bims-medebr 2026-02-08 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–02–08
twenty-one papers selected by
Regina F. Fernández, Johns Hopkins University

Astrocytic response to traumatic brain injury to rescue neuronal mitochondrial dysfunction through mitochondrial transfer.
Ketone bodies mitigate against systemic inflammation-induced changes in brain energy metabolism and delirium-like deficits in aged mice.
Pharmacokinetic effects of a single dose nutritional ketone ester supplement on brain glucose and ketone metabolism in alcohol use disorder.
Prostaglandin D2 Synthase Controls Schwann Cells Metabolism and Peripheral Myelin Homeostasis.
Lipid alterations in hereditary peripheral neuropathies: common mechanisms in disease heterogeneity?
Five energy metabolism pathways show distinct regional distributions and lifespan trajectories in the human brain.
Spatial Mapping of CoQ10 Repletion by BPM31510 in a Genetic Mouse Model (Coq4F147C) of Coenzyme Q Deficiency.
Acetyl-CoA availability regulates neuronal metabolism, growth, and synaptic activity.
Connections between physics and metabolism in brain functions.
Irisin regulates mitochondrial function to support synaptogenesis in the developing hippocampus.
Bidirectional relationship between mitochondrial dysfunction and dysregulated lipid metabolism in Multiple Sclerosis: potential mechanisms and therapeutic implications.
Metabolic reprogramming of microglia: Effects on development, disease, and therapeutic potential.
Spatially resolved transcriptome-metabolome integration reveals region-specific glial lipid dysregulation associated with Alzheimer's pathology.
Mechanical Stretch Disrupts Calcium Dynamics and Redistributes Piezo1 in Human Astrocytes.
Metabolic Stroke: Atypical Presentation of Succinic Semialdehyde Dehydrogenase Deficiency.
Disengaging the Engine: Histone Deacetylases 1 and 2-Mediated Acetylation of Hexokinase-2 Regulates Energy Metabolism in Microglia Following Intracerebral Hemorrhage.
Association of preterm birth and neonatal metabolism with neurodevelopment at 1 year of age: a prospective cohort study.
Spatiotemporal profiling of secondary neurodegeneration in a mouse model of cortical stroke: Role of N-acetylneuraminic acid.
Amyloid precursor protein interacts with the mitochondrial phosphatase PGAM5 and regulates mitochondrial respiration.
Mitochondrial specialization and signaling shape neuronal function.
ACSL1-Dependent Microglial Lipoimmunometabolic Reprogramming Underlies Cognitive Deficits in Alcohol Use Disorder.

bioRxiv. 2026 Jan 23. pii: 2026.01.22.701145. [Epub ahead of print]

Astrocytic response to traumatic brain injury to rescue neuronal mitochondrial dysfunction through mitochondrial transfer.

Gopal V Velmurugan, Hemendra J Vekaria, Alexander G Rabchevsky, Kai Saito, Josh M Morganti, Samir Patel, Brad Hubbard, Patrick G Sullivan.

As highly dynamic organelles, mitochondria play an essential role in neuronal survival and synaptic function. Excitotoxicity is as a critical factor that promotes mitochondrial dysfunction after traumatic brain injury (TBI). Intercellular mitochondrial transfer and exogenous mitochondrial transplantation are emerging concepts to understand mitochondrial trafficking in response to mitochondrial dysfunction; however, robust in vivo evidence remains limited on the extent of these processes in the central nervous system (CNS). There is a significant knowledge gap in our understanding of mitochondrial transfer mechanisms under both normal physiological conditions and after experimental TBI. Mouse lines expressing mitochondrial green-fluorescent dendra-2 (mtD2) and GFP (mtGFP) targeted to inner and outer mitochondrial membranes, respectively, were used to study astrocyte-specific (Aldh1l1-CreER; mtD2 f/f - AmtD2 and Aldh1l1-CreER; mtGFP f/f - AmtGFP) and neuron-specific (CamK2aCre; mtD2 f/f - NmtD2 and CamK2aCre; mtGFP f/f - NmtGFP) mitochondrial dynamics and bioenergetics in acute TBI and excitotoxicity. At 24 hrs following TBI, neurons in the NmtD2 mouse brain exhibited rapid and significant alterations in mitochondrial morphology, including changes in total mitochondrial volume, volume distribution, and sphericity. Synaptic neuronal (SN) mitochondria display robust deficits in mitochondrial bioenergetics and complex protein levels while non-synaptic neuronal (NSN) mitochondria show State III bioenergetics and complex proteins at control levels. These findings are accompanied by a marked increase in astrocyte-derived mitochondria (AmtGFP) transfer to neurons at 24 hrs post-injury, compared to control animals, but no increase in transfer to neuronal synapses. While TBI also altered astrocytic mitochondrial morphology in the cortex, astrocytic mitochondrial bioenergetics remained preserved. Single-cell RNA-seq analysis of astrocytes revealed significant transcriptional reprogramming following TBI, characterized by the upregulation of genes associated with mitochondrial homeostasis and the machinery for organelle trafficking. In vitro co-cultures of primary cortical astrocytes and neurons demonstrated that astrocytes can transfer mitochondria to neurons via direct contact and that NMDA-mediated excitotoxicity further enhanced this astrocyte-to-neuron mitochondrial transfer. Furthermore, astrocytic-derived extracellular vesicles containing mitochondria (EV-mito) deliver mitochondria to neurons and EV-mediated mitochondrial transfer significantly ameliorated NMDA-induced mitochondrial dysfunction in primary cortical neurons. Together, these findings show that astrocytes take on a TBI-related phenotype that facilitates dynamic changes in mitochondrial networks and mitochondrial trafficking to neurons. Astrocytic transfer of respiratory-competent mitochondria support is an intrinsic neuroprotective response to injury that supports mitochondrial function in neuronal soma, dendrites, and axons but not at the neuronal synapse. Finally, we show therapeutic potential of exogenous mitochondrial transfer, particularly via EV-mito, for treating neurological disorders associated with excitotoxicity, such as TBI.

DOI: https://doi.org/10.64898/2026.01.22.701145
bioRxiv. 2026 Feb 01. pii: 2026.01.22.701114. [Epub ahead of print]

Ketone bodies mitigate against systemic inflammation-induced changes in brain energy metabolism and delirium-like deficits in aged mice.

Pierre-Louis Hollier, M K Kirsten Chui, Javier Cuitavi, Paul Denver, Hugh J Delaney, John C Newman, Colm Cunningham.

Acute systemic inflammation affects brain function, with detrimental consequences in aged individuals. These include delirium, an acute neuropsychiatric syndrome characterized by fluctuating disturbances in attention, perception and cognition. Delirium is associated with disrupted brain energy metabolism but our understanding of this during acute systemic inflammation is limited. Here we hypothesized that LPS-induced systemic inflammation would disrupt brain energy metabolism in aged C57BL6J mice and that the consequent functional impairments would be mitigated by ketone body utilization. We investigated ketone body effects in sickness behaviour, inflammation, energy metabolism and cognitive function. Real-time changes in utilisation of energy sources were quantified by indirect calorimetry and administration of radioisotope-labelled glucose and betahydroxybutyrate. Mass-spectrometry metabolomics was used to index severity of behavioural distrurbances to changes in hippocampal energy metabolism. LPS precipitated hypoglycemia and induced a whole-body switch from carbohydrate to lipid utilisation. Despite this, hippocampal insulin resistance and preserved brain glucose was observed while alternative carbohydrates, mannose and fructose, became depleted. Ketone ester treatment reversed insulin resistance, mitigated sickness behaviour and prevented delirium-like cognitive dysfunction without altering pro-inflammatory responses. Our results show that promoting ketone body usage mitigates systemic inflammation-induced brain energy disruption and prevents delirium-like cognitive deficits in aged mice.

DOI: https://doi.org/10.64898/2026.01.22.701114
Psychiatry Res Neuroimaging. 2026 Jan 29. pii: S0925-4927(26)00019-3. [Epub ahead of print]357 112154

Pharmacokinetic effects of a single dose nutritional ketone ester supplement on brain glucose and ketone metabolism in alcohol use disorder.

Xinyi Li, Anthony J Young, Zhenhao Shi, Juliana Byanyima, Sianneh Vesslee, Rishika Reddy, Timothy Pond, Mark Elliott, Ravinder Reddy, Robert K Doot, Jan-Willem van der Veen, Henry R Kranzler, Ravi Prakash Reddy Nanga, Jacob G Dubroff, Corinde E Wiers.

  Acute alcohol use reduces brain glucose metabolism while increasing uptake of acetate, a byproduct of alcohol. This metabolic shift persists in individuals with alcohol use disorder (AUD) and may offer a treatment target. Recent studies show that ketone therapies can lessen alcohol withdrawal and cravings. In this study, we tested whether a single dose of a ketone ester (KE) supplement affects brain energy use and alcohol craving. Ten participants (five with AUD, five healthy controls) received two FDG-PET brain scans-one after taking 395 mg/kg KE and one at baseline-in a randomized order. Additionally, five AUD participants underwent magnetic resonance spectroscopy to measure cingulate β-hydroxybutyrate (BHB). KE lowered blood glucose and increased BHB in both groups. Brain scans revealed a 17% reduction in glucose metabolism, especially in the frontal, occipital, and cingulate cortices, as well as the hippocampus, amygdala, and insula. No major differences were observed between AUD and control groups. KE significantly reduced alcohol craving in AUD participants and tripled cingulate BHB levels. These findings suggest that a single KE dose can rapidly shift brain energy use from glucose to ketones, and may help reduce cravings in AUD, supporting its potential as a therapeutic approach.

Keywords:  Beta-hydroxybutyrate; Brain energetics; Ketone ester; Krebs cycle; Metabolism

DOI:  https://doi.org/10.1016/j.pscychresns.2026.112154
Glia. 2026 Mar;74(3): e70137

Prostaglandin D2 Synthase Controls Schwann Cells Metabolism and Peripheral Myelin Homeostasis.

Amelia Trimarco, Matteo Audano, Rosa La Marca, Marta Pellegatta, Paolo Canevazzi, Mariaconcetta Cariello, Marta Falco, Silvia Pedretti, Gabriele Imperato, Alessandro Cestaro, Paola Podini, Giorgia Dina, Angelo Quattrini, Luca Massimino, Donatella Caruso, Nico Mitro, Carla Taveggia.

  We previously reported that in the absence of Prostaglandin D2 synthase (L-PGDS) peripheral nerves are hypomyelinated in development while in adulthood they present aberrant myelin sheaths. We now demonstrate that L-PGDS expressed in Schwann cells is part of a coordinated program that controls myelin homeostasis, describing a new physiological pathway implicated in preserving peripheral myelin. In vivo and in vitro lipidomic, metabolomic, and transcriptomic analyses confirmed that myelin lipids composition, Schwann cells' energetic metabolism, and key enzymes controlling these processes are altered in the absence of L-PGDS. Moreover, Schwann cells undergo a metabolic rewiring, turn to acetate as the main energetic source, and produce ketone bodies to ensure glial cell and neuronal survival. All these changes correlate with morphological myelin alterations. Collectively, we posit that myelin lipids serve as a reservoir to provide ketone bodies, which together with acetate represent the adaptive substrates Schwann cells can rely on to sustain the axo-glial unit and preserve the integrity of the PNS.

Keywords:  L‐PGDS; Schwann cell; ketone bodies; lipidomics; metabolomics; myelin homeostasis; transcriptomic

DOI:  https://doi.org/10.1002/glia.70137
Mol Neurodegener. 2026 Feb 04.

Lipid alterations in hereditary peripheral neuropathies: common mechanisms in disease heterogeneity?

Koen Kuipers, Sam Vanherle, Kirsten Poelmans, Esther Wolfs, Jeroen Bogie, Tim Vangansewinkel.



Keywords:  Demyelination; Lipid metabolism; Neurodegeneration; Neurons; Peripheral neuropathy; Schwann cells

DOI:  https://doi.org/10.1186/s13024-026-00932-6
PLoS Biol. 2026 Jan;24(1): e3003619

Five energy metabolism pathways show distinct regional distributions and lifespan trajectories in the human brain.

Moohebat Pourmajidian, Justine Y Hansen, Golia Shafiei, Bratislav Misic, Alain Dagher.

Energy metabolism involves a series of biochemical reactions that generate ATP, utilizing substrates such as glucose and oxygen supplied via cerebral blood flow. Energy substrates are metabolized in multiple interrelated pathways that are cell- and organelle-specific. These pathways not only generate energy but are also fundamental to the production of essential biomolecules required for neuronal function and survival. How these complex biochemical processes are spatially distributed across the cortex is integral to understanding the structure and function of the brain. Here, using curated gene sets and whole-brain transcriptomics, we generate maps of five fundamental energy metabolic pathways: glycolysis, pentose phosphate pathway, tricarboxylic acid cycle, oxidative phosphorylation and lactate metabolism. We find consistent divergence between primarily energy-producing and anabolic pathways, particularly in unimodal sensory cortices. We then explore the spatial alignment of these maps with multi-scale structural and functional attributes, including metabolic uptake, neurophysiological oscillations, cell type composition, laminar organization and macro-scale connectivity. We find that energy pathways exhibit unique relationships with the cellular and laminar organization of the cortex, pointing to the higher energy demands of large pyramidal cells and efferent projections. Finally, we show that metabolic pathways exhibit distinct developmental trajectories from the fetal stage to adulthood. The primary energy-producing pathways peak in childhood, while the anabolic pentose phosphate pathway shows greater prenatal expression and declines throughout life. Together, these results highlight the rich biochemical complexity of energy metabolism organization in the brain.

DOI: https://doi.org/10.1371/journal.pbio.3003619
J Lipid Res. 2026 Jan 28. pii: S0022-2275(26)00013-1. [Epub ahead of print] 100987

Spatial Mapping of CoQ10 Repletion by BPM31510 in a Genetic Mouse Model (Coq4F147C) of Coenzyme Q Deficiency.

Eliana Barriocanal-Casado, Sylwia A Stopka, Alba Pesini, Juan J Aristizabal-Henao, Srada Karmacharya, Devon Van Cura, Ryan Zhang, Kelsey R Nickerson, Kashni Grover, Oksana Zavidij, Sarah R Wessel, Niven R Narain, Vijay Modur, Stephane Gesta, Michael A Kiebish, Catarina M Quinzii.

  Primary Coenzyme Q10 (CoQ10) deficiency is a rare mitochondrial disorder caused by mutations in genes involved in CoQ biosynthesis (e.g., COQ4) that result in impaired mitochondrial respiration, oxidative stress, and dysfunction across multiple organ systems due to decreased mitochondrial levels of CoQ10. Although oral CoQ10 supplementation has been examined for standard of care, poor absorption and inadequate tissue and intracellular distribution have resulted in a lack of clinically significant efficacy. BPM31510 is a lipid nanoparticle formulation of oxidized CoQ10 designed to improve bioavailability and targeted uptake into the mitochondria. In the current study, we assessed the efficacy of BPM31510 to increase CoQ levels in Coq4F147C mice, a novel genetic knock-in model of primary CoQ deficiency. CoQ9, the main form of CoQ in mice, and CoQ10 were significantly decreased in brain, kidney, heart, and muscle of Coq4F147C mice compared to Coq4+/+ mice. BPM31510 treatment significantly increased oxidized CoQ10 levels across all tissues, mediated by the nanoliposome biodistribution of oxidized CoQ10 in BPM31510. MALDI-MSI demonstrated regional and spatial restoration of CoQ10 within the brain, including the cerebellum, myocardium, and renal cortex of Coq4F147C mice. These results demonstrate that BPM31510 successfully concentrates pharmacologically active CoQ10 in target tissues that are not reachable with oral therapy, in a genetic model of primary CoQ deficiency. We enabled the visualization of sub-organ CoQ10 localization to specifically demonstrate CoQ10 restoration. This study establishes proof-of-concept for spatial quinomics, a new methodology that combines spatial metabolomics with quinomics to evaluate next-generation CoQ10-based therapeutics for mitochondrial disorders.

Keywords:  CoQ10 deficiency; MALDI; MSI; mass spectrometry; mitochondrial disease; quinomics

DOI:  https://doi.org/10.1016/j.jlr.2026.100987
bioRxiv. 2026 Jan 20. pii: 2026.01.20.700435. [Epub ahead of print]

Acetyl-CoA availability regulates neuronal metabolism, growth, and synaptic activity.

Eric R McGregor, Cassandra J McGill, Nicholas L Arp, Josef P Clark, Dominique A Baldwin, Di Kuang, Gonzalo Fernandez-Fuente, Yun Hwa Choi, Keenan S Pearson, Jason K Nagorski, Judith A Simcox, Jing Fan, Luigi Puglielli, Rozalyn M Anderson.

The metabolite acetyl-CoA plays a central role in cellular metabolic homeostasis. As part of the secretory pathway, acetyl-CoA is imported into the endoplasmic reticulum (ER) by a membrane-bound transporter AT-1 (SLC33A1). AT-1 has been linked to peripheral neuropathy (heterozygous mutations), developmental delay with premature death (homozygous mutations) and intellectual disability with progeria (duplication). These phenotypes can be reproduced in the mouse. Here, we show that AT-1 overexpression in primary neurons impacts diverse phenotypes related to neuronal function and plasticity. At the gene level, AT-1 induces brain aging signatures, and key differences in ribosomal and synaptic processes were identified in both the transcriptome and the proteome. Changes in mitochondria-associated pathways were reflected in an increase in expression of mitochondrial master regulator PGC-1α and its target genes. Functionally, marked differences in mitochondrial membrane potential, architecture, and respiration were detected. Tracing experiments indicated altered glucose utilization in glycogen storage and nucleotide production. Shifts in redox metabolism were linked to differences in levels of NAD-dependent SIRT1 and CtBP2, with consequences for acetylated lysine modification. Depletion of lipid stores was associated with greater plasticity in fuel substrate utilization and a major shift in cellular lipid composition. These broad-scale changes in metabolism were coincident with reduced expression of synaptic proteins and reduced activity among synaptic networks, indicating that neuronal electrophysiology and network communication are coordinated at least in part through neuronal acetyl-CoA metabolism.

DOI: https://doi.org/10.64898/2026.01.20.700435
iScience. 2026 Feb 20. 29(2): 114643

Connections between physics and metabolism in brain functions.

Fanny Mochel, Alfonso de Oyarzábal Sanz, Leticia Pías Peleteiro, Juliana Ribeiro-Constante, Patricia Bassereau, Kevin Chalut, Laurent Cognet, Leroy Cronin, Stuart Hameroff, Francisco J López-Murcia, Eva K Pillai, Marta Sales-Pardo, Anne Straube, Adrien Hallou, Angeles Garcia-Cazorla.

  Advances in molecular biology have shaped our understanding of cellular biology. Yet, this molecular-centric approach has overshadowed the role of physical processes governing cellular homeostasis. In genetic disorders, particularly inherited metabolic diseases, phenotypic heterogeneity cannot solely be explained by genetic variants. Mechanical properties of cells and tissues may account for this variability, given the interplay between biological and physical cues in metabolic regulations. In July 2024, we organized an international symposium with world experts in physics, chemistry, and neurobiology to explore the physical regulation of brain metabolism in health and disease. Topics included mechanotransduction in neurodevelopment and brain aging, the physics of neurotransmission and cellular trafficking, and emerging methods to model cellular metabolism, analyze single-cell mechanical and transcriptional signals, and track nanoparticles in intact brain tissue. This effort aims to foster an interdisciplinary framework for neuroscience and train scientists across disciplines, while integrating art to stimulate creativity and integrative thinking.

Keywords:  Biophysics; Cell biology; Human metabolism

DOI:  https://doi.org/10.1016/j.isci.2026.114643
Mol Cell Neurosci. 2026 Feb 01. pii: S1044-7431(26)00003-5. [Epub ahead of print] 104073

Irisin regulates mitochondrial function to support synaptogenesis in the developing hippocampus.

Mary R Josten, Kyra N Parker, Crystal Dillon, Heiko Jansen, Gary A Wayman.

  Hippocampal synapse proliferation is a critical period in brain development that demands vast supplies of chemical energy. Maternally derived hormones exert vital effects on mitochondrial function in the developing brain, thus determining neuronal synapse proliferative capacity. Here we investigated the mechanisms by which irisin, through the neuronal uncoupling proteins (UCPs) UCP2, UCP4, and UCP5, regulates mitochondrial function to facilitate the growth and maturation of dendritic spines in developing hippocampal neurons. Irisin treatment increased mitochondrial respiration and mitochondrial membrane potential, but not reactive oxygen species production in an in vitro model of developing hippocampal neurons. Irisin treatment also increased the expression of UCP2, UCP4, and UCP5. Knockdown of UCP2, UCP4, and UCP5 exerted differential effects on basal and irisin-stimulated phenotypes in cultured neurons, while overexpression of UCP2, UCP4, or UCP5 exerted differential effects on basal mitochondrial membrane potential, reactive oxygen species levels, and synaptogenesis. Together, these data suggest a role for irisin in regulating neuronal mitochondrial function through a UCP-dependent mechanism to support synaptogenesis during hippocampal development.

Keywords:  Irisin; Mitochondria; Synaptogenesis; Uncoupling proteins

DOI:  https://doi.org/10.1016/j.mcn.2026.104073
Neurobiol Dis. 2025 Dec;pii: S0969-9961(25)00376-6. [Epub ahead of print]217 107159

Bidirectional relationship between mitochondrial dysfunction and dysregulated lipid metabolism in Multiple Sclerosis: potential mechanisms and therapeutic implications.

Tian Xie, Ho Tin Fok, Zehao Quan, Chun-Yuan Ku, Isaac Oluwatobi Akefe, Daniel Schweitzer.

   BACKGROUND: Multiple Sclerosis (MS) is a heterogeneous neuroinflammatory disease with complex aetiology and diverse clinical presentations, often accompanied by neurodegenerative pathology. While current therapies primarily focus on immunomodulation, emerging evidence underscores a critical bidirectional interplay between mitochondrial dysfunction and lipid dysregulation in driving MS progression. Understanding this metabolic-mitochondrial axis may reveal novel therapeutic opportunities beyond immune modulation.
OBJECTIVE: This scoping review systematically maps recent literature (2015-2025) to delineate the mechanistic connections between mitochondrial dysfunction and lipid dysregulation in MS, identify current knowledge gaps, and highlight translational opportunities for targeted intervention.
METHODS: A systematic search of PubMed, Embase, and Scopus was conducted in 2025 following PRISMA-ScR guidelines. Thirty-six eligible studies examining mitochondrial-lipid interactions in human MS and preclinical models were included and synthesised thematically.
RESULTS: Evidence converges on a self-reinforcing pathological cycle in MS, where dysregulated lipid metabolism impairs mitochondrial integrity, amplifying reactive oxygen species generation, energy failure, and further lipid disruption. This cascade contributes to oligodendrocyte injury, demyelination, ferroptosis, and axonal degeneration. Importantly, therapeutic strategies that restore lipid-mitochondrial homeostasis, such as mitochondrial antioxidants, lipid modulators, and metabolically active immunotherapies, demonstrate promising neuroprotective effects in preclinical studies.
CONCLUSION: The evidence supports a model in which the bidirectional feedback loop between mitochondrial dysfunction and lipid dysregulation represents a significant mechanism contributing to neurodegeneration in MS. Clinically, these insights highlight opportunities for earlier diagnosis and more personalised disease management through the integration of lipid-based biomarkers into patient monitoring and treatment selection. Targeting this metabolic axis holds significant promise for developing next-generation disease-modifying therapies to slow disease progression, enhance neuroprotection, and improve functional recovery across different MS subtypes.

Keywords:  Demyelination; Lipid metabolism; Mitochondria; Multiple sclerosis; Neurodegeneration; Neuroinflammation

DOI:  https://doi.org/10.1016/j.nbd.2025.107159
Neural Regen Res. 2026 Jan 27.

Metabolic reprogramming of microglia: Effects on development, disease, and therapeutic potential.

Haiwei Zhang, Mengmeng Jin, Peng Jiang, Ying Liu.

   ABSTRACT: Microglia, the immune sentinels of the central nervous system, play vital roles in maintaining neural homeostasis and mediating responses to injury and disease. Their functions, including synaptic pruning to neuroinflammation, are tightly linked to their metabolic state. Emerging evidence suggests that metabolic reprogramming is a key driver of microglial activation, functional transitions, and interactions with neurons and other glial cells. This review summarizes current findings on the developmental origins, region-specific adaptations, and metabolic plasticity of microglia. We review lipid metabolism, energy utilization, and oxidative stress responses, which underlie immune regulation and neuroprotective functions. By integrating molecular, transcriptomic, and metabolomic insights, we provide a comprehensive understanding of microglial metabolism and highlight potential therapeutic strategies targeting metabolic pathways in neurodegenerative and central nervous system diseases.

Keywords:  energy metabolism; functional states; human induced pluripotent stem cells; lipid metabolism; metabolic reprogramming; microglia; neurodegenerative disease; neuroinflammation

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01298
bioRxiv. 2026 Jan 24. pii: 2026.01.23.701345. [Epub ahead of print]

Spatially resolved transcriptome-metabolome integration reveals region-specific glial lipid dysregulation associated with Alzheimer's pathology.

Linfeng Xu, Hyunjun Yang, Julio Leon, Xiangpeng Li, Abby Oehler, Cyrus Modavi, Adam R Abate, Carlo Condello.

Glial cells maintain the brain's lipid and energy balance, and their breakdown is increasingly recognized as a causal contributor to Alzheimer's disease (AD). While this concept is established, no approach has directly shown how glial homeostatic failure manifests across brain regions and microenvironments or how it links local pathology, such as plaques, to global metabolic imbalance. To address this gap, we developed iMIST, an integrated platform that combines MALDI-based metabolite imaging, histology, and spatial transcriptomics within a single tissue section to align molecular and anatomical information. Using a mouse model of late-onset AD that recapitulates both amyloid deposition and metabolic vulnerability, iMIST revealed that glial lipid dysregulation is widespread but spatially specialized. In gray matter, plaque-associated microglia were associated with upregulated glycerophospholipid-remodeling in cortico-thalamic areas indicating metabolic stress around local pathology. In contrast, white matter tracts rich in lipid-producing oligodendrocytes show plaque-independent deficits in galactosylceramide metabolism reflecting their high myelin demand. Both processes intensify with age, transforming adaptive glial responses into persistent metabolic dysfunction. Together, these findings demonstrate the spatial interplay between global glial metabolic imbalance and local microenvironmental stressors associated with AD pathology. By integrating transcriptomic and metabolomic information in situ , iMIST provides a framework for uncovering how regional glial vulnerability shapes the pathogenesis of neurodegenerative diseases.

DOI: https://doi.org/10.64898/2026.01.23.701345
Ann Biomed Eng. 2026 Feb 05.

Mechanical Stretch Disrupts Calcium Dynamics and Redistributes Piezo1 in Human Astrocytes.

Shahrzad Shiravi, Akash Chakka, Xi Xiao, Meilin Fernandez Garcia, Alexandra Yufa, Angela Mitevska, Carina Seah, Huanyao Gao, Laura M Huckins, Kristen J Brennand, John D Finan.

   PURPOSE: Astrocytes regulate the activity of nearby neurons so disruption of astrocyte calcium dynamics by traumatic brain injury (TBI) could have profound consequences for neural network activity in the brain. This study aimed to define how mechanical stretch injury alters calcium signaling, mitochondrial membrane potential, and mechanosensitive ion channel organization in human induced pluripotent stem cell (hiPSC)-derived astrocytes.
METHODS: Human iPSC-derived astrocytes were subjected to controlled two-dimensional stretch injury across multiple severities. Live-cell calcium and mitochondrial membrane potential imaging, Piezo1 immunostaining, and RNA sequencing were used to assess functional and transcriptional responses.
RESULTS: Cell viability, mitochondrial membrane potential, and spontaneous calcium transients declined in a severity-dependent manner. At moderate injury levels, reductions in mitochondrial function, calcium dynamics, and Piezo1 spatial distribution were transient. RNA sequencing identified 196 differentially expressed genes, including downregulation of mitochondrial and oxidative metabolic pathways and upregulation of cortical thinning-associated pathways.
CONCLUSION: This platform captures functional and molecular hallmarks of astrocyte injury and provides a human in vitro model for studying mechanobiological pathways linking TBI to neurodegenerative processes.

Keywords:  Calcium dynamics; Mitochondrial dysfunction; Piezo1; RNA sequencing; Traumatic brain injury; hiPSC-derived astrocytes

DOI:  https://doi.org/10.1007/s10439-026-03995-0
JIMD Rep. 2026 Mar;67(2): e70071

Metabolic Stroke: Atypical Presentation of Succinic Semialdehyde Dehydrogenase Deficiency.

Sharmila Kiss, Richard J Leventer, Cormac Duff, Emma Macdonald-Laurs, Olivia-Paris Quinn, Fahaz Nazer, Michelle Cao, Abisha Srikumar, Jenzen Dalina, Mary Eggington, Joy Yaplito- Lee.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in ALDH5A1, encoding the mitochondrial enzyme SSADH. This enzyme catalyses the conversion of succinic semialdehyde to succinic acid in the γ-aminobutyric acid (GABA) degradation pathway. SSADH deficiency leads to the accumulation of neurotoxic metabolites, including γ-hydroxybutyrate (GHB), and presents with developmental delay, hypotonia, ataxia, seizures, behavioral disturbances, and intellectual disability. We report a 10-month-old Caucasian male with global developmental delay, central hypotonia, and delayed motor milestones. He presented acutely with left-sided hemiplegia following irritability and vomiting. Brain MRI showed bilateral (right > left) T2 hyperintensities and diffusion restriction in the globus pallidus. Urine organic acid analysis via gas chromatography-mass spectrometry revealed markedly elevated 4-hydroxybutyric acid and 4,5-dihydroxyhexanoic lactone, pathognomonic for SSADH deficiency. Molecular testing identified compound heterozygous ALDH5A1 variants: c.278G>T p.(Cys93Phe) and c.612G>A p.(Trp204*), both previously reported as pathogenic. Parental segregation confirmed trans configuration. Three weeks postillness, he developed focal seizures, which have remained well controlled on levetiracetam. His seizure onset in infancy is notably earlier than the typical early childhood onset (~9 years) reported in SSADH deficiency. This case expands the phenotypic spectrum of SSADH deficiency to include metabolic stroke as a presenting feature in infancy and highlights the importance of early recognition and molecular confirmation to guide management and emerging therapeutic strategies.

DOI: https://doi.org/10.1002/jmd2.70071
Adv Sci (Weinh). 2026 Feb 03. e00194

Disengaging the Engine: Histone Deacetylases 1 and 2-Mediated Acetylation of Hexokinase-2 Regulates Energy Metabolism in Microglia Following Intracerebral Hemorrhage.

Zhiwen Jiang, Heng Yang, Xinjie Gao, Zengyu Zhang, Ruiyuan Weng, Yuchao Fei, Jiabin Su, Hanqiang Jiang, Wei Ni, Yuxiang Gu.

  Microglia-mediated neuroinflammation is closely associated with the pathogenesis of secondary brain injury following spontaneous intracerebral hemorrhage (ICH). However, the relationship between immune response regulation and metabolic patterns in microglia remains unclear. Histone Deacetylases 1 and 2, a class of lysine deacetylases, regulates gene transcription by modulating histone acetylation modifications and is widely involved in various cellular activities of microglia. In this study, we observed that knockout of HDAC1/2 in microglia alleviated neurological deficits caused by ICH, preserved white matter integrity, and accelerated hematoma clearance post-ICH. Mechanistically, we found that after ICH, microglia exhibited increased expression of hexokinase 2 (HK2) and enhanced glycolysis. HDAC1/2 knockout/pharmacological inhibition affected the acetylation level of HK2, inhibited its glycolytic activity, and promoted a metabolic shift in activated microglia from glycolysis to fatty acid oxidation. This shift was associated with reduced pro-inflammatory responses and enhanced phagocytic activity in microglia. Enhanced fatty acid oxidation may have a detrimental effect on mitochondrial function, and HDAC1/2 inhibition simultaneously promoted mitophagy in microglia. Additionally, HDAC1/2 inhibition triggered microglial apoptosis and suppressed proliferation, ultimately leading to a reduction in microglial cell numbers. Overall, this study reveals the potential mechanisms by which targeting HDAC1/2, through acetylation modifications and transcriptional regulation, modulates microglial function and metabolism after ICH, thereby exerting protective effects.

Keywords:  HK2; acetylation; autophagy; fatty acid oxidation; glycolysis; histone deacetylase 1/2; intracerebral hemorrhage; microglia; mitochondrial

DOI:  https://doi.org/10.1002/advs.202500194
Eur J Pediatr. 2026 Feb 04. 185(2): 118

Association of preterm birth and neonatal metabolism with neurodevelopment at 1 year of age: a prospective cohort study.

Jinghan Wang, Ganchong Liao, Bin Yu, Hong Lv, Tao Jiang, Yanyun Wang, Yuqi Yang, Rui Qin, Tianyu Sun, Xin Xu, Shuifang Lei, Yangqian Jiang, Tao Jiang, Jiangbo Du, Guangfu Jin, Hongxia Ma, Hongbing Shen, Zhengfeng Xu, Zhibin Hu, Yuan Lin.

  Preterm infants are susceptible to metabolic disruptions due to physiologically immature development, and early metabolic dysregulation may contribute to neurodevelopmental impairments that persist throughout infancy and beyond. This study aims to investigate the associations between preterm birth, neonatal metabolism, and later neurodevelopment, and to explore the potential mediating role of neonatal metabolism. In this prospective birth cohort of 9023 in China, linear regression analyses were employed in discovery and validation sets to identify metabolites associated with preterm birth. Metabolites were then categorized as extremely high (> 90th percentile) or low (< 10th percentile), and their associations with preterm birth were assessed using meta-analysis and logistic regression. Among 2086 infants with neurodevelopmental assessments at 1 year old, we applied restricted cubic splines and linear regression to evaluate associations between extreme metabolite levels and neurodevelopment. Mediation analysis was then performed to assess the potential mediating effects of neonatal metabolism. Preterm birth was associated with extremely low levels of four metabolites and extremely high levels of seven metabolites (e.g., 17-hydroxyprogesterone, alanine, and multiple carnitines/acylcarnitines), indicating perturbed neonatal metabolic profiles. Moreover, extremely high levels of free carnitine (C0) were associated with poorer cognition (β = -0.47; 95% CI -0.75, -0.19) and receptive communication (β = -0.32; 95% CI -0.61, -0.03), with C0 accounting for 10.3% of the relative effect on cognition and 7.2% on receptive communication among preterm infants.
CONCLUSION: Preterm infants exhibit metabolic perturbations linked to suboptimal neurodevelopment at 1 year of age, offering compelling evidence for the biological mechanism underlying preterm birth outcomes.
WHAT IS KNOWN: • Preterm birth is known to disrupt neonatal metabolism and to adversely affect neurodevelopment, but the underlying biological mechanisms remain controversial.
WHAT IS NEW: • Preterm infants are prone to extreme metabolic perturbations, which are associated with subsequent suboptimal neurodevelopmental outcomes. • Free carnitine acted as a potential biomarker of the effects of preterm birth on suboptimal cognition and receptive communication.

Keywords:  Birth cohort; Mediation analysis; Neurodevelopment; Newborn screening; Preterm birth

DOI:  https://doi.org/10.1007/s00431-026-06771-3
Neural Regen Res. 2026 Feb 05.

Spatiotemporal profiling of secondary neurodegeneration in a mouse model of cortical stroke: Role of N-acetylneuraminic acid.

Yiyang Zhou, Zihao Chen, Keyang Chen, Fen Xiong, Hongchang Gao.

   ABSTRACT: Post-stroke cognitive impairment is a severe sequela of cerebral ischemia, with its underlying mechanisms remaining elusive and specific diagnostic biomarkers currently lacking. Growing evidence suggests that secondary neurodegeneration is closely associated with post-stroke cognitive impairment, although its metabolic basis has not been fully elucidated. Therefore, this study aimed to investigate the spatiotemporal changes and metabolic characteristics of secondary neurodegeneration and cognitive function after cortical stroke. We established a photothrombotic mouse model for post-stroke cognitive impairment research and conducted longitudinal assessments with final endpoints at 14, 32, and 84 days postsurgery. Voxel-based morphometry analysis of whole-brain regions using magnetic resonance imaging revealed that only the hippocampus exhibited gray matter alterations consistent with secondary neurodegeneration pathology. Morris water maze and open field tests demonstrated persistent impairments in recent and remote memory, along with anxietylike behaviors in photothrombotic mice. Untargeted metabolomic and lipidomic analyses were established to comprehensively characterize secondary neurodegeneration-related metabolic disturbances in the hippocampus, highlighting pathophysiological mechanisms involving oxidative stress, lipid peroxidation, neurotransmitter dysregulation, and disrupted energy metabolism. These important mechanisms were verified by immunohistochemistry, immunofluorescence staining, and real-time polymerase chain reaction. The screened potential biomarker, N-acetylneuraminic acid, was validated via targeted metabolomics in both photothrombotic mouse serum and 148 clinical samples, showing significant elevation in both cohorts. Receiver operating characteristic curve analysis and decision curve analysis confirmed the clinical utility of N-acetylneuraminic acid in diagnosing post-stroke cognitive impairment (area under the curve = 0.951, 95% confidence interval: 0.903-0.980). Flow cytometry and immunofluorescence staining revealed that N-acetylneuraminic acid activates microglia-driven neuroinflammation and oxidative stress. Our findings elucidate a potential pathological mechanism of post-stroke cognitive impairment: cortical stroke induces hippocampal accumulation of N-acetylneuraminic acid, which promotes microglial oxidative stress and inflammation, thereby triggering hippocampal secondary neurodegeneration and leading to persistent cognitive deficits. Importantly, N-acetylneuraminic acid serves as a dual-functional biomarker capable of predicting post-stroke cognitive impairment progression while dynamically tracking secondary neurodegeneration.

Keywords:  ; cognitive dysfunction; hippocampus; inflammation; magnetic resonance imaging; metabolomics; neurodegenerative diseases; oxidative stress; stroke; voxel-based morphometry

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00846
bioRxiv. 2026 Jan 21. pii: 2026.01.20.700642. [Epub ahead of print]

Amyloid precursor protein interacts with the mitochondrial phosphatase PGAM5 and regulates mitochondrial respiration.

Kriti Shukla, Zhi Zhang, Kendra S Plafker, Satoshi Matsuzaki, Casandra Salinas-Salinas, Yvonne Thomason, Samah Houmam, Dylan Barber, Anna Fakye, Kenneth M Humphries, Scott M Plafker, Jialing Lin, Heather C Rice.

Amyloid Precursor Protein (APP) has been reported to partially localize to mitochondria, and mitochondrial dysfunction is a key feature of Alzheimer's disease; however, the mechanisms linking APP to mitochondrial functions remain incompletely defined. In this study, we found that mitochondria isolated from the brains of APP knockout (KO) mice have impaired substrate-specific respiration and electron transport chain function. We identified a novel interaction between APP and phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial phosphatase. We determined that APP and PGAM5 co-localize at mitochondria-ER contact sites (MERCS), and we confirm an endogenous interaction using proximity ligation assays in mouse brain slices. Using in vitro binding assays, we demonstrate a direct interaction between the linker region of APP and a region of PGAM5 that includes the Kelch-like ECH-associated protein 1 (Keap-1) binding domain. PGAM5 is known to anchor a portion of Nuclear respiratory factor 2 (Nrf2) through Keap1 at the outer mitochondrial membrane to regulate the expression of mitochondrial respiratory chain complexes and enzymes. Consistent with this, we found that the Nrf2-regulated genes Hmox1 (Heme oxygenase-1) and Nnqo1 (NADH:quinone oxidoreductase 1), which are involved in mitochondrial respiration, are downregulated in APP KO astrocytes. Together, these findings suggest that APP supports mitochondrial function by modulating PGAM5-Keap1-Nrf2 signaling, providing a mechanistic link between loss of APP function and impaired mitochondrial respiration.

DOI: https://doi.org/10.64898/2026.01.20.700642
Trends Neurosci. 2026 Feb 03. pii: S0166-2236(25)00263-2. [Epub ahead of print]

Mitochondrial specialization and signaling shape neuronal function.

Benjamin Chun-Kit Tong, Francesco Gubinelli, Lena F Burbulla, Angelika B Harbauer.

  Neurons are specialized cells designed to process information and transmit it, often across long distances. In many neurons, the axonal volume far exceeds the somato-dendritic volume, creating a need for long-range transport and local polarization mechanisms. In addition, action potential firing and restoration of ionic gradients, as well as dynamic changes in synaptic plasticity, further increase the energetic demands of neurons. In this review, we highlight the roles mitochondria play in vertebrate neuronal biology and how mitochondrial functionality is tuned to support the unique demands of neurons. We cover the influence of mitochondrial positioning, ATP generation and Ca2+ buffering on neuronal function, and explore the role of mitochondria in neurotransmitter metabolism and local protein translation.

Keywords:  Ca(2+) signaling; local translation; neuronal cell biology; neurotransmitter metabolism; respiration; transport

DOI:  https://doi.org/10.1016/j.tins.2025.12.006
Adv Sci (Weinh). 2026 Feb 05. e19760

ACSL1-Dependent Microglial Lipoimmunometabolic Reprogramming Underlies Cognitive Deficits in Alcohol Use Disorder.

Liang Hao, Xing-Rui Cao, Bai-Qiang Li, Fu-Ying Zhao, Jia-Mei Wang, Rui-Kang Gao, Zhi-Peng Cao, Zhen-Xian Du, Hua-Qin Wang.

  Alcohol use disorder (AUD) leads to cognitive impairment dependent on prefrontal cortex (PFC) dysfunction, yet the underlying cellular and molecular mechanisms, particularly the role of microglia, remain poorly understood. Through re-analysis of single-cell RNA sequencing data from AUD patients, we identified aberrant activation of lipid metabolic pathways in microglia and pinpointed acyl-CoA synthetase long-chain family member 1 (ACSL1) as a central regulator. In animal and cellular models, chronic ethanol exposure induced ACSL1 upregulation, triggering lipid droplet accumulation, neuroinflammatory activation, and aberrant microglia-neuron interactions mediated via PTPRM signaling. Pharmacological inhibition of ACSL1 reversed these pathological phenotypes. We further developed a dual-targeted lipid nanoparticle system for microglia-specific ACSL1 silencing, which effectively ameliorated ethanol-induced cognitive deficits in mice. Our study unveils ACSL1-mediated lipoimmunity reprogramming of microglia as a core mechanism underlying cognitive impairment in AUD and proposes a novel targeted therapeutic strategy.

Keywords:  ACSL1; alcohol use disorder (AUD); cognitive deficits; lipoimmunometabolic reprogramming; microglia

DOI:  https://doi.org/10.1002/advs.202519760