

DOI:  https://doi.org/10.1007/s12035-026-05767-2
Front Neurosci. 2026 ;20 1776973

NMR metabolomics reveals metabolic alterations in a novel mouse model of neurodegeneration.

Grace V Mercer, Haley Adams, Drew P Locke, Sophie Kiefte, Nikita Harvey, Rachel Coffey, Céline M Schneider, Lindsay S Cahill.

   Introduction: The relationship between brain metabolism and neurodegenerative diseases is poorly understood. To investigate the pathophysiology of neurodegeneration, we used decrepit (dcr) mice, a mouse model with a mutation in a mitochondrial associated gene (mitochondrial ribosomal protein L3, Mrpl3) that results in reproducible, adult-onset degeneration of the brain.
Methods: Metabolite profiles were determined using 1H magic angle spinning nuclear magnetic resonance (600 MHz spectrometer) and ex vivo tissue samples from five brain regions in female and male dcr and healthy control mice (n = 39-44 mice/genotype/sex from 44-145 days of age).
Results: The relative concentration of acetate, N-acetylaspartate, gamma-aminobutyric acid, glutamine, and asparagine were decreased in the dcr mice compared to controls (p < 0.05). When the data was disaggregated by sex, the male dcr mice showed decreased relative concentrations of acetate, N-acetylaspartate, gamma-aminobutyric acid, asparagine, and choline-containing compounds compared to controls (p < 0.05) while the female dcr mice had an elevated relative glucose concentration compared to controls (p < 0.05).
Discussion: The dcr mice show evidence of significant metabolic dysregulation and add to the existing literature on the metabolic consequences of neurodegeneration. This work motivates future studies to understand the connection between mitochondrial dysfunction, metabolic alterations and neurodegeneration using the dcr mouse model.

Keywords:  MRPL3; metabolomics; mouse; neurodegeneration; nuclear magnetic resonance; sex differences

DOI:  https://doi.org/10.3389/fnins.2026.1776973
Nat Rev Neurosci. 2026 Mar 04.

Mitochondrial dynamics in neurodevelopment and neurodevelopmental disorders.

Carissa L Sirois, Jiyoun Lee, Audrey L Chambers, Xinyu Zhao.

Mitochondrial deficits have been found in individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). However, how mitochondria are regulated during brain development and how their dysregulation contributes to NDDs remains unclear. Mitochondria are continuously generated and degraded, dynamically remodelled through fusion and fission and actively transported to specific cellular compartments. Altered mitochondrial dynamics have been linked to several human diseases, and there is rising interest in their roles in neurodevelopment. However, most studies of mitochondrial contributions to NDDs have focused on the metabolic consequences of their dysfunction. This Review focuses on the mitochondrion itself, with particular emphasis on mitochondrial dynamics. We summarize recent advances in understanding the mechanisms that regulate mitochondrial dynamics during brain development and discuss how genetic and epigenetic alterations that affect mitochondrial dynamics contribute to NDDs. Finally, we consider mitochondrial dynamics as a potential therapeutic target for treatment of NDDs.

DOI: https://doi.org/10.1038/s41583-026-01031-7
NeuroImmune Pharm Ther. 2026 Feb 16.

Analyses of astrocyte-neuron lactate shuttle transporter levels in brain tissues from people with HIV-associated neurocognitive impairment and Alzheimer's disease.

Ali Boustani, Anna Laird, Leeann Shu, Erin E Sundermann, David J Moore, Robert Rissman, Jerel A Fields.

   Objectives: With the success of antiretroviral therapy (ART), people with HIV (PWH) are living longer. As they age, they increasingly face age-related comorbidities, including neurodegenerative conditions. The astrocyte-neuron lactate shuttle (ANLS) is a key mechanism that couples astrocytic glycolysis to neuronal oxidative metabolism, ensuring an adequate energy supply for synaptic activity. Disruption of this system has been implicated in both Alzheimer's disease (AD) and HIV-associated neurocognitive impairment (HIV-NCI), conditions characterized by some overlapping cognitive deficits yet distinct pathological drivers.
Methods: We investigated the expression of major ANLS transporters, including glucose transporters (GLUT1, GLUT3) and monocarboxylate transporters (MCT1, MCT2, MCT4), in postmortem frontal cortex from individuals with AD and PWH. There were two HIV cohorts based on viral suppression (suppressed/non-suppressed), and both were stratified by neurocognitive status (neurocognitively normal/neurocognitively impaired), while AD participants were compared to cognitively healthy participants. Quantitative immunoblotting and immunofluorescence imaging characterized disease-specific alterations.
Results: In AD, both endothelial (GLUT155 kDa) and astrocytic (GLUT145 kDa) isoforms were significantly reduced, along with MCT1, indicating widespread impairment of glucose and lactate transport. GLUT3, the neuronal glucose transporter, also showed a marked reduction. In contrast, in virally non-suppressed (VNS) PWH, GLUT145 kDa and MCT4 were downregulated, while virally suppressed (VS) PWH maintained preserved expression. Correlation analyses revealed strong GLUT3-MCT1 coupling in AD, suggestive of coordinated neuronal-astrocytic adaptation, but disrupted GLUT1-MCT4 relationships in VNS PWH, reflecting ANLS uncoupling under viremia.
Conclusions: These findings identify shared and distinct patterns of metabolic disruption: degeneration-driven ANLS failure in AD versus inflammation-driven uncoupling in HIV-NCI.

Keywords:  Alzheimer’s disease; HIV-associated NCI; astrocyte-neuron lactate shuttle; neurocognitive impairment

DOI:  https://doi.org/10.1515/nipt-2025-0019
Nat Commun. 2026 Mar 05.

Post-catalysis structures of mitochondrial complex I with ubiquinol-10 bound in the active site.

Injae Chung, Caroline S Pereira, John J Wright, Guilherme M Arantes, Judy Hirst.

Respiratory complex I is a multi-subunit energy-transducing membrane enzyme essential for mitochondrial and cellular energy metabolism. It couples NADH oxidation and ubiquinone-10 (Q10) reduction to the concomitant pumping of four protons to generate the proton-motive force that powers oxidative phosphorylation. Despite recent advances in structural knowledge of complex I, many mechanistic aspects including the reactive binding poses of Q10, how Q10 reduction initiates the proton transfer cascade, and how protons move through the membrane domain, remain unclear. Here, we use electron cryomicroscopy to determine structures of mammalian complex I, reconstituted into phospholipid nanodiscs containing exogenous Q10 and reduced by NADH, to global resolutions of 2.0 to 2.6 Å. Two conformations of a reduced Q10H2 molecule are observed, fully inserted into the Q-binding channel in the turnover-relevant closed state. By comparing the quinone species bound in oxidised and reduced complex I structures, paired with molecular dynamics simulations to investigate the charge states of key surrounding residues, we propose a series of substrate binding poses that Q10 transits through for reduction. Our highly hydrated structures exhibit near-continuous proton-transfer connections along the length of the membrane domain, enabling comparisons between them to assist in identifying the proton-transfer control points that are essential to catalysis.

DOI: https://doi.org/10.1038/s41467-026-70030-0
Brain Commun. 2026 ;8(1): fcag040

Plasmalogen deficiency and the Alzheimer's disease risk of apolipoprotein E4.

Jenny Hällqvist, Jan-Willem Taanman, Andreas Göteson, Wendy E Heywood, Jonathan M Schott, John Hardy, Mikael Landén, Henrik Zetterberg, Kevin Mills, Lionel Ginsberg.

  The ε4 allele of the APOE gene, encoding the E4 isoform of apolipoprotein E, is the leading genetic risk factor for late-onset Alzheimer's disease. While many potential mechanisms have been proposed to explain this risk, no dominant or unifying process has yet emerged. Here, we explore the primary function of apolipoprotein E in lipid transport and metabolism, by examining its lipid association properties, to establish whether they show isoform dependence and thereby could mediate Alzheimer's risk. We focus on ethanolamine plasmalogen, a phospholipid subclass known to be depleted in Alzheimer's disease brain. We purified apolipoprotein E from human cerebrospinal fluid by immunoprecipitation using an anti-pan-apolipoprotein E monoclonal antibody bound to magnetic beads, then conducted lipidomic and proteomic analyses of the precipitates by mass spectrometry. The cerebrospinal fluid samples were obtained from cognitively intact, relatively young individuals with no evidence of amyloid pathology and with known apolipoprotein E isoform status (E3E3, n = 5; E3E4, n = 4; E4E4, n = 5). The molar ratio of ethanolamine plasmalogen to apolipoprotein E was 29.5% lower for E4E4 than for E3E3 (P = 0.007) with a biological gradient: E3E3 > E3E4 > E4E4 (P = 0.03). No similar trends and differences were found for phosphatidyl ethanolamine, a chemically related lipid (P = 0.5). Compared to E3E3, the molar ratio of ethanolamine plasmalogen to phosphatidyl ethanolamine was significantly reduced for E3E4 (P = 0.0016) and E4E4 (P = 0.0001). The latter deficiency was similar in magnitude to that found in Alzheimer's disease brain relative to control. The finding that ethanolamine plasmalogen is depleted in apolipoprotein E4 relative to E3 strengthens the view that brain deficiency of this same lipid contributes to Alzheimer's disease causation, rather than being an effect of the neurodegeneration. Simultaneously, these results supply a potential mechanism for the risk of E4 versus E3, the former being less able to counteract the tissue defect. The apolipoprotein E4 lipid depletion cannot itself be a consequence of Alzheimer's disease, since cerebrospinal fluid samples were taken from individuals with no evidence of the condition. The biological gradient in ethanolamine plasmalogen deficiency mirrors the relationship of Alzheimer's disease risk (odds ratio) to E4 allelic dose. Ethanolamine plasmalogen deficiency could be linked to, or indeed drive, several metabolic pathways implicated in Alzheimer's pathogenesis, including amyloid-beta deposition and cholesterol dysregulation. Future studies should extend approaches to therapeutic intervention in Alzheimer's disease which attempt to reverse this lipid abnormality.

Keywords:  Alzheimer’s disease; apolipoprotein E; ethanolamine plasmalogen; isoform; lipidomics

DOI:  https://doi.org/10.1093/braincomms/fcag040
Eur J Neurosci. 2026 Mar;63(5): e70449

Mitochondrial-Derived Vesicles: An Emerging Whisperer in Neurological Disorders.

Nermeen Z Abuelezz, Fayza Eid Nasr, Amira Emad Abd El Aziz, Mariam K Ahmed, Nesrine S El Sayed.

  Mitochondrial dysfunction is a pivotal feature in the pathogenesis of various neurological and neurodegenerative disorders. The brain, with its high metabolic demands, is particularly vulnerable to impaired mitochondrial function, leading to oxidative stress, disturbed calcium homeostasis, and hyperactivated microglial responses. Mitochondrial disturbances majorly contribute to neuronal damage, synaptic dysfunction, and cognitive decline, making mitochondria a crucial target for therapeutic intervention in brain disorders. In this context, mitochondrial-derived vesicles (MDVs) are increasingly emerging as a novel aspect of mitochondrial biology with significant implications for brain health and disease. Prior to mitophagy, MDVs are released from stressed mitochondria, incorporating either healthy or damaged mitochondrial components as an earlier defense mechanism to maintain mitochondrial integrity and homeostasis. Furthermore, MDVs contribute to intercellular communication and extracellular neuroinflammation signaling, potentially influencing the progression of neurological disorders. This review provides a thorough overview of MDVs' subpopulations, highlighting the most recently reported MDVs roles across multiple neurological disorders and exploring their potential in diagnostic and therapeutic settings. Additionally, we further analyze the current limitations that hinder broader clinical applications of MDVs and present future perspectives and key recommendations to overcome these obstacles, aiming to enhance their effectiveness in diagnosis, therapy, and brain-targeted drug delivery.

Keywords:  mitochondrial communication; mitochondrial dysfunction; mitophagy; neurodegenerative disorders; vesicles

DOI:  https://doi.org/10.1111/ejn.70449
Clin Sci (Lond). 2026 Feb 27. pii: CS20258150. [Epub ahead of print]

Advances in Understanding Lipid Metabolism in Oligodendrocyte Development and Neurodegenerative Diseases.

Qing-Qing Sun, Ming-Yue Bao, Rui Gao, Shu-Kun Wang, Yao Zhang, Li-Bin Wang, Yuan Zhang, Xing Li.

  Lipids are indispensable architectural and functional components of central nervous system (CNS) myelin, with cholesterol, sphingolipids, and phospholipids collectively constituting 70-80% of myelin membrane composition. Oligodendrocytes (OLs), the sole myelin-producing cells in the CNS, exhibit exquisite metabolic specialization to sustain lifelong myelination and remyelination. Mounting evidence implicates lipid metabolic dysregulation-spanning cholesterol efflux defects, sphingolipid imbalance, and peroxisomal dysfunction-as a convergent mechanism underlying OL differentiation failure and progressive demyelination in neurodegenerative diseases. This review explores the role of lipid metabolic rewiring in governing oligodendrocyte precursor cells (OPCs) fate determination, highlighting three crucial axes: the interplay between mitochondria and peroxisomes in lipid biosynthesis, the potential toxicity of accumulated myelin debris in the microenvironment, and the regulation of OPC differentiation through lactylation modification on lipid metabolism and the interaction between glycolipid metabolisms. We further synthesize emerging therapeutic strategies targeting these pathways, including immunometabolism modulators, precision lipid interventions; diet-microbiome synergies: ketogenic diets combined with butyrate-producing probiotics to amplify endogenous remyelination. By integrating lipidomics datasets and recent clinical trial evidence, we propose a shift from broad metabolic suppression to spatially resolved modulation of lipid flux. This synthesis not only clarifies the dual roles of lipids in OL development and degeneration but also highlights druggable targets for personalized treatment of neurodegenerative diseases.

Keywords:  Lipid metabolism; Neurodegenerative disease; Oligodendrocyte; Oligodendrocyte progenitor cell; Remyelination

DOI:  https://doi.org/10.1042/CS20258150
Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261427020

A novel therapy for pyridoxine-dependent epilepsy due to biallelic pathogenic variants in ALDH7A1: secondary mitochondrial energy deficiency and improvements of neurodevelopmental outcomes on triheptanoin treatment.

Anastasia Ambrose, Morganne McCabe, Shalini Bahl, David Sinasac, Thomas Snyder, Saadet Mercimek-Andrews.

   Background: Pyridoxine-dependent epilepsy (PDE) due to biallelic pathogenic variants in ALDH7A1 (PDE-ALDH7A1) is an metabolic disease of lysine catabolism. Current standard treatment includes pyridoxine, arginine, and lysine- or protein-restricted diet. Pyridoxine treats seizures. Arginine and lysine- or protein-restricted diet decrease elevated α-aminoadipic semialdehyde (α-AASA) and Δ1- piperideine-6-carboxylate (P6C) levels to improve neurodevelopmental outcomes. We previously reported abnormalities in tricarboxylic acid (TCA) cycle and electron transport chain in PDE-ALDH7A1. We report a new patient with PDE-ALDH7A1 who did not show any improvements in neurodevelopment on the current standard therapy. We hypothesized that triheptanoin will provide substrate to TCA cycle and improve abnormal energy metabolism leading to improvements in neurodevelopmental outcome.
Objective: To treat this patient with triheptanoin to improve neurodevelopmental outcome.
Design: Due to complex I deficiency and lack of response to the current standard therapy, we applied triheptanoin novel therapy.
Methods: A 4-year-old male had compound heterozygous variants in ALDH7A1 and markedly elevated urine α-AASA. The goal dose of triheptanoin was 50% of the estimated energy requirement (EER). We assessed efficacy of triheptanoin using neuropsychological assessments. We measured 6-oxopipecolic acid using liquid chromatography tandem mass spectrometry.
Results: Triheptanoin was started at 10 mL/day. There was nausea up to 3 weeks after each dose increase, which has improved allowing us to increase triheptanoin gradually. The maximum actual dose of triheptanoin was 40% of EER. Cognitive composite score improved from 16% to 63% on treatment. All chemistry and biochemical investigations were normal. 6-oxopipecolic acid levels did not normalize. Triheptanoin treatment seemed to be safe and tolerated well.
Conclusion: Triheptanoin is an anaplerotic agent to provide substrates to the TCA cycle. This novel therapy improved neurodevelopmental outcome in our patient with PDE-ALDH7A1. We think that trihepatonoin should be the part of the current standard therapy to improve neurodevelopmental outcomes in patients with PDE-ALDH7A1.

Keywords:  6-oxo-pipecolate; ALDH7A1; developmental delay; neurodevelopmental outcome; pyridoxine-dependent epilepsy; triheptanoin

DOI:  https://doi.org/10.1177/26330040261427020
J Alzheimers Dis. 2026 Mar 06. 13872877261418994

Region-specific ups and downs in mitochondrial numerical densities during Alzheimer's disease progression: A pilot study in human brains.

Anna-Lena Balsliemke, Barbara Ahlemeyer, Eugen Schmidl, Till Acker, Anne Schänzer, Eveline Baumgart-Vogt.

  BackgroundMitochondrial dysfunction is an important pathogenic factor in Alzheimer´s disease (AD) progression. Most studies analysed disturbances in the mitochondrial metabolism and oxidative stress or focussed on mitochondrial dynamics such as mitochondrial trafficking, fusion-fission and mitophagy.ObjectiveVery limited data exist regarding changes in the mitochondrial numerical density at different levels of AD neuropathologic changes (ADNC) in human brains.MethodsMitochondrial numerical densities were analysed by morphometry using the marker protein ATP5B in sections of 13 brain areas of 8 patients with either low, mid or high ADNC, 6 patients with tauopathy and 10 control patients. Patient samples were classified according to the ABC score.ResultsIn comparison to control patients, we detected increases in mitochondrial densities at low (not in all cases), mid and high ADNC in neurons of the frontal (25%) and temporal (11%) neocortices, pontine nuclei (30%) and Purkinje neurons of the cerebellum (30%). Contrarily, mitochondrial densities decreased by 20% in hippocampal neurons of the entorhinal cortex and CA3 region at mid and high ADNC. Only minor changes occurred in other brain regions investigated (e.g., parietal and occipital neocortices, inferior olive, substantia nigra, striatum). In tauopathy patients, changes in mitochondrial densities were comparable to those in AD patients, except for a stronger decrease in the entorhinal cortex (40%) and a greater increase in the temporal neocortex (30%).ConclusionsIn the neocortex, primarily affected by extracellular amyloid-β (Aβ) deposits, mitochondrial densities in neurons increased, whereas they decreased in the hippocampus, at first enriched in intracellular neurofibrillary tangles.

Keywords:  Alzheimer's disease; amyloid-β; energy metabolism/oxidative stress; fatty acids; hippocampus; immunocytochemistry; lipidmetabolism; mitochondria; mitochondrial numerical density; neurofibrillary tangles; tauopathies

DOI:  https://doi.org/10.1177/13872877261418994
Methods Enzymol. 2026 ;pii: S0076-6879(25)00526-9. [Epub ahead of print]727 233-251

Reconstitution approaches for understanding cellular lipid dynamics.

Dazhi Li, Justin L Korfhage, Karin M Reinisch.

  Lipid transport is essential for membrane biogenesis and maintenance. Newly synthesized phospholipids are produced on the cytosolic leaflet of the endoplasmic reticulum (ER). Redistribution of lipids in cells is achieved by lipid scramblases across the lipid bilayer or alternatively, by lipid transport proteins (LTPs) to other organelles. Despite their important functions, the molecular identities and mechanisms of these proteins are only now emerging. Here, we describe reconstitution approaches with purified proteins and artificial membranes to study lipid dynamics in vitro, including a fluorescence-based assay to identify lipid scrambling activity and a fluorescence resonance energy transfer (FRET)-based assay to assess protein-mediated lipid transfer between liposomes or between liposomes and lipid monolayers. Together, these methods enable mechanistic studies of cellular lipid dynamics regulated by proteins.

Keywords:  Artificial lipid droplets; Lipid scramblase assay; Lipid transfer assay; Liposomes

DOI:  https://doi.org/10.1016/bs.mie.2025.11.022
Sci Rep. 2026 Feb 28.

MALDI-TOF mass spectrometry imaging of sulfatide lipid expression in the CNS of mice with experimental autoimmune encephalomyelitis.

Krista A Berlin, Carol Chase Huizar, Celeste Garza, Thomas G Forsthuber, Stephan B H Bach.



Keywords:  CNS; EAE; Lipid imaging; Mass spectrometry imaging; Multiple sclerosis; Neuroinflammation

DOI:  https://doi.org/10.1038/s41598-026-41147-5
Cell. 2026 Feb 27. pii: S0092-8674(26)00115-7. [Epub ahead of print]

Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.

Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley.

  The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the generation of reducing equivalents that power oxidative phosphorylation. Nevertheless, the requirement for components of the TCA cycle is context-specific, raising the question of which TCA cycle outputs support cell fitness. Here, we demonstrate that citrate clearance is an essential function of the TCA cycle. As citrate production increases, so do TCA cycle activity and dependence upon aconitase 2 (ACO2), the enzyme that initiates citrate catabolism in the TCA cycle. Disrupting citrate catabolism activates the integrated stress response and impairs cell fitness, and these effects are reversed by preventing citrate production or promoting mitochondrial citrate efflux. In vivo, ACO2 deficiency induces citrate accumulation and triggers tubular degeneration in the kidney, a tissue that physiologically takes up circulating citrate. Thus, intracellular citrate accumulation can be a metabolic liability, and citrate clearance is a major function of ACO2 in the TCA cycle.

Keywords:  ACO2; TCA cycle; cell metabolism; citrate; integrated stress response

DOI:  https://doi.org/10.1016/j.cell.2026.01.028
Neurobiol Dis. 2026 Mar 02. pii: S0969-9961(26)00085-9. [Epub ahead of print] 107341

ACSS2 mediates prenatal alcohol exposure-related morphological and behavioral phenotypes.

K M Dodson, E M Periandri, A Yadav, M Lopes, A J Barfield, A Ola, F N de Luna Vitorino, C Cearlock, B A Garcia, C Hill, S E Maloney, G Egervari.

  The metabolic enzyme Acetyl-CoA Synthetase 2 (ACSS2) recently emerged as an unexpected regulator of molecular and behavioral changes associated with alcohol use. Its role during prenatal exposure, however, remains unknown. Here, we use a combination of proteomic, genomic and behavioral approaches to establish ACSS2 as a key mediator of prenatal alcohol exposure-related phenotypes. We define the developmental window during which ACSS2 translocates to nuclei in the mouse brain, and show that alcohol-derived acetate is incorporated into fetal brain histone acetylation in utero. Using genetically engineered mice not expressing ACSS2, we demonstrate that loss of this enzyme attenuates chronic prenatal alcohol exposure-induced craniofacial abnormalities, motor function deficits, cognitive impairments as well as associated chromatin and gene expression changes in the dorsal hippocampus and the cerebellar vermis. Our results outline a previously unknown mechanism underlying prenatal alcohol exposure-related phenotypes regulated by ACSS2, which will inform the development of future therapeutic interventions.

Keywords:  Behavior; Epigenetics; Gene expression; Morphology; Prenatal alcohol exposure

DOI:  https://doi.org/10.1016/j.nbd.2026.107341
Behav Brain Res. 2026 Mar 03. pii: S0166-4328(26)00120-8. [Epub ahead of print]506 116144

β-hydroxybutyrate alleviates motor impairment and neurological damage in hypoxic-ischemic encephalopathy mice.

Zhixi Huang, Bingchun Lin, Cuihui Li, Xiaoyan Huang, Lin Zhu, Yunlong Xu, Chuanzhong Yang.

  Hypoxic-ischemic encephalopathy (HIE) is a major reason for neonatal mortality and long-term neurological deficits, with limited efficacy from current standard treatments like therapeutic hypothermia. β-hydroxybutyrate (BHB) is an abundant ketone body synthesized in the liver, possesses energy supply, anti-inflammatory, antioxidant, and anti-apoptotic activities. This study aims to investigate the effect of exogenous BHB on motor impairments and brain damage in HIE mice. Ten-day-old mouse pups underwent left common carotid artery ligation followed by hypoxia to induce HIE. Control underwent Sham surgery. BHB (300 mg/kg, i.p.) was administered daily for 39 consecutive days. Cylinder and rotarod tests were used to assess long-term functional outcomes, while Nissl and TUNEL staining assessed brain atrophy and apoptosis. Immunofluorescence was used to evaluate neuronal integrity, microglial activation and synaptic density. BHB serum and inflammatory markers in brain were measured using ELISA. Consecutive BHB treatment significantly improved motor function and reduced brain atrophy in HIE mice. These improvements were correlated with a recovery in the number of neurons and synapses in the motor cortex and striatum, alongside a reduction in apoptotic cell death. Furthermore, BHB reduced microglial activation and neuroinflammation. Notably, motor improvement persisted for eight weeks after the cessation of BHB treatment, suggesting long-lasting effects in diminishing lesion impact independent of continuous intervention. Consecutive BHB treatment improves motor function, maintains neuronal architecture, and reduces microglial activation and neuroinflammation in HIE mice, demonstrating sustained benefits in reducing lesion impact. These findings highlight the potential of BHB as a viable therapeutic intervention for HIE.

Keywords:  Microgliosis; Motor impairment; Neonatal hypoxia-ischemia encephalopathy; Neuroinflammation; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.bbr.2026.116144
Prog Lipid Res. 2026 Feb 28. pii: S0163-7827(26)00004-4. [Epub ahead of print]101 101379

Omega-3 and omega-6 polyunsaturated fatty acids in neurodevelopment and prematurity: Correcting imbalances and closing the Preterm PUFA Gap.

Simon C Dyall, J Thomas Brenna, Susan E Carlson, Michael A Crawford, Camilia R Martin, Norman Salem.

  Preterm birth has a worldwide prevalence of around 11 %, and > 95 % of preterm infants now survive into adulthood. However, improved survival is accompanied by increased risks of later life chronic disorders. The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), which are essential for optimum brain and visual system development, and cardiovascular and immune system function. Fetal demand for ARA and DHA is high, especially in the last trimester. Prior to birth they are provided by placental transfer, enriched by placental biomagnification, which occurs in parallel with placental bioreduction of linoleic acid (LA). However, after birth preterm infant feeding results in marked decreases in tissue levels of ARA and DHA, and concomitant increases in LA. This phenomenon we term the Preterm PUFA Gap, which may be a key factor in adverse health consequences of preterm birth. The review begins with a summary of the evidence highlighting the importance of DHA in reducing the risk of early preterm birth. We then develop the concept of the Preterm PUFA Gap, including discussion of the conflicting results of intervention trials with ARA and DHA. This is followed by a review of potential approaches to close the Preterm PUFA Gap.

Keywords:  ARA; Brain; DHA; Lung; Omega-3 fatty acids; Omega-6 fatty acids; Preterm infant

DOI:  https://doi.org/10.1016/j.plipres.2026.101379
Exp Mol Med. 2026 Mar 06.

HMGCS2-dependent β-OHB/H3K9bhb ameliorates synaptic plasticity and cognition in Alzheimer's disease.

Haitao Yu, Fangzhou Wang, Jia-Qi Yuan, Jia Chen, Ke-Yu Zhang, Dongdong Jia, Juan Gong, Yuming Mao, Shuguang Bi, Yu-Qi Zhang, Zi-Chong Lan, Hao-Yan Yu, Gao-Shang Chai.

Ketogenic diet (KD) can significantly ameliorate cognition in Alzheimer's disease (AD), but the specific mechanism is not clear. Histone3-lysine9-β-hydroxybutyrylation (H3k9bhb), a novel histone modification mark induced by ketogenesis-generated β-hydroxybutyrate (β-OHB), may be involved in the prevention and treatment of AD. Here we report that β-OHB and H3K9bhb were reduced in the hippocampus of triple transgenic AD male mice (3xTg-AD) mice. Reduced H3K9bhb levels were also observed in patients with AD. The 3xTg-AD mice exhibited a low enrichment of H3K9bhb on the promoters of NMDA receptor subunits and Syn1 and axon-related genes together with impaired synaptic plasticity, all of which were rescued by 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2, a rate-limiting enzyme of β-OHB synthesis) upregulation. Moreover, β-OHB replenishment enhanced H3K9bhb in 3xTg-AD mice, leading to an increase of NMDA receptor subunits and Syn1 and cognitive function in an HMGCS2-dependent manner. Thus, HMGCS2 is a key molecular switch of cognitive impairment, and targeting HMGCS2 or β-OHB replenishment appropriately may serve as a novel therapeutic strategy for AD treatment.

DOI: https://doi.org/10.1038/s12276-026-01664-9