bims-medebr 2025-11-23 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–11–23
twenty-one papers selected by
Regina F. Fernández, Johns Hopkins University

Comparative Evaluation of Hyperpolarized [13C]pyruvate and [13C]lactate for Imaging Neuronal and Glioma Metabolism.
Metabolic Flexibility of Microglia: Energy Substrate Utilization and Impact on Neuronal Metabolism.
Traumatic brain injury exacerbates mitochondrial dysfunction in APP/PS1 knock-in mice through time-dependent pathways.
Targeting glycolysis and maintaining glucose homeostasis for treating perioperative neurocognitive disorder: a narrative review.
Cholesterol Transport from ER to Outer Mitochondria by ERLIN2 in Steroid Metabolism.
DDHD2 possesses both lipase and transacylase capacities that remodel triglyceride acyl chains.
Spatial lipidomics reveals altered lipid profiles in TMEM63A mutant rats with hypomyelination.
Anatomical Associations Between Focal Mitochondrial Metabolism and Patterns of Neurodegeneration in Amyotrophic Lateral Sclerosis.
The Ketogenic Diet: A Possible Intervention for Improving Hippocampal Function in Neurological Disorders.
Dual-modal metabolic analysis reveals hypothermia-reversible uncoupling of oxidative phosphorylation in neonatal brain hypoxia-ischemia.
The metabolic engine of cognition: microglia-neuron interactions in health, ageing and disease.
Neuronal metabolism: Surprisingly flexible.
Metabolic pathway dysregulation in diffuse axonal injury: a multimodal biomarker approach for early diagnosis and mechanistic insights.
Tryptophan Metabolism in Neurodevelopment and Its Implications For Neurodevelopmental Disorders.
Contrary Effects of Cholesterol on Single-Component and Synaptic Vesicle Mimicking Lipid Bilayers.
Sirtuin 3, a mitochondrial metabolic enzyme, links the mitochondrial function to neurophysiology in depression.
Creatine kinase imaging (CKI) for in vivo whole-brain mapping of creatine kinase reaction kinetics.
Modulating mitochondrial metabolism: a neuroprotective mechanism for hypoxic-ischemic preconditioning.
High Glucose Aggravates Cerebral Ischemia/Reperfusion via Truncated NLRP3-Mediated Hexokinase-2 Translocation.
Proteomic Profiling Reveals Mitochondrial Dysregulation in Rapidly Progressive Alzheimer's: Role of DLDH in Amyloid Beta Aggregation.
Amyloid-beta glycation induces neuronal mitochondrial dysfunction and Alzheimer's pathogenesis via VDAC1-dependent mtDNA efflux.

ACS Sens. 2025 Nov 21.

Comparative Evaluation of Hyperpolarized [13C]pyruvate and [13C]lactate for Imaging Neuronal and Glioma Metabolism.

Jun Chen, Maheen Zaidi, Jaideep Chaudhary, Zohreh Erfani, Sarah Al Nemri, Erik J Plautz, Xiaodong Wen, Erin H Seeley, Brenda L Bartnik-Olson, Ian R Corbin, Jae Mo Park.

  Glucose and lactate are primary substrates in cerebral energy metabolism. Hyperpolarized [1-13C]pyruvate has become a powerful imaging agent for metabolic neuroimaging due to its central role in glucose and lactate metabolism, ability to cross the blood-brain barrier, and translational utility in neurological disorders. In particular, [1-13C]pyruvate enables an assessment of mitochondrial metabolism in the cerebral cortex through its conversion to [13C]bicarbonate. While it is not yet confirmed that production of [13C]bicarbonate primarily reflects neuronal metabolism, the higher affinity of neuronal transporters for lactate over pyruvate has motivated interest in hyperpolarized lactate as a more physiologic probe of neuronal metabolism. Here, we identify the predominant cellular source of [13C]bicarbonate and evaluate [1-13C]lactate as an imaging agent for neuronal metabolic imaging. Ex vivo NMR and mass spectrometry imaging of brain tissue collected after bolus injection of [U-13C3]pyruvate revealed that pyruvate dehydrogenase dominates pyruvate carboxylase in the cortex, supporting the neuronal origin of [13C]bicarbonate production. Although the bicarbonate fraction among the total 13C products in vivo was higher following hyperpolarized [1-13C]lactate injection, the signal sensitivity was markedly reduced due to lactate's shorter T1 and larger endogenous pool. Isotopomer analysis of brain tissue harvested 2 min after injection of [U-13C3]pyruvate or [U-13C3]lactate showed comparable labeling of mitochondrial intermediates. In glioma-bearing rats, in vivo imaging revealed an elevated pyruvate-to-lactate ratio within the tumor, highlighting altered redox and transport dynamics in malignancy. These findings demonstrate that both hyperpolarized [1-13C]pyruvate and [1-13C]lactate can effectively probe neuronal and glioma metabolism, although pyruvate outperforms lactate in detecting pyruvate dehydrogenase flux.

Keywords:  hyperpolarization; lactate metabolism; mass spectrometry imaging; neuroimaging; neuron

DOI:  https://doi.org/10.1021/acssensors.5c03203
J Neurochem. 2025 Nov;169(11): e70304

Metabolic Flexibility of Microglia: Energy Substrate Utilization and Impact on Neuronal Metabolism.

Emil W Westi, Rebecca Birch Carlsen, Jens Velde Andersen, Zeliha Kilic, Dana Alnajar, Nadia K Holmgaard, Belén García Sintes, Agustin Cota-Coronado, Sonia Sanz Muñoz, Céline Galvagnion, Blanca I Aldana.

  Microglia, the main resident immune cells of the brain, play critical roles in maintaining neuronal function and homeostasis. Microglia's metabolic flexibility enables rapid adaptation to environmental changes, yet the full extent of their metabolic capabilities and influence on neuronal metabolism remains unclear. While microglia predominantly rely on glucose oxidative metabolism under homeostatic conditions, they shift towards glycolysis upon proinflammatory activation. In this study, we investigated microglial metabolism and its impact on neuronal metabolic homeostasis using isotope tracing with stable carbon 13C-enriched substrates and gas chromatography-mass spectrometry (GC-MS) analysis. Primary microglia were incubated with 13C-labeled glucose, glutamine, or GABA in the presence or absence of lipopolysaccharide (LPS) to assess metabolic adaptations upon an inflammatory challenge. Additionally, neurons co-cultured with quiescent or activated microglia (either with LPS or amyloid-β) were incubated with 13C-enriched glucose to examine microglia-neuron metabolic interactions. Our findings confirm that microglia readily metabolize glucose and glutamine, with LPS stimulation slightly changing the glycolytic activity, as indicated by subtle changes in extracellular lactate. Importantly, we demonstrate for the first time that microglia take up and metabolize the inhibitory neurotransmitter GABA, suggesting a novel metabolic function. Furthermore, microglial presence directly influences neuronal metabolism and neurotransmitter homeostasis, highlighting a previously unrecognized aspect of neuron-microglia metabolic crosstalk. Collectively, these findings provide new insights into microglial metabolism and its role in neuronal function, with implications for neuroinflammatory and neurodegenerative diseases in which microglial metabolism is dysregulated.

Keywords:  GABA metabolism; amyloid‐beta; glutamine; metabolic flexibility; neuroimmune interactions; neurons

DOI:  https://doi.org/10.1111/jnc.70304
bioRxiv. 2025 Oct 02. pii: 2025.10.01.679790. [Epub ahead of print]

Traumatic brain injury exacerbates mitochondrial dysfunction in APP/PS1 knock-in mice through time-dependent pathways.

Elika Z Moallem, Hemendra J Vekaria, Teresa Macheda, Margaret R Hawkins, Kelly N Roberts, Samir P Patel, Patrick G Sullivan, Adam D Bachstetter.

  Cerebral hypometabolism occurs in both traumatic brain injury (TBI) and Alzheimer's disease (AD), but whether these conditions act through distinct or overlapping mechanisms is unclear. TBI disrupts cerebral metabolism via blood-brain barrier damage, altered glucose transporter expression, calcium buffering abnormalities, and oxidative damage to metabolic enzymes. AD-related hypometabolism is linked to amyloid-β (Aβ) effects on mitochondria, including impaired respiration, oxidative stress, and altered mitophagy, fusion, and fission. We tested whether TBI-induced mitochondrial dysfunction exacerbates Aβ-mediated impairment using a closed-head injury (CHI) model in APP/PS1 knock-in (KI) mice. Injuries were delivered at 4-5 months of age, before plaque formation and mitochondrial deficits in KI mice. Bioenergetics were measured at 1, 4, and 8 months post-injury in hippocampus and cortex using Seahorse assays on isolated mitochondria. At 1 month, genotype-by-injury interactions revealed greater dysfunction in KI mice than either condition alone, with males more vulnerable than females. At 4-8 months, amyloid-mediated effects predominated, while TBI-specific changes were no longer apparent, suggesting recovery or convergence onto shared mechanisms. These results indicate that TBI can temporarily worsen mitochondrial dysfunction in the context of early amyloidosis, with sex influencing vulnerability. Findings provide insight into the temporal relationship between TBI and amyloid-induced mitochondrial deficits and support the importance of sex as a biological variable in neurodegenerative disease progression.

Keywords:  Amyloid; Bioenergetics; Neurodegeneration; Neurotrauma; Sex differences

DOI:  https://doi.org/10.1101/2025.10.01.679790
Br J Anaesth. 2025 Nov 14. pii: S0007-0912(25)00738-X. [Epub ahead of print]

Targeting glycolysis and maintaining glucose homeostasis for treating perioperative neurocognitive disorder: a narrative review.

Xuejie Fei, Yunruoxue Lu, Lei Zhang.

  Perioperative neurocognitive disorder (PND) is a significant neurological complication in ageing surgical populations. PND is characterised by cognitive decline and associated with prolonged hospitalisation, functional impairment, and increased mortality. Emerging evidence implicates dysregulated cerebral glucose metabolism as a pivotal pathophysiological mechanism of PND. This review synthesises clinical and experimental findings to elucidate the dual role of glycolytic flux in PND pathogenesis. While physiological glycolysis supports neuroenergetics and protection, its aberrant activation during anaesthesia/surgery triggers lactate accumulation, disrupts metabolic homeostasis, and promotes neuroinflammation and oxidative stress. We analysed different effects of anaesthetics and found that intravenous anaesthetics (e.g. propofol) and inhalation anaesthetics (e.g. sevoflurane, isoflurane) differ in their effects on metabolic pathways and their correlation with PND. In addition, surgical trauma further amplifies metabolic reprogramming through mechanisms such as neuroimmune activation. Critically, perturbations in glycolytic-lactic acid dynamics impair synaptic plasticity, neuronal function, and glial responses, establishing a cycle that accelerates cognitive deterioration. By describing the intersection of brain glucose metabolism and neurocognition, this review proposes targeting glycolytic homeostasis as a potential research direction and new strategy to address clinical challenges encountered in PND diagnosis and management.

Keywords:  cognitive decline; glucose homeostasis; glycolysis; lactate; perioperative neurocognitive disorder

DOI:  https://doi.org/10.1016/j.bja.2025.10.018
Mol Cell Biol. 2025 Nov 18. 1-16

Cholesterol Transport from ER to Outer Mitochondria by ERLIN2 in Steroid Metabolism.

Himangshu S Bose, William E Burak, Randy M Whittal.

  Cholesterol trafficking from the endoplasmic reticulum (ER) through the mitochondria-associated ER membrane (MAM) and finally to mitochondria is essential for mammalian survival. ER lipid raft-associated protein 2 (ERLIN2) scaffolds raft-like microdomains in the trans-Golgi network, endosomes, and plasma membrane. We found that ERLIN2 assists in rolling cholesterol trafficking-associated lipid vesicles by facilitating the intermediate folding of cholesterol trafficker steroidogenic acute regulatory protein (StAR) from the ER to MAM prior to delivery to the outer mitochondrial membrane. Each ERLIN2-StAR interaction is short. The absence of ERLIN2 ablates mitochondrial cholesterol transport. Over time, StAR association with ERLIN2 increases from the ER to MAM, thereby enhancing mitochondrial cholesterol transport. Thus, ERLIN2 is central for regulating mitochondrial cholesterol trafficking required for mitochondrial steroid metabolism.

Keywords:  Steroids; cholesterol; endoplasmic reticulum; mitochondria associated-ER membrane (MAM); pregnenolone; steroidogenic acute regulatory protein (StAR)

DOI:  https://doi.org/10.1080/10985549.2025.2583172
Proc Natl Acad Sci U S A. 2025 Nov 25. 122(47): e2500527122

DDHD2 possesses both lipase and transacylase capacities that remodel triglyceride acyl chains.

Lingshuang Wu, Yong Mi Choi, Mohyeddine Omrane, Jiyao Chai, Shujuan Gao, Abdou Rachid Thiam, Daniel Canals, Michael V Airola.

  Hereditary spastic paraplegia subtype SPG54 is a genetic neurological disorder caused by mutations in the DDHD2 gene. Excessive lipid droplet accumulation is observed in the brains of SPG54 patients and DDHD2 knockout mice, consistent with DDHD2's reported neutral lipase activity. Here, we find recombinant human DDHD2 preferentially hydrolyzes diacylglycerol (DAG) over phospholipids, with a slight preference for DAG over triacylglycerol (TAG). DDHD2 also exhibits transacylase activity, which enables transfer of acyl chains from TAGs to DAGs and monoacylglycerols to remodel the acyl chains of TAGs. A predicted hydrophobic amphipathic helix on DDHD2 is essential for lipid droplet binding in vitro and in cells, and its lack reduces the enzymatic activity and TAG acyl chain remodeling. Adipose triglyceride lipase, but not hormone sensitive lipase, also has transacylation activity and can remodel TAG acyl chains, but to a lesser extent than DDHD2. Taken together, this provides evidence that DDHD2 is a neutral lipid lipase and transacylase whose broad specificity enables TAG acyl-chain remodeling.

Keywords:  lipase; lipid droplets; transacylase; triglycerides

DOI:  https://doi.org/10.1073/pnas.2500527122
Sci Rep. 2025 Nov 21. 15(1): 41398

Spatial lipidomics reveals altered lipid profiles in TMEM63A mutant rats with hypomyelination.

Junyu Wang, Liang Wang, Yu Zhang, Kai Gao, Jiangxi Xiao, Lin Nie, Jihang Luo, Shiqi Yang, Ye Wu, Yuwu Jiang, Huifang Yan, Jingmin Wang.

  Hypomyelinating leukodystrophies (HLDs) are genetic disorders characterized by deficient myelination. While TMEM63A variants are associated with HLD19, the specific lipid alterations in affected brain regions remain to be fully characterized. This study aimed to investigate the spatial distribution of lipid changes in a Tmem63a mutant rat model of hypomyelination. A homozygous Tmem63a c.500G > A p.(G167E) knock-in rat model (Tmem63aG167E/G167E) was established. Brain sections from Tmem63aG167E/G167E and Tmem63aWT rats (n = 3/group) were analyzed using MALDI-MSI for lipid profiling across nine distinct brain regions. Myelin structure was characterized by transmission electron microscopy (TEM) and g-ratio quantification. Statistical analyses included Mann-Whitney U tests for g-ratio distributions and ROC analysis for feature screening. Out of 702 analyzed features, 124 were differentially expressed. Lipids constituted the most altered class (43 features), including 22 glycerophospholipid, 9 fatty acid, 5 sphingolipid, 5 sterol lipid, and 2 prenol lipid species. These alterations were predominantly observed in white matter-rich regions and gray-white matter junctions. TEM revealed thinner and less dense myelin sheaths in Tmem63aG167E/G167E rats, with a reduced proportion of optimal g-ratios. This study provides a comprehensive spatial lipidomic characterization in a Tmem63a mutant rat model, revealing significant lipid alterations associated with hypomyelination. These findings offer new insights into the pathology of hypomyelination and highlight specific lipid species for future investigation.

Keywords:   TMEM63A mutation; Hypomyelination; MALDI-MSI; Spatial lipidomics

DOI:  https://doi.org/10.1038/s41598-025-25371-z
Ann Neurol. 2025 Nov 21.

Anatomical Associations Between Focal Mitochondrial Metabolism and Patterns of Neurodegeneration in Amyotrophic Lateral Sclerosis.

Marlene Tahedl, We Fong Siah, Efstratios Karavasilis, Jennifer C Hengeveld, Mark A Doherty, Russell L McLaughlin, Orla Hardiman, Ee Ling Tan, Foteini Christidi, Jana Kleinerova, Peter Bede.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) has a very specific neuroimaging signature, but the molecular underpinnings of the strikingly selective anatomic involvement have not elucidated to date. Accordingly, a large neuroimaging study was conducted with 258 participants to evaluate associations between patterns of neurodegeneration and focal metabolic metrics.
METHODS: Structural and diffusivity alterations were systematically evaluated in a genetically stratified cohort. Voxelwise associations between neurodegeneration and physiological mitochondrial indices were systematically evaluated over the entire brain and also examined in specific regions.
RESULTS: Significant topological associations were identified between physiological mitochondria tissue density, nicotinamide adenine dinucleotide (NADH)-ubiquinone oxidoreductase, succinate dehydrogenase, cytochrome c oxidase (COX), mitochondrial respiratory capacity (MRC), tissue respiratory capacity (TRC), and propensity to focal atrophy in ALS. Anatomic correlations between mitochondrial metrics and morphometric change were particularly strong in GGGGCC hexanucleotide repeat carriers in C9orf72. Diffusivity analyses also confirmed associations between brain metabolism and microstructural degeneration. Higher focal mitochondria tissue density was associated with higher likelihood of frontal, temporal, cerebellar, opercular, thalamic, cingulum, putamen, corpus callosum, and corona radiata degeneration. Uncinate fasciculus degeneration was associated with higher Complex I, II, COX, and TRC activity. Topological associations were readily replicated in an external validation cohort.
INTERPRETATION: Our data indicate that brain regions with high metabolic activity are particularly vulnerable to neurodegeneration in ALS. Anatomic associations between physiological cerebral metabolism and patterns of neurodegeneration implicate mitochondrial dysfunction in the pathophysiology of ALS. Although mitochondrial dysfunction may not be the primary etiological factor, it may represent a shared bottleneck of multiple converging molecular and genetic pathways, offering a potential opportunity for meaningful pharmacological intervention. ANN NEUROL 2025.

DOI: https://doi.org/10.1002/ana.78099
Nutr Rev. 2025 Nov 15. pii: nuaf210. [Epub ahead of print]

The Ketogenic Diet: A Possible Intervention for Improving Hippocampal Function in Neurological Disorders.

Davood Jahanmehr, Alireza Ahmadi, Mohammadmahdi Fadaei, Amirhossein Sangi Nasab Lahijan, Mahdi Shafiee Sabet, Hossein Kalantari Dehaghi, Reza Asadi-Golshan.

  With a focus on the hippocampus, in this review we examined the emerging role of the ketogenic diet (KD) in treating neurological disorders. There are multiple pathways through which various versions of the KD influence the hippocampus: energy metabolism shifts, neurotransmitter modulation, neuroinflammation control, and synaptic plasticity and epigenetic regulation modifications. Both animal studies and clinical research, with emphasis on epilepsy and Alzheimer disease, have revealed the therapeutic potential of KDs. By modifying energy metabolism and lowering neuroinflammation, KDs may have therapeutic uses such as treatment of epilepsy and Alzheimer disease. In addition, ketones may stabilize hippocampal neuronal networks and reduce amyloid-beta toxicity. Individualized factors and the duration and timing of KD intervention play critical roles in achieving optimal outcomes, such as enhanced hippocampal function and neuroprotection. While preclinical studies have demonstrated enhanced hippocampal synaptic plasticity and neuroprotection, the long-term neurological and metabolic effects of KDs require further clinical validation. There are still a number of important research gaps, especially with regard to the application of animal findings to humans. Future studies should concentrate on long-term human trials using standardized designs to investigate how KDs can affect the nervous system.

Keywords:  Alzheimer disease; epilepsy; hippocampus; ketogenic diet; neurogenesis; neuroprotection

DOI:  https://doi.org/10.1093/nutrit/nuaf210
bioRxiv. 2025 Sep 29. pii: 2021.11.29.470404. [Epub ahead of print]

Dual-modal metabolic analysis reveals hypothermia-reversible uncoupling of oxidative phosphorylation in neonatal brain hypoxia-ischemia.

Naidi Sun, Yu-Yo Sun, Rui Cao, Hong-Ru Chen, Yiming Wang, Elizabeth Fugate, Marchelle R Smucker, Yi-Min Kuo, P Ellen Grant, Diana M Lindquist, Chia-Yi Kuan, Song Hu.

Hypoxia-ischemia (HI), which disrupts the oxygen supply-demand balance in the brain by impairing blood oxygen supply and the cerebral metabolic rate of oxygen (CMRO 2 ), is a leading cause of neonatal brain injury. However, it is unclear how post-HI hypothermia helps to restore the balance, as cooling reduces CMRO 2 . Also, how transient HI leads to secondary energy failure (SEF) in neonatal brains remains elusive. Using photoacoustic microscopy, we examined the effects of HI on CMRO 2 in awake 10-day-old mice, supplemented by bioenergetic analysis of purified cortical mitochondria. Our results show that while HI suppresses ipsilateral CMRO 2 , it sparks a prolonged CMRO 2 -surge post-HI, associated with increased mitochondrial oxygen consumption, superoxide emission, and reduced mitochondrial membrane potential necessary for ATP synthesis-indicating oxidative phosphorylation (OXPHOS) uncoupling. Post-HI hypothermia prevents the CMRO 2 -surge by constraining oxygen extraction fraction, reduces mitochondrial oxidative stress, and maintains ATP and N-acetylaspartate levels, resulting in attenuated infarction at 24 hours post-HI. Our findings suggest that OXPHOS-uncoupling induced by the post-HI CMRO 2 -surge underlies SEF and blocking the surge is a key mechanism of hypothermia protection. Also, our study highlights the potential of optical CMRO 2 -measurements for detecting neonatal HI brain injury and guiding the titration of therapeutic hypothermia at the bedside.

DOI: https://doi.org/10.1101/2021.11.29.470404
Nat Metab. 2025 Nov 21.

The metabolic engine of cognition: microglia-neuron interactions in health, ageing and disease.

Evridiki Asimakidou, Stefano Pluchino, Bianca Ambrogina Silva, Luca Peruzzotti-Jametti.

Cognitive impairment is associated with perturbations of fine-tuned neuroimmune interactions. At the molecular level, alterations in cellular metabolism can compromise brain function, driving structural damage and cognitive deficits. In this Review, we focus on the bidirectional interactions between microglia, the brain-resident immune cells and neurons to dissect the metabolic determinants of brain resilience and cognition. We first outline these metabolic pathways during development and adult life. Then, we delineate how these processes are perturbed in ageing, as well as in metabolic, neuroinflammatory and neurodegenerative disorders. By doing so, we provide a mechanistic understanding of the metabolic pathways relevant to cognitive function in health and disease, thus paving the way for novel therapeutic targets based on the emerging field of neuroimmunometabolism.

DOI: https://doi.org/10.1038/s42255-025-01409-4
Curr Biol. 2025 Nov 17. pii: S0960-9822(25)01318-1. [Epub ahead of print]35(22): R1098-R1101

Neuronal metabolism: Surprisingly flexible.

Andrés Köhler-Solís, Stefanie Schirmeier.

Neuronal function is costly and depends on efficient metabolism. Thus, metabolic perturbation is thought to be detrimental for neuronal function and contributes to the development of neurodegeneration. A study now shows that this is not necessarily the case and that neurons are capable of substantial metabolic rearrangement.

DOI: https://doi.org/10.1016/j.cub.2025.10.010
Front Neurol. 2025 ;16 1677730

Metabolic pathway dysregulation in diffuse axonal injury: a multimodal biomarker approach for early diagnosis and mechanistic insights.

Weiliang Chen, Shengwen Li, Taotao Zhang, Kaijie Sun, Chunyu Yao, Wen Su, Lisheng Xu, Guanjun Wang, Chunfei Xu.

   Background: Diffuse axonal injury (DAI), a severe subtype of traumatic brain injury (TBI), lacks reliable early diagnostic biomarkers, contributing to poor clinical outcomes. Systemic metabolic pathway dysregulation in DAI remains poorly characterized, limiting targeted therapeutic strategies.
Objectives: Identify DAI-specific metabolic network disruptions and evaluate their diagnostic and prognostic utility.
Methods: In this prospective cohort study, serum metabolomics profiling, pathway enrichment analysis, and machine learning were integrated with clinical assessments in 64 adults with acute TBI (30 DAI, 34 non-DAI). Untargeted metabolomics via UPLC-LTQ-Orbitrap MS identified differential metabolites, which were mapped to biological pathways using MetaboAnalyst 5.0. Diagnostic and prognostic performance of pathway-based models was assessed using ROC analysis.
Results: DAI patients exhibited distinct metabolic perturbations, with significant dysregulation in mitochondrial fatty acid oxidation (FAO) and phospholipid metabolism. Key discriminative metabolites included carnitine C8:1 (VIP = 3.26) and lysophosphatidylcholine 22:3 sn-2, which correlated with Marshall CT scores (ρ = 0.62, p < 0.001) and pupillary reflex loss. A multi-parameter model integrating FAO and phospholipid degradation markers achieved superior diagnostic accuracy (AUC = 0.927, 95% CI: 0.86-0.98) compared to clinical models (AUC = 0.744). Pathway disruptions further predicted 3-month functional outcomes (GOSE AUC = 0.912).
Conclusion: DAI involves systemic metabolic network dysfunction centered on mitochondrial energetics and lipid metabolism. Pathway-centric biomarkers enhance diagnostic precision and prognostication, offering a novel framework for biomarker-driven management of TBI. These findings highlight mitochondrial FAO and phospholipid homeostasis as potential therapeutic targets, addressing a critical gap in DAI care.

Keywords:  biomarkers; diffuse axonal injury; fatty acid oxidation; metabolic pathway; phospholipid metabolism; traumatic brain injury

DOI:  https://doi.org/10.3389/fneur.2025.1677730
Mol Neurobiol. 2025 Nov 20. 63(1): 97

Tryptophan Metabolism in Neurodevelopment and Its Implications For Neurodevelopmental Disorders.

Maria Grazia Giuliano, Paola Tognini.

  The role of tryptophan metabolism has been recognized in a wide range of physiological and pathological processes but is still only partially understood. Growing evidence highlights the importance of maintaining tryptophan homeostasis throughout life, with its disruption now linked to various neuropsychiatric conditions spanning from early life to aging. While it is increasingly evident that alterations in tryptophan metabolism have significant implications for both neurodevelopmental and neurodegenerative disorders, research has predominantly focused on the latter, leaving neurodevelopmental aspects comparatively underexplored. This review provides a comprehensive overview of both preclinical and clinical studies, highlighting the intricate relationship between tryptophan metabolism and neurodevelopment. Particular focus is given to the kynurenine pathway and gut microbiota-derived indole production, two interconnected metabolic branches with profound effects on brain maturation, plasticity, and immune regulation. Finally, we examine the pathophysiological consequences of tryptophan dysregulation in neurodevelopmental disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, and Rett syndrome. We also discuss potential therapeutic strategies targeting tryptophan metabolism in these conditions.

Keywords:  Gut microbiota; Indole; Kynurenine; Neurodevelopment; Neurodevelopmental disorders; Tryptophan

DOI:  https://doi.org/10.1007/s12035-025-05437-9
J Phys Chem Lett. 2025 Nov 19. 12347-12353

Contrary Effects of Cholesterol on Single-Component and Synaptic Vesicle Mimicking Lipid Bilayers.

Ankur Chaudhary, Parth Sarathi Nayak, Debsankar Saha Roy, Ankur Gupta, Sudipta Maiti.

Cholesterol is a major determinant of biological lipid membrane properties. Its physiological levels are affected by widely used prescription drugs. The effect of changing the cholesterol content has been extensively studied in model lipid bilayers, but it still remains a matter of debate. Here we compare the effect of cholesterol on synaptic vesicle-mimicking (consisting of POPE, POPC, POPS) and single-component bilayers (containing POPC). We quantify the effects of cholesterol on the mechanical properties of the membrane (e.g., lipid packing, polarity, and the force needed for an AFM tip to break through the bilayer), and their relationship to membrane fusion. Cholesterol increases lipid chain packing both in PC/PE/PS and in POPC. However, in PC/PE/PS, contrary to POPC, cholesterol decreases the breakthrough force and accelerates spontaneous vesicle fusion. So, cholesterol may drive the properties of specific biological membranes in a direction that is opposite to that observed for simpler bilayers.

DOI: https://doi.org/10.1021/acs.jpclett.5c03435
Prog Neuropsychopharmacol Biol Psychiatry. 2025 Nov 14. pii: S0278-5846(25)00317-3. [Epub ahead of print] 111563

Sirtuin 3, a mitochondrial metabolic enzyme, links the mitochondrial function to neurophysiology in depression.

Cong-Ya Chen, Ya-Ting Wang, Ling-Jie Liu, Yi Zhang.

  Depression, characterized by sustained low moods and even suicidal tendencies, has been intimately linked with mitochondrial dysfunction. This dysfunction is significantly connected with various psychiatric disorders, suggesting its potential role in the pathogenesis and progression of depression. Sirtuin 3 (SIRT3), a potent deacetylase enzyme primarily located within mitochondria, orchestrates mitochondrial function and mitigates various dysfunctions, e.g., insufficient cellular energy supply and oxidative stress. Insufficient cellular energy supply and oxidative stress disrupt normal neuroplasticity and neuroinflammation in the nervous system, as well as disturbances of the hypothalamic-pituitary-adrenal axis in peripheral systems. This review aims to elucidate that SIRT3 can be a potential target for depression, thereby summarizing the mechanisms by which SIRT3 is involved in the pathogenesis and progression of depression by regulating mitochondrial function.

Keywords:  Depression; Inflammation; Mitochondrial function; Oxidative stress; Sirtuin 3

DOI:  https://doi.org/10.1016/j.pnpbp.2025.111563
Proc Natl Acad Sci U S A. 2025 Nov 25. 122(47): e2505323122

Creatine kinase imaging (CKI) for in vivo whole-brain mapping of creatine kinase reaction kinetics.

Mark Widmaier, Antonia Kaiser, Pontus Pandurevic, Song-I Lim, André Döring, Zhiwei Huang, Daniel Wenz, Ying Xiao, Yun Jiang, Yan Lin, Lijing Xin.

  The creatine kinase (CK) is a key enzyme involved in brain bioenergetics, playing an important role in brain function and the pathogenesis of neurological and psychiatric diseases and cancers. However, imaging its activity noninvasively in the human brain remains a significant challenge. This study aims to advance 31P magnetic resonance fingerprinting for Creatine Kinase Imaging (CKI). The method was implemented and validated on a clinical 7 Tesla MRI scanner. CKI enables whole-brain mapping of CK forward rate constant, revealing regional differences. Furthermore, a functional CKI (fCKI) study demonstrated a CK activation map in response to visual stimulation, revealing an increase in CK forward rate constant in the visual cortex. The novel imaging modalities, CKI and fCKI, have the potential to offer insights into brain bioenergetics both at rest and during activity, in both healthy and pathological conditions.

Keywords:  31P MRS; MRI; bioenergetics; brain; creatine kinase

DOI:  https://doi.org/10.1073/pnas.2505323122
Cell Regen. 2025 Nov 16. 14(1): 45

Modulating mitochondrial metabolism: a neuroprotective mechanism for hypoxic-ischemic preconditioning.

Wenxin Li, Guo Shao, Ruifang Qi.

  Hypoxia-ischemia plays a role in the physiological and pathological processes of various diseases and presents a common challenge for humans under extreme environmental conditions. Neurons are particularly sensitive to hypoxia-ischemia, and prolonged exposure may lead to irreversible brain damage. The primary mechanisms underlying this damage include energy depletion, mitochondrial dysfunction, oxidative stress, inflammation, and apoptosis. Mitochondria serve as primary organelles for adenosine triphosphate (ATP) production, and mitochondrial dysfunction plays a crucial role in mediating hypoxic pathophysiological processes. Hypoxic-ischemic preconditioning (H/IPC) is an endogenous cellular protective mechanism that reduces the damage caused by lethal hypoxic stressors. In this review, we summarize the potential role of H/IPC and its protective effects on mitochondrial quality control and function. This perspective offers a new approach for treating diseases caused by hypoxia-ischemia.

Keywords:  Hypoxia; Hypoxic/ischemic preconditioning; Ischemia; Mitochondrial; Neuroprotection

DOI:  https://doi.org/10.1186/s13619-025-00268-4
CNS Neurosci Ther. 2025 Nov;31(11): e70660

High Glucose Aggravates Cerebral Ischemia/Reperfusion via Truncated NLRP3-Mediated Hexokinase-2 Translocation.

Hengchang Zhang, Ruoyi Guo, Xiang Li, Yang Zhang, Lujun Zhou, Junjie Wang, Yudi Huang, Zengqiang Yuan, Lijuan Song, Yajin Liao.

   BACKGROUND: High blood glucose is a well-established risk factor for poor outcomes in ischemic stroke. However, the underlying molecular mechanisms linking high blood glucose to worsened stroke outcomes remain unclear.
OBJECTIVES: Previous studies have implicated the NLRP3 inflammasome, a key mediator of neuroinflammation, in cerebral ischemia/reperfusion (I/R) injury. Under high blood glucose conditions, NLRP3 activation is amplified, potentially driving a vicious cycle of inflammation and neuronal death. Yet, how high blood glucose specifically modulates NLRP3 activation and its downstream pathways remains unclear. This study aimed to investigate the specific mechanisms by which high glucose enhances NLRP3 inflammasome activity and contributes to worsened brain injury following cerebral I/R.
METHODS: We employed a combination of in vitro and in vivo experimental approaches to explore the impact of high glucose on NLRP3 inflammasome activation and its consequences on ischemic stroke outcomes. In vitro experiments were conducted by culturing various immune cells in high-glucose conditions to evaluate the activation of the NLRP3 inflammasome and the mitochondrial association of HK2. In vivo, mice with genetic knockouts of Nlrp3, Pycard (the gene encoding ASC), or microglial-specific Hk2 were subjected to transient middle cerebral artery occlusion (tMCAO).
RESULTS: Our findings revealed that the activation of the NLRP3 inflammasome was enhanced post cerebral I/R under high glucose and a N-terminal truncation of NLRP3 (miniNLRP3) was induced. Overexpression of PKA could promote the generation of miniNLRP3, while inhibition of PKA decreased the generation of miniNLRP3. In addition, treatment with pan serine protease could block PKA and LPS mediated generation of miniNLRP3. Overexpression of the N-terminal truncation of NLRP3 could potentiate the activation of the NLRP3 inflammasome under high glucose conditions by promoting the dissociation of Hexokinase 2 (HK2) from mitochondria. In addition, knockout of Nlrp3, Pycard, or microglial Hk2, could all attenuate cerebral I/R-induced brain injury under high blood glucose in mice.
CONCLUSION: Our study elucidates PKA-mediated generation of a 30 kD N-terminal truncation of NLRP3 (miniNLRP3) in a serine protease-dependent manner, which could potentiate the activation of the NLRP3 inflammasome under high glucose conditions via promoting the dissociation of HK2 from mitochondria. These findings add a new dimension to our understanding of NLRP3 regulation in the context of stroke injury, and suggest that the PKA-miniNLRP3-HK2-NLRP3 pathway is a promising therapeutic strategy to improve stroke outcomes in patients with elevated blood glucose levels.

Keywords:  HK2; NLRP3; PKA; high‐glucose; ischemia/reperfusion; miniNLRP3

DOI:  https://doi.org/10.1111/cns.70660
Mol Neurobiol. 2025 Nov 19. 63(1): 73

Proteomic Profiling Reveals Mitochondrial Dysregulation in Rapidly Progressive Alzheimer's: Role of DLDH in Amyloid Beta Aggregation.

Saima Zafar, Aneeqa Noor, Neelam Younas, Mohsin Shafiq, Kathrin Dittmar, Oleksandr Yagensky, Matthias Schmitz, Isidre Ferrer, Peter Hermann, Inga Zerr.

  Alzheimer's disease (AD) is presented as multiple clinical variants depending upon the rate of progression and familial background; however, the exact molecular mechanisms associated with these subtypes and their treatments are yet to be understood. The current study is based on a global proteome analysis of brain samples from patients (n = 38) with rapidly progressive AD (rpAD-survival time < 3 years), sporadic AD (spAD-survival time of 8-10 years), and healthy controls. Proteome analysis revealed a differential regulation of 79 proteins and highlighted the dysregulation of mitochondrial machinery and glucose metabolism in rpAD. Dihydrolipoamide dehydrogenase (DLDH), a mitochondrial oxidoreductase, showed a significant reduction and delocalization in rpAD. In vitro analysis revealed a potential role of DLDH in the aggregation of amyloid beta. Rapid progression in AD may be influenced by the energy homeostasis and redox dysfunction linked with the DLDH.

Keywords:  Alzheimer’s disease (AD); DLDH; Metabolic networks; Metabolism; Post-translational modification; Proteomics; Rapidly progressive Alzheimer’s disease (rpAD)

DOI:  https://doi.org/10.1007/s12035-025-05327-0
Proc Natl Acad Sci U S A. 2025 Nov 25. 122(47): e2505046122

Amyloid-beta glycation induces neuronal mitochondrial dysfunction and Alzheimer's pathogenesis via VDAC1-dependent mtDNA efflux.

Firoz Akhter, Asma Akhter, Xiongwei Zhu, Hillary Schiff, Arianna Maffei, Justin T Douglas, Qifa Zhou, Zhen Zhao, Donghui Zhu.

  Glycation, the nonenzymatic attachment of reactive dicarbonyls to proteins, lipids, or nucleic acids, contributes to the formation of advanced glycation end-products (AGEs). In Alzheimer's disease (AD), amyloid-beta (Aβ) undergoes posttranslational glycation to produce glycated Aβ (gAβ), yet its pathological role remains poorly understood. Here, we demonstrate that gAβ promotes neuronal mitochondrial DNA (mtDNA) efflux via a VDAC1-dependent mechanism, activating the innate immune cGAS-STING pathway. Using aged AD mice and human AD brain samples, we observed cGAS-mtDNA binding and cGAS-STING activation in the neuronal cytoplasm. Knockdown of RAGE, cGAS, or STING, as well as pharmacological inhibition of VDAC1, protected APP mice from mitochondrial dysfunction and Alzheimer's-like pathology. Neuron-specific cGAS knockdown confirmed its pivotal role in driving neuroinflammation and cognitive deficits. Treatment with ALT-711, an AGE cross-link breaker, alleviated gAβ-associated pathology. Furthermore, RAGE inhibition in APP knock-in mice suppressed innate immune activation and disease-associated gene expression, as revealed by spatially resolved transcriptomics. Collectively, our findings establish a mechanistic link between gAβ and innate immune activation, identifying VDAC1, the AGE-RAGE axis, and the cGAS-STING pathway as promising therapeutic targets in AD.

Keywords:  Alzheimer’s disease; glycated amyloid-beta; innate immunity; mitochondrial DNA

DOI:  https://doi.org/10.1073/pnas.2505046122