bims-medebr 2025-06-15 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–06–15
twenty-six papers selected by
Regina F. Fernández, Johns Hopkins University

An Overview of Oligodendrocyte Metabolism.
Metabolic Imaging of Hyperpolarized [1-13C]Pyruvate in a Ferret Model of Traumatic Brain Injury.
Aging-related dysregulation of energy metabolism and mitochondrial dynamics in microglia.
Sex-Specific Differences in the Transport and Availability of Energy Substrates in the Hippocampus of Rats During Neurodevelopment.
Drosophila models uncover substrate channeling effects on phospholipids and sphingolipids in peroxisomal biogenesis disorders.
In Preclinical Epilepsy, GLUT1 and GFAP Dysregulation in Cells Surrounding the Third Ventricle, Including Tanycytes, Is Differentially Restored with Ketogenic Diet Treatment.
Bioinformatic Analysis of Alzheimer's Disease Metabolomic Datasets for Ceramides and Gangliosides.
Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection.
Aspartate in the Brain: A Review.
A Case of Adult-Onset VLCAD Deficiency.
The balancing act between lipid droplets and lysosomes for membrane functionality in age-related neurodegeneration and inflammation.
Polyunsaturated fatty acids in lipid membranes regulate human neuronal function and amyloid-β production.
Analysis of neuronal cardiolipin and monolysocardiolipin from biological samples with cyclic ion mobility mass spectrometry.
Lipid profiling of Parkinson's disease brain highlights disruption in Lysophosphatidylcholines, and triacylglycerol metabolism.
Metabolic and Endocrine Dysfunctions in Traumatic Brain Injury: Implications for Cognitive Recovery and Therapeutic Strategies.
Lipid Alterations and Pathogenic Roles in Synucleinopathies.
Restoring glucose metabolism in Alzheimer's disease by targeting integrated stress response.
Emerging roles of pyruvate dehydrogenase phosphatase 1: a key player in metabolic health.
Glycogen depletion in astrocytes induces sex-dimorphic remodeling of astrocytic and synaptic structures with concomitant anxiety-like behaviors and maternal care deficits.
The role of polyunsaturated fatty acids in neurodevelopmental pediatric outcomes in the settings of gestational diabetes and obesity: A comprehensive review.
Multi-omics Analysis of Energy Metabolism Pathways Across Major Psychiatric Disorders.
Associations between Aβ deposition and neurometabolic alterations in Alzheimer's disease: Insights from hybrid 3D MRSI-PET imaging.
Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific regulatory mechanisms.
High Succinate peak in Magnetic Resonance Spectroscopy: A Diagnostic Clue for the Leukoencephalopathy Result from Succinate Dehydrogenase Deficiencies.
Protocols for Metabolomic Analyses to Assess Changes in Central Carbon Metabolism from Neural Tissue.
High-spatial-resolution mass spectrometry imaging of biological tissues using a microfluidic probe.

Adv Neurobiol. 2025 ;43 155-179

An Overview of Oligodendrocyte Metabolism.

Qi Han, Jin Cheng.

  Oligodendrocytes (OLs) exhibit complex metabolic interactions essential for neuronal function and CNS health. This chapter analyzes the metabolism of OLs, particularly glucose, lipid, and amino acid metabolism, and their impact on myelin synthesis, maintenance, and CNS resilience. OLs utilize glucose for energy through glycolysis and the pentose phosphate pathway, supporting ATP production and antioxidative defenses. Lipid synthesis, including cholesterol and sphingolipid production, is critical for maintaining myelin integrity and rapid signal conduction. Furthermore, amino acid pathways, such as those involving glutamine and serine, modulate OL differentiation and remyelination. OLs also provide metabolic support to neurons through lactate shuttling and their interactions with astrocytes in the Panglial network, ensuring sustained energy flow. Dysregulation of OL metabolic functions underlies demyelinating diseases, such as multiple sclerosis, neurodegenerative disorders, and neuropsychiatric conditions, highlighting the therapeutic potential of targeting OL metabolism to enhance remyelination and neuroprotection.

Keywords:  Amino acid metabolism; Glucose metabolism; Glutamate-glutamine cycle; Lactate shuttle; Lipid metabolism; Metabolic interaction; Myelin synthesis

DOI:  https://doi.org/10.1007/978-3-031-87919-7_7
Int J Mol Sci. 2025 Jun 01. pii: 5327. [Epub ahead of print]26(11):

Metabolic Imaging of Hyperpolarized [1-13C]Pyruvate in a Ferret Model of Traumatic Brain Injury.

Dirk Mayer, Abubakr Eldirdiri, Amanda L Hrdlick, Boris Piskoun, Joshua C Rogers, Aditya Jhajharia, Minjie Zhu, Julie L Proctor, Ulrich H Leiste, William L Fourney, Jody C Cantu, Gary Fiskum, Molly J Goodfellow.

  It is increasingly recognized that early perturbation of energy metabolism might have important implications in management and ultimately the neurological outcome in patients with traumatic brain injury (TBI). At the same time, treatments and screening tools successfully developed in preclinical TBI models have failed to translate to the clinic. As ferrets possess primate-like gyrencephalic brains that may better replicate the human response to neurologic injury, the goal of this study was to noninvasively measure brain energy metabolism after injury in a ferret model of TBI. To this end, metabolic imaging of hyperpolarized (HP) [1-13C]pyruvate (Pyr) and its conversion to lactate (Lac) and bicarbonate (Bic) was performed in ferrets before and after combined under-vehicle blast and controlled cortical impact injury. Reduced Bic/Pyr, reflecting reduced pyruvate dehydrogenase activity, was detected 8-10 days post-injury whereas no difference in Lac/Pyr was observed. These results demonstrate the feasibility of using metabolic imaging of HP [1-13C]Pyr to measure perturbations in brain energy metabolism in a novel highly translatable animal model of TBI. The method may contribute to both improved understanding of injury mechanisms and more effective drug development.

Keywords:  energy metabolism; ferret; hyperpolarized 13C pyruvate; metabolic imaging; traumatic brain injury

DOI:  https://doi.org/10.3390/ijms26115327
J Clin Biochem Nutr. 2025 May;76(3): 239-244

Aging-related dysregulation of energy metabolism and mitochondrial dynamics in microglia.

Yoki Nakamura, Manaya Nakano, Kazue Hisaoka-Nakashima, Norimitsu Morioka.

  Microglia, the primary immune cells of the central nervous system, play a pivotal role in maintaining brain homeostasis. Recent studies have highlighted the involvement of microglial dysfunction in the pathogenesis of various age-related neurodegenerative diseases, such as Alzheimer's disease. Moreover, the metabolic state of microglia has emerged as a key factor in these diseases. Interestingly, aging and neurodegenerative diseases are associated with impaired mitochondrial function and a metabolic shift from oxidative phosphorylation to glycolysis in microglia. This metabolic shift may contribute to sustained microglial activation and neuroinflammation. Furthermore, the leakage of mitochondrial DNA into the cytoplasm, because of mitochondrial dysfunction, has been implicated in triggering inflammatory responses and disrupting brain function. This review summarizes recent advances in understanding the role of microglial metabolic shifts, particularly glycolysis, and mitochondrial dysfunction. It also explores the potential of targeting microglial metabolism, for instance by modulating mitophagy or intervening in specific metabolic pathways, as a novel therapeutic approach for changes in brain function and neurodegenerative diseases associated with aging.

Keywords:  Alzheimer’s disease; aging; glycolysis; microglia; mitochondria

DOI:  https://doi.org/10.3164/jcbn.24-202
Mol Neurobiol. 2025 Jun 11.

Sex-Specific Differences in the Transport and Availability of Energy Substrates in the Hippocampus of Rats During Neurodevelopment.

Kiara França Campos, Adriana Fernanda Kuckartz Vizuete, Diorlon Nunes Machado, Andrey Vinicios Soares Carvalho, Luz Elena Durán-Carabali, Carlos Alexandre Netto.

  The mammalian brain uses several energy substrates during development, such as lactate, ketone bodies, and glucose, to avoid energy imbalances that may lead to cellular dysfunction. Sex differences in brain function are well-documented, with males being more susceptible to neurodevelopmental disturbances than females; however, the underlying reason for this vulnerability is not fully elucidated. Present study aimed to investigate sex differences in energy metabolism at different postnatal ages. Wistar rats of both sexes were evaluated on postnatal days (PND) 1, 7, 14, 21, and 60. Biochemical parameters included the immunocontent of ketone bodies (KB) and glucose transporters, glucose uptake in the hippocampus, and the levels of lactate, glucose, and beta-hydroxybutyrate (BOHB) in serum and cerebrospinal fluid. Moreover, beta-hydroxybutyrate dehydrogenase (BHD) activity was evaluated in the liver and the hippocampus. Immunofluorescence staining was performed to label the distribution of monocarboxylate transporters (MCTs) in the hippocampus and the corpus callosum. Serum lactate and BOHB levels were higher at PND1 than at other ages. Animals at PND14 predominantly utilize BOHB as a substrate, followed by a transition phase to glucose during weaning. Female rats exhibited an increase in the immunocontent of MCT2, MCT1, MCT4, and GLUT1 throughout postnatal development, suggesting a metabolic advantage over males due to greater uptake efficiency of energy substrates. Present findings reveal sex-specific differences in the expression of glucose and MCTs monocarboxylate transporters during postnatal brain development. A deeper understanding of these metabolic differences among healthy individuals may elucidate crucial sex-specific features of in neurological disorders, such as hypoxia-ischemia. This understanding could facilitate the advancement of more precise and targeted therapeutic interventions.

Keywords:  Hippocampus; Ketone bodies; Metabolism; Neurodevelopment; Sex dimorphism

DOI:  https://doi.org/10.1007/s12035-025-05118-7
PLoS One. 2025 ;20(6): e0324143

Drosophila models uncover substrate channeling effects on phospholipids and sphingolipids in peroxisomal biogenesis disorders.

Michael F Wangler, Yu-Hsin Chao, Mary Roth, Ruth Welti, James A McNew.

Peroxisomal Biogenesis Disorders Zellweger Spectrum (PBD-ZSD) disorders are a group of autosomal recessive defects in peroxisome formation that produce a multi-systemic disease presenting at birth or in childhood. Well documented clinical biomarkers such as elevated very long chain fatty acids (VLCFA) are key biochemical diagnostic findings in these conditions. Additional, secondary biochemical alterations such as elevated very long chain lysophosphatidylcholines are allowing newborn screening for peroxisomal disease. In addition, a more widespread impact on metabolism and lipids is increasingly being documented by metabolomic and lipidomic studies. Here we utilize Drosophila models of pex2 and pex16 as well as human plasma from individuals with PEX1 mutations. We identify phospholipid abnormalities in Drosophila larvae and brain characterized by differences in the quantities of phosphatidylcholine (PC) and phosphatidylethanolamines (PE) with long chain lengths and reduced levels of intermediate chain lengths. For diacylglycerol (DAG), the precursor of PE and PC through the Kennedy pathway, the intermediate chain lengths are increased suggesting an imbalance between DAGs and PE and PC that suggests the two acyl chain pools are not in equilibrium. Altered acyl chain lengths are also observed in PE ceramides in the fly models. Interestingly, plasma from human subjects exhibit phospholipid alterations similar to the fly model. Moreover, human plasma shows reduced levels of sphingomyelin with 18 and 22 carbon lengths but normal levels of C24. Our results suggest that peroxisomal biogenesis defects alter shuttling of the acyl chains of multiple phospholipid and ceramide lipid classes. In contrast, DAG species with intermediate fatty acids are actually more abundant in PBD. These data suggest an imbalance between de novo synthesis of PC and PE through the Kennedy pathway and remodeling of existing PC and PE through the Lands cycle. This imbalance is likely due to overabundance of very long acyl chains in PBD and a subsequent imbalance due to substrate channeling effects. Given the fundamental role of phospholipid and sphingolipids in nervous system functions, these observations suggest PBD-ZSD are diseases characterized by widespread cell membrane lipid abnormalities.

DOI: https://doi.org/10.1371/journal.pone.0324143
Nutrients. 2025 May 28. pii: 1824. [Epub ahead of print]17(11):

In Preclinical Epilepsy, GLUT1 and GFAP Dysregulation in Cells Surrounding the Third Ventricle, Including Tanycytes, Is Differentially Restored with Ketogenic Diet Treatment.

Parisa Rafiei, Huda S Mian, Shruthi H Iyer, Samantha B Draves, Stephanie A Matthews, Daniel E Rendon, Emma J Neesen, Madeline Dunlay, McKenna Revis, Adrianna L Glisan, Timothy A Simeone, Kristina A Simeone.

  Background/Objectives: Hyperexcitable neuronal activity associated with seizures may disrupt brain homeostasis resulting in abnormal glucose and nutrient management and metabolism. Specialized ependymal cells known as tanycytes line the third ventricle wall bridging communication between the brain, CSF, and blood. Despite their positional importance, whether tanycytes are impacted by epilepsy is unknown. Here, known protein markers of tanycytes were assessed in the Kcna1-null mouse model of genetic epilepsy with spontaneous recurrent seizures (SRS mice). Further, whether an anti-seizure metabolic ketogenic diet (KD), previously proven effective in SRS mice, restored protein levels was determined. Methods: Known tanycyte proteins, including glucose transporter 1 (GLUT1), glial fibrillary acidic protein (GFAP), and doublecortin (DCX, to determine potential neurogenic differences) were examined throughout the anterior-posterior axis of the third ventricle using immunofluorescent histochemistry. Results: Decreased GLUT1 immunoreactivity and elevated GFAP levels were found in the SRS cohorts. The number of neurogenic DCX-expressing cells did not differ. Two weeks of KD treatment reduced GFAP to WT levels. GLUT1 remained low in KD-treated SRS mice. Conclusions: These data suggest that the expression of proteins important for the structure and function of tanycytes is altered in preclinical epilepsy and is differentially restored with KD treatment. Whether tanycytes actively participate in the pathophysiology of epilepsy or associated comorbidities is an intriguing possibility given their integral role in brain homeostasis.

Keywords:  DCX; GFAP; GLUT1; Kcna1-null mouse; Kv1.1 knockout mouse; epilepsy; hypothalamus; ketogenic diet; metabolic therapy; seizure; tanycyte

DOI:  https://doi.org/10.3390/nu17111824
Methods Mol Biol. 2025 ;2925 407-412

Bioinformatic Analysis of Alzheimer's Disease Metabolomic Datasets for Ceramides and Gangliosides.

Sofía C Ayala Rodríguez, Sabrina Cajuste, Shyamal Waghwala, Sanjoy K Bhattacharya.

  Alzheimer's Disease (AD) is a significant neurodegenerative condition that adversely affects memory, cognition, and motor function. It involved multiple pathologies, with amyloid beta and tau proteins playing crucial roles. Prior to observable cognitive decline, alterations in neuronal cells contribute to disease progression. Sphingomyelin, found in lipid rafts and myelin sheaths, regulates CNS cell growth, differentiation, and apoptosis. Dysregulation in sphingolipid metabolism may impact early AD stages. Ceramides, derived from sphingomyelin hydrolysis, play a role in amyloid beta-related neurodegeneration. Gangliosides, abundant in human brains, interact with cholesterol and other lipids in lipid rafts. Ongoing studies explore GM1, a type of ganglioside, and its relationship with amyloid beta aggregation, potentially influencing AD pathogenesis.Researchers can investigate lipid differences between AD and control brain samples by conducting a meta-analysis on proteomic databases, focusing on gangliosides and ceramides. Analyzing data by brain region may reveal specific dysregulated lipids and proteins in AD brains. In this book chapter, we discuss the processing of raw data sets through MS-DIAL.

Keywords:  Alzheimer’s Disease; Ceramides; Gangliosides; MS-DIAL; Metabolomics; Proteomics

DOI:  https://doi.org/10.1007/978-1-0716-4534-5_27
Mol Metab. 2025 Jun 10. pii: S2212-8778(25)00094-8. [Epub ahead of print] 102187

Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection.

Thomas J Waller, Catherine A Collins, Monica Dus.

  Neurons rely on tightly regulated metabolic networks to sustain their high-energy demands, particularly through the coupling of glycolysis, the citric acid cycle, and oxidative phosphorylation. Here, we investigate the role of pyruvate kinase (PyK), a key glycolytic enzyme, in maintaining axonal and synaptic integrity in the Drosophila melanogaster neuromuscular system. Using genetic deficiencies in PyK, we show that disrupting glycolysis induces progressive synaptic and axonal degeneration and severe locomotor deficits. These effects require the conserved dual leucine zipper kinase (DLK, Wallenda/Wnd in flies), Jun N-terminal kinase (JNK), and activator protein 1 (AP-1) Fos transcription factor axonal damage signaling pathway and the SARM1 NADase enzyme, a key driver of axonal degeneration. As both DLK and SARM1 regulate degeneration of injured axons (Wallerian degeneration), we probed the effect of PyK loss on this process. Consistent with the idea that metabolic shifts may influence neuronal resilience in context-dependent ways, we find that pyk knockdown delays Wallerian degeneration following nerve injury, suggesting that reducing glycolytic flux can promote axon survival under stress conditions. This protective effect is partially blocked by DLK knockdown and fully abolished by SARM1 overexpression. Together, our findings help bridge metabolism and neurodegenerative signaling by demonstrating that glycolytic perturbations causally activate stress response pathways that dictate the balance between protection and degeneration depending on the system's state. These results provide a mechanistic framework for understanding metabolic contributions to neurodegeneration and highlight the potential of metabolism as a target for therapeutic strategies.

Keywords:  Axon; Glycolysis; Kinase; Metabolism; Neurodegeneration; Stress Response; Synapse

DOI:  https://doi.org/10.1016/j.molmet.2025.102187
Neurochem Res. 2025 Jun 12. 50(3): 199

Aspartate in the Brain: A Review.

Caroline D Rae, Benjamin D Rowlands, Vladimir J Balcar.

  L-Aspartate (aspartic acid; C4H7NO4; 2-aminobutanedoic acid) is a non-essential α-amino acid found ubiquitously throughout the body, including in the brain. Aspartate is one of the protein-forming amino acids and the formation of tRNA-aspartate complex is catalysed by aspartyl tRNA synthetase. Free aspartate, which is the main subject of this review, plays key roles in metabolism, as an amino donor and acceptor. It contributes to the synthesis of protein, arginine and nitric oxide, asparagine, N-acetylaspartate and N-methyl-D-aspartate. Its major metabolic role in the brain is recycling reducing equivalents (protons) between the cytoplasm and mitochondrial matrix as part of the malate-aspartate shuttle. L-Aspartate's actions on synaptic receptors, as well as its possible presence in nerve terminals and synaptic vesicles, are, in principle, consistent with a role as an excitatory neurotransmitter. The evidence is far from conclusive and at times controversial. The role of D-aspartate in brain function is even less certain but, it appears that, rather than being a minor neurotransmitter, D-aspartate is more likely to be involved in fine regulation of endocrine and homeostatic processes. Much research remains to be done in this area. The diversity of its functions and chemistry make aspartate a complex molecule to investigate and measure in vivo. Perturbations of aspartate metabolism have been described in a range of neurological deficits, particularly those of white matter. Here, we examine what is known about the various roles of aspartate in brain, its metabolism, transport and compartmentation, its role as a neurotransmitter or a more general signalling molecule, and what is currently known about its role(s) in disease processes.

Keywords:   d-aspartate; Energy metabolism; Malate aspartate shuttle; Neurotransmitter

DOI:  https://doi.org/10.1007/s11064-025-04454-3
J Clin Neuromuscul Dis. 2025 Jun 02. 26(4): 196-199

A Case of Adult-Onset VLCAD Deficiency.

Ishwarya Thiruvuru, P Philo Hazeena, Rithvik Ramesh, Sundar Shanmugam, Deepa Avadhani, Lakshmi Narasimhan Ranganathan.

   ABSTRACT: Mitochondrial fatty acid β-oxidation disorders are autosomal recessive disorders that impair mitochondrial β-oxidation and transport of fatty acids. These disorders have diverse clinical presentations. The neonatal-onset form presents with hyperammonemia, transient hypoglycemia, metabolic acidosis, cardiomyopathy, and sudden death. The Late-onset form presents with neuropathy, myopathy, and retinopathy. We report a case of a 25-year-old man who presented with episodic weakness, exercise intolerance, myalgia, and rhabdomyolysis. Whole-exome sequencing identified a pathogenic variant in acyl-Coenzyme A dehydrogenase very long chain gene, confirming a diagnosis of very long-chain acyl-Coenzyme A dehydrogenase deficiency (autosomal recessive).

Keywords:  VLCAD deficiency; adult-onset myopathy; fatty acid oxidation disorder; metabolic myopathy; recurrent rhabdomyolysis

DOI:  https://doi.org/10.1097/CND.0000000000000524
Prog Lipid Res. 2025 Jun 05. pii: S0163-7827(25)00023-2. [Epub ahead of print]99 101341

The balancing act between lipid droplets and lysosomes for membrane functionality in age-related neurodegeneration and inflammation.

Mariana I Tsap, Halyna R Shcherbata.

  Age-related neurodegenerative disorders are often associated with disruptions in lipid metabolism. A critical aspect is the impairment of the interaction between lipid droplets (LDs) and lysosomal function, leading to the accumulation of toxic lipid species. This accumulation triggers cellular stress, inflammation, and defective waste processing within cells, disrupting cellular homeostasis and amplifying neuroinflammatory processes. Recent studies have shown that alterations in phospholipid and fatty acid homeostasis drive neuroinflammation and oxidative stress, exacerbating neurodegenerative processes. This review focuses on the role of neuropathy target esterase (PNPLA6/NTE) and NTE-related esterase (PNPLA7/NRE) in lipid metabolism, highlighting how dysregulation of these enzymes contributes to neurodegeneration, inflammation, and lysosomal dysfunction. Additionally, we discuss the involvement of lipid rafts, sphingolipids, and phospholipase enzymes, particularly PLA2 family members, in cellular signaling and membrane dynamics. By examining the relationship between lipid metabolism, inflammatory signaling, and lysosomal storage disorders, we aim to provide a comprehensive understanding of how LDs and lysosomes interact to influence cellular homeostasis in neurodegenerative conditions, which could lead to new therapeutic strategies addressing lipid dysregulation in age-related neurological disorders.

Keywords:  Fatty acids; Inflammaging; Lipid droplets; Lipid membranes; Lysosomes; PNPLA6/NTE

DOI:  https://doi.org/10.1016/j.plipres.2025.101341
iScience. 2025 Jun 20. 28(6): 112557

Polyunsaturated fatty acids in lipid membranes regulate human neuronal function and amyloid-β production.

Satoshi Morita, Takayuki Kondo, Hisanori Tokuda, Yoshihisa Kaneda, Takayuki Izumo, Yoshihiro Nakao, Haruhisa Inoue.

  The effects and mechanisms of polyunsaturated fatty acids (PUFAs) including docosahexaenoic acid (DHA) and arachidonic acid (ARA) contained in the lipid membrane of neurons in the production of amyloid β (Aβ), a pathogenic molecule in Alzheimer's disease (AD), remain unclear. In this study, we cultured human cortical neurons differentiated from induced pluripotent stem cells (iPSCs) under conditions of PUFA deficiency being progressively alleviated. Under PUFA-deficient conditions, increasing the total PUFA composition ratio in the lipid membrane enhanced membrane fluidity and reduced Aβ production. Furthermore, in conditions where the overall PUFA deficiency was resolved, altering the specific ratios of DHA and ARA promoted the synchronous activity and morphological complexity of neuronal cells while maintaining consistent membrane fluidity. These findings demonstrate that the overall PUFA composition in the lipid membrane as well as the specific ratios of DHA and ARA within the total PUFAs regulate neuronal function and pathophysiology.

Keywords:  Cell Biology; Molecular Biology; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2025.112557
Front Physiol. 2025 ;16 1592008

Analysis of neuronal cardiolipin and monolysocardiolipin from biological samples with cyclic ion mobility mass spectrometry.

Katlynn J Emaus, Carmen A Dunbar, Joseph Caruso, Brandon T Ruotolo, Joseph M Wider, Thomas H Sanderson.

  The mitochondrial phospholipid cardiolipin (CL) is essential for proper mitochondrial function and energy production. Cardiolipin has four distinct fatty acid tails with varying expression compositions, resulting in a highly variable tissue-specific distribution of isomer expression. Neuronal cardiolipin has a remarkable variety of subspecies and has recently been used as a biomarker to predict brain injury severity following cardiac arrest and traumatic brain injury. Multiple conditions have been associated with disordered cardiolipin remodeling, including Alzheimer's disease, Parkinson's disease, Barth syndrome, and astrocytoma. The clinical relevance of cardiolipin as a biomarker and the importance of the mechanistic role of cardiolipin remodeling in disease emphasize the demand for a reliable and accurate means of the identification and quantification of cardiolipin. In this study, we outline the use of a novel method of cardiolipin analysis using cyclic ion mobility mass spectrometry (cIMS-MS) to isolate and identify cardiolipin subspecies in several biological samples. Furthermore, cIMS-MS established the composition of the cardiolipin profile by individual subspecies across biological samples under basal conditions. Monolysocardiolipin (MLCL), the precursor of mature cardiolipin and a primary diagnostic biomarker of Barth syndrome, was isolated from cardiolipin and identified. The monolysocardiolipin:cardiolipin ratio was quantified in brain samples from tafazzin-knockout (KO) mice, demonstrating accumulation of MLCL and providing direct evidence for the validity of this cIMS-MS methodology through genetic loss-of-function. The novel, multiple-pass feature of cIMS-MS enabled the isolation and amplification of less abundant cardiolipin subspecies in both standards and biological samples. This protocol enables rapid analysis of biological samples, allowing researchers to further dissect the mechanistic role of cardiolipin in injury pathology, with simplified sample preparation and reduced potential for artifact introduction.

Keywords:  cardiolipin; clinical application; cyclic ion mobility mass spectrometry; mass spectrometry; monolysocardiolipin

DOI:  https://doi.org/10.3389/fphys.2025.1592008
NPJ Parkinsons Dis. 2025 Jun 11. 11(1): 159

Lipid profiling of Parkinson's disease brain highlights disruption in Lysophosphatidylcholines, and triacylglycerol metabolism.

Ali Yilmaz, Nadia Ashrafi, Romana Ashrafi, Sumeyya Akyol, Nazia Saiyed, Ieva Kerševičiūtė, Migle Gabrielaite, Juozas Gordevicius, Stewart F Graham.

Parkinson's disease (PD) is the second most common neurodegenerative disorder following Alzheimer's disease, with a 1.5 times higher prevalence in males. Several lipid-related genetic risk factors for PD have been identified, and the brain lipid signature of PD patients is distinguishable from controls. To elucidate the molecular mechanisms underlying PD and its sex differences, we conducted a lipidomic analysis of postmortem brain samples from the primary motor cortex (Brodmann area 4) of 40 PD patients and 43 age- and sex-matched matched controls. Mass spectrometry based lipidomics analysis revealed notable differences in 95 lipid species, especially Triacylglycerols and Lysophosphatidylcholines. Notably, sex-stratified analysis suggested that mitochondrial dysfunction may explain the higher prevalence of PD in males. These findings highlight lipid dysregulation in PD and point to potential biomarkers for diagnosis, warranting further validation.

DOI: https://doi.org/10.1038/s41531-025-01023-x
Behav Brain Res. 2025 Jun 07. pii: S0166-4328(25)00284-0. [Epub ahead of print] 115697

Metabolic and Endocrine Dysfunctions in Traumatic Brain Injury: Implications for Cognitive Recovery and Therapeutic Strategies.

Jigar Manilal Haria, Naveen Kumar Singh, Jayballabh Kumar, Sanjeev Kumar Jain, DattaSai Pamidimarri.

  Traumatic brain injury (TBI) triggers a chain reaction of intricate metabolic abnormalities, sometimes leading to ongoing cognitive deficits. These abnormalities comprise dysregulation in trace element homeostasis, disrupted neurotransmitter modulation, increased lipid peroxidation, compromised glucose metabolism, and organ-specific metabolic changes. Most recent studies suggest that metabolic abnormalities are the root cause of cognitive decline in post-traumatic stress disorder (TBI). Restoring metabolic balance through therapeutic modalities, such as antioxidant therapy to combat lipid peroxidation, glucose modulators to normalise cerebral energy metabolism, and trace element supplementation, shows promise. Furthermore, increasingly understood as important determinant of long-term neurocognitive outcomes are endocrine dysfunctions, especially post-traumatic hypopituitarism and growth hormone deficiency (GHD). Growth hormone replacement therapy has been shown to improve cognitive function and overall recovery. Biomarkers such as insulin-like growth factor-1 (IGF-1), neuroinflammatory cytokines (IL-6 and TNF-α), and oxidative stress markers (like malondialdehyde) can facilitate early diagnosis, which may allow for targeted and timely intervention. This review supports metabolism-oriented, biomarker-guided therapeutic approaches to improve neurocognitive recovery and patient quality of life, highlighting the critical role that metabolic and endocrine abnormalities play in post-TBI cognitive impairment.

Keywords:  TBI; brain; hormone therapy; lipid peroxidation; metabolic dysfunction; neurocognition

DOI:  https://doi.org/10.1016/j.bbr.2025.115697
Cold Spring Harb Perspect Med. 2025 Jun 09. pii: a041646. [Epub ahead of print]

Lipid Alterations and Pathogenic Roles in Synucleinopathies.

Estela Area-Gómez, Saranna Fanning, Ulf Dettmer.

Mounting evidence highlights a role for lipid alterations and defects in lipid signaling in age-related neurodegenerative diseases such as Parkinson's disease (PD) and related conditions (collectively referred to as synucleinopathies). This growing interest is driven by several key findings: (1) lipid membranes are components of Lewy bodies and Lewy neurites, which are prototypical proteinaceous intraneuronal inclusions of PD and other synucleinopathies, primarily composed of α-synuclein (αS); (2) αS shares structural similarities with lipid-binding proteins and has been reported to bind to lipids; (3) glucocerebrosidase, a key enzyme in sphingolipid metabolism, is a major PD risk factor; (4) other enzymes involved in glycolipid and phospholipid regulation, such as diacylglycerol kinase-θ and fatty acid elongase-7, also contribute to PD risk; (5) αS alterations impact lipid homeostasis; (6) αS transiently binds lipid membranes, affecting its conformation. Given these findings, we review what is known about the role of lipids in normal αS biology as well as in the pathogenesis of PD and related conditions. We also highlight areas where further research is warranted.

DOI: https://doi.org/10.1101/cshperspect.a041646
Neurotherapeutics. 2025 Jun 05. pii: S1878-7479(25)00096-0. [Epub ahead of print] e00618

Restoring glucose metabolism in Alzheimer's disease by targeting integrated stress response.

Hui Sun, Shenrui Guo, Hongfu Jin, Lin Ding, Yuanyuan Chen, Yu Zhang, Kun He, Qi Huang, Jinyuan Gu, Suyun Chen, Hui Wang, Chenglai Fu, Yafu Yin, Weiwei Cheng.

  Cerebral glucose hypometabolism has been consistently associated with Alzheimer's disease (AD). With extensive efforts to eliminate AD pathologies, including the removal of amyloid-β (Aβ) plaques and hyperphosphorylated Tau, strategies aimed at restoring glucose metabolism in the brain regions most affected by AD are believed to have significant clinical implications. In this study, we demonstrated that glucose hypometabolism preceded neuronal death in triple-transgenic AD (3xTg-AD) mice, likely attributable to reduced expression of glucose transporter type 1 (GLUT1) or glucose transporter type 3 (GLUT3). Furthermore, we observed aberrant activation of the integrated stress response (ISR) pathway in AD models, with Aβ and Tau phosphorylation contributing to the activation of the ISR and subsequent reduction in GLUT1/3 expression. Inhibiting ISR activation by utilizing the ISR inhibitor ISRIB can effectively restore GLUT1/3 expression in both in vitro and in vivo models. Importantly, ISRIB treatment improved cognitive function and brain glucose metabolism in 3xTg-AD mice. Our findings suggest that targeting the ISR pathway to restore GLUTs expression may be a potential therapeutic strategy for AD.

Keywords:  Alzheimer's disease; Glucose hypometabolism; Glucose transporters; ISRIB; Integrated stress response

DOI:  https://doi.org/10.1016/j.neurot.2025.e00618
Front Physiol. 2025 ;16 1596636

Emerging roles of pyruvate dehydrogenase phosphatase 1: a key player in metabolic health.

Vikalp Kumar, Miriam L Greenberg.

  Pyruvate dehydrogenase phosphatase (PDP), a structurally conserved member of the protein phosphatase C family (PP2C) of proteins, is a key regulatory enzyme responsible for reactivation of the mitochondrial gate-keeper, pyruvate dehydrogenase (PDH). Tissue-specific expression of PDP isozymes, specifically PDP1 and PDP2 facilitate regulation of the multi-subunit PDH, influencing flux of substrates to the TCA cycle. PDP1 is a heterodimeric, Ca2+ sensitive isoform, predominantly expressed in muscle tissue where its role in regulating PDH activity is well established. Emerging research suggests that it is involved in various diseases, including pancreatic ductal adenocarcinoma, cardiomyogenesis defects, traumatic brain injury, and Barth syndrome. In this review, we discuss recent studies revealing the crucial role of PDP1 and its dysregulation in various metabolic disorders, thereby highlighting its potential as a therapeutic target for these debilitating diseases.

Keywords:  barth syndrome; cancer; cardiomyogenesis; pyruvate dehydrogenase complex; pyruvate dehydrogenase phosphatase 1; traumatic brain injury

DOI:  https://doi.org/10.3389/fphys.2025.1596636
Biol Sex Differ. 2025 Jun 11. 16(1): 41

Glycogen depletion in astrocytes induces sex-dimorphic remodeling of astrocytic and synaptic structures with concomitant anxiety-like behaviors and maternal care deficits.

Xiaotong Shi, Yuanyuan Zhu, Zhaoyichun Zhang, Ningcan Ma, Danyi He, You Wu, Ziyi Dai, Xinyan Qin, Yingyi Chen, Youyi Zhao, Haopeng Zhang, Jing Huang, Hui Zhang, Ze Fan.

   BACKGROUND: Maternal care is an instinctive social behavior indispensable for survival and gene transmission. Postpartum maternal behavior is profoundly affected by mother's emotional state via incompletely elucidated complex mechanisms including metabolic regulation. Brain glycogen, primarily located in astrocytes, is a potent modulator for brain plasticity and provides neuroprotection against bioenergetic insults. The regulation of brain glycogen is of relevance to hormonal control that might be linked to sex-dimorphic responses in mental health. The present study aims to investigate the involvement of glycogen in the sex differences of brain structural plasticity, and to characterize the impacts on affective and maternal behaviors in both sexes.
METHODS: Male and female brain-type glycogen phosphorylase knock-in (Pygb-KI) mice were generated to exhaust glycogen in astrocytes in both sexes. Metabolomics, seahorse and relative assay kits were utilized to detect the changes in downstream metabolites to assess the effects of astrocytic glycogen depletion on energy metabolism. Virus-labeling, immunostaining combined with sholl analysis were performed to explore the morphological changes in astrocytes, neurons and dendrite spines. In addition, affective behaviors were assessed using the open field and elevated plus maze tests to quantify anxiety-like phenotypes, and the tail suspension test to evaluate depressive-like components of behavior. Maternal care was analyzed through pup retrieval assays and nest-building behavior, while offspring development was tracked via survival rates and ultrasonic vocalizations. Expression of hormonal receptors was identified via qPCR and immunofluorescence staining.
RESULTS: Pygb-KI mice exhibited glycogen deficiency in astrocytes in both sexes, causing disrupted energy metabolic patterns, particularly in glycolysis. Subsequently, we observed in female-specific decreases in area, branching, and length of astrocytes and loss of mature dendritic spines in neurons. This sex-dimorphic phenotype was in accordance with the phenomenon that Pygb-KI females displayed anxiety-like behaviors in adulthood, irrespective of the virgin or lactating stage. Assessment of maternal behaviors revealed that Pygb-KI lactating mice displayed maternal care obstacles, and offspring nursed by Pygb-KI dams showed reduced survival rate and social deficits during development. Estradiol signaling was attenuated while glucocorticoid signaling was elevated in Pygb-KI females during the lactation stage.
CONCLUSION: Our findings demonstrate that astrocytic glycogen depletion induces female-specific disruption of structural plasticity in astrocytes and synapses, with these morphological alterations correlating with sex-dimorphic abnormalities in anxiety-like and maternal behaviors. These results reveal a sexually dimorphic mechanism whereby astrocytic glycogen loss selectively impairs structural plasticity in females, thereby underscoring the critical role of glycogen homeostasis in female-specific neurobehavioral adaptations essential for species survival.

Keywords:  Anxiety; Glycogen; Maternal behavior; Sex differences; Structural plasticity

DOI:  https://doi.org/10.1186/s13293-025-00723-6
Neuroscience. 2025 Jun 09. pii: S0306-4522(25)00701-8. [Epub ahead of print]579 227-238

The role of polyunsaturated fatty acids in neurodevelopmental pediatric outcomes in the settings of gestational diabetes and obesity: A comprehensive review.

Urja Ashish Mhatre, Ishika Jindal, Arina Mojavery, Bianca-Marie Thompson, Samar Salah Karar, Mariana Rubio Aparicio, Nadine Simon Abusada, Livas Kwarisiima, Amar Basil Ghadieh, Hossam Tharwat Ali.

  Obesity is one of the major concerns of global health. Globally, 6-12% of women with obesity also curse with gestational diabetes mellitus (GDM). Obesity and GDM constitute a major risk to maternal and fetal health with evidence suggesting an association with offspring cardiometabolic risk, respiratory disorders, and neurodevelopmental problems. Fatty acids, specifically polyunsaturated fatty acids (PUFAs), play a crucial role in fetal neurodevelopment and during early life stages. In addition to their neurogenesis-promoting properties, PUFAs have anti-apoptotic effects and provide neuroprotection against brain injury and oxidative stress. Some lipid metabolism enzymes have been recognized at synaptic terminals, proving PUFAs play a role in synaptogenesis, locally modulating synaptic transmission. On a cellular level, PUFAs suppress the production of arachidonic-acid-derived eicosanoids which modulate the production of pro-inflammatory and immunoregulatory cytokines. On a subcellular level, when ingested through the diet, PUFAs are distributed and enriched into cells and their membranes where they impact both metabolism and survival. For instance, mitochondria maintain both cellular homeostasis and calcium concentrations in the cell. Maternal PUFA concentrations during pregnancy are hypothesized to be associated with children's cognitive and neuropsychiatric outcomes, including intelligence and IQ traits and autism spectrum disorders. Most recent evidence demonstrated a positive association between maternal dietary intake of PUFAs and fetal neurodevelopment. Nevertheless, establishing clear, evidence-based guidelines on the appropriate types, doses, and timing of PUFA supplementation for high-risk pregnancies could improve maternal and pediatric health outcomes.

Keywords:  Gestational diabetes mellitus; Neurodevelopment; Neurogenesis; Obesity; Polyunsaturated fatty acid

DOI:  https://doi.org/10.1016/j.neuroscience.2025.06.019
Mol Neurobiol. 2025 Jun 11.

Multi-omics Analysis of Energy Metabolism Pathways Across Major Psychiatric Disorders.

Shiqi Zou, Ana Paula Mendes-Silva, Fernanda C Dos Santos, Mahbod Ebrahimi, James L Kennedy, Vanessa F Goncalves.

  The brain requires a large amount of energy, primarily obtained through glucose metabolism, which appears to be disrupted in various neuropsychiatric disorders. The etiology of neuropsychiatric disorders is complex and involves genetic factors that are slowly being identified. To investigate whether glucose metabolism-related genes are associated with major psychiatric disorders, we conducted secondary analyses using genome-wide association study (GWAS) summary statistics for major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ). Based on predefined glucose metabolism pathway genes, we conducted a multi-layer integrative analysis using gene-level approaches including multi-marker analysis of genomic annotation (MAGMA), transcriptome-wide association studies (TWAS) with joint-tissue imputation (JTI), and summary-based Mendelian randomization (SMR). We further explored gene expression patterns across tissues, druggability, and applied gene network analysis to evaluate the interactions. MAGMA identified 1 significant gene for MDD, 19 for BD, and 32 for SCZ, with gene RBKS shared across all three disorders. TWAS-JTI detected 17 and 35 transcriptome-wide significant genes for BD and SCZ, respectively, while SMR prioritized 2 and 9 putatively causal genes. For MDD, no convergent evidence emerged from TWAS-JTI or SMR analyses. Integrated analysis highlighted NDUFS2, NDUFS7, and NDUFC2 in the oxidative phosphorylation pathway as potential therapeutic targets. Finally, gene network analysis highlighted enrichment in mitochondrial respiratory chain complex I biogenesis, NADH dehydrogenase complex assembly, and ATP synthesis. Our results reinforce the role of energy metabolic disturbance in psychiatric disorders, particularly in BD and SCZ. These findings open avenues for targeted therapeutic interventions, warranting further validation across populations.

Keywords:  Bipolar disorder; Energy metabolism; Major depressive disorder; Post genome-wide association studies (post-GWAS) analysis; Schizophrenia

DOI:  https://doi.org/10.1007/s12035-025-05133-8
Alzheimers Dement. 2025 Jun;21(6): e70332

Associations between Aβ deposition and neurometabolic alterations in Alzheimer's disease: Insights from hybrid 3D MRSI-PET imaging.

Miao Zhang, Jialin Hu, Yaoyu Zhang, Ziyu Meng, Yibo Zhao, Yudu Li, Wen Jin, Xiao-Hang Qian, Lijun Wang, Guanyu Ye, Xu-Feng Jiang, Ya-Dong Li, Jian Ye, Huidong Tang, Jun Liu, Parashkev Nachev, Zhi-Pei Liang, Biao Li, Yao Li.

   INTRODUCTION: Understanding the neurometabolic changes associated with amyloid-β (Aβ) deposition is important for early Alzheimer's disease (AD) diagnosis, but their spatial relationships remained unexplored due to technical limitations.
METHODS: We investigated the relationship between Aβ deposition and neuronal and glial metabolites using high-resolution 3D magnetic resonance spectroscopic imaging (MRSI) (8-min scan, 2 × 3 × 3 mm3 resolution) and Aβ-positron emission tomography (Aβ-PET) imaging. N-acetylaspartate, myo-inositol, and creatine maps were obtained from 174 participants: 39 controls, 65 mild cognitive impairment (MCI), and 70 AD patients.
RESULTS: N-Acetylaspartate levels were negatively correlated with Aβ, while myo-inositol levels were positively correlated globally. Regional associations with Aβ include N-acetylaspartate reductions in frontal cortex, anterior cingulate cortex, and precuneus, and myo-inositol increases in precuneus, lateral temporal, and lateral parietal cortices. Combined MRSI and PET biomarkers achieved the highest diagnostic accuracy for MCI and AD .
DISCUSSION: Hybrid high-resolution 3D MRSI and Aβ-PET imaging provides valuable insights into Aβ's impact on neurometabolic changes, improving early AD diagnosis.
HIGHLIGHTS: Hybrid 3D magnetic resonance spectroscopic imaging-positron emission tomography (MRSI-PET) imaging reveals Aβ deposition impact on neurometabolism in Alzheimer's disease (AD). N-acetylaspartate (NAA) as a neuronal metabolic marker is negatively associated with Aβ globally and locally. Myo-inositol (mI) as a glial metabolic marker is positively associated with Aβ globally and locally. Combining 3D magnetic resonance spectroscopic imaging (MRSI) and PET biomarkers improves diagnostic accuracy for mild cognitive impairment (MCI) and AD.

Keywords:  alzheimer's disease; amyloid‐β; magnetic resonance spectroscopic imaging; myo‐inositol; n‐acetylaspartate

DOI:  https://doi.org/10.1002/alz.70332
Life Metab. 2025 Jun;4(3): loaf012

Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific regulatory mechanisms.

Jack Devine, Anna S Monzel, David Shire, Ayelet M Rosenberg, Alex Junker, Alan A Cohen, Martin Picard.

  Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors. This predicts that some individuals should have consistently high, while others show consistently low mitochondrial oxidative phosphorylation (OxPhos) capacity across organ systems. Here, we test this assumption using multi-tissue molecular and enzymatic assays in mice and humans. Across up to 22 mouse tissues, neither mitochondrial OxPhos capacity nor mitochondrial DNA (mtDNA) density was correlated between tissues (median r = -0.01 to 0.16), indicating that animals with high mitochondrial content or capacity in one tissue may have low content or capacity in other tissues. Similarly, RNA sequencing (RNAseq)-based indices of mitochondrial expression across 45 tissues from 948 women and men (genotype-tissue expression [GTEx]) showed only small to moderate coherence between some tissues, such as between brain regions (r = 0.26), but not between brain-body tissue pairs (r = 0.01). The mtDNA copy number (mtDNAcn) also lacked coherence across human tissues. Mechanistically, tissue-specific differences in mitochondrial gene expression were partially attributable to (i) tissue-specific activation of energy sensing pathways, including the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the integrated stress response (ISR), and other molecular regulators of mitochondrial biology, and (ii) proliferative activity across tissues. Finally, we identify subgroups of individuals with distinct mitochondrial distribution strategies that map onto distinct clinical phenotypes. These data raise the possibility that tissue-specific energy sensing pathways may contribute to idiosyncratic mitochondrial distribution patterns among individuals.

Keywords:  disease risk; energy sensing; gene regulation; inter-organ crosstalk; mitochondrial biogenesis; mitochondrion

DOI:  https://doi.org/10.1093/lifemeta/loaf012
Iran J Child Neurol. 2025 ;19(1): 97-105

High Succinate peak in Magnetic Resonance Spectroscopy: A Diagnostic Clue for the Leukoencephalopathy Result from Succinate Dehydrogenase Deficiencies.

Habibe Koc Ucar, Leman Tekin Orgun, Ebru Arhan, Ayse Serdaroglu, Kursad Aydin.

  The Succinate Dehydrogenase (SDH) enzyme is known as Complex-II in the electron transport chain. This study reports the clinical and molecular investigations of three pediatric patients (two of whom are siblings), with histochemical and biochemical evidence of a severe, isolated complex II deficiency due to SDH gene mutations. The patients presented with severe hypotonia, developmental delay, spasticity, macrocephaly, and megalencephaly. Magnetic Resonance Imaging (MRI) revealed signal changes in the frontal, temporal, parietal, occipital cerebral, and cerebellar white matter, corpus striatum, thalamus, substantia nigra, inferior olivary nucleus, pyramidal tracts at the level of the pons and posterior limb of the internal capsule. Other typical findings involved a high succinate peak at 2.42 ppm and lactate peak at 1.3 ppm in Magnetic Resonance Spectroscopy (MRS). The siblings presented due to compound heterozygous c.143A>T (p. Asp48Val) and c.308T>C (p. Met103Thr) SDHB mutations, while the other patient presented due to compound heterozygous c.1754G>A (p. Arg585Gln) and c.1786G>C (p. Asp596His) SDHA mutation. The demonstration of succinate peak, particularly MRS, is highly diagnostic regarding SDH deficiency. MRS should be a standard part of routine radiological exams when there is a suspicion of a neurometabolic disease, especially mitochondrial disorders. Additionally, employing Next-Generation Sequencing (NGS) is advisable for patients as it allows for accurate diagnosis without requiring invasive procedures like muscle biopsies.

Keywords:  Complex-II-deficiencies; Leukoencephalopathy; Magnetic resonance spectroscopy; Succinate dehydrogenase

DOI:  https://doi.org/10.22037/ijcn.v19i1.35156
Methods Mol Biol. 2025 ;2925 329-382

Protocols for Metabolomic Analyses to Assess Changes in Central Carbon Metabolism from Neural Tissue.

Mai Noureldein, Darcy Cochran, Fatema Bhinderwala, Shulei Lei, Jade Woods, Jordan Rose, Darrell D Marshall, Eli Riekeberg, Aline De Lima Leite, Martha Morton, Eric D Dodds, Rodrigo Franco, Robert Powers.

  Metabolomics has been successfully applied to study neurological and neurodegenerative disorders, including Parkinson's disease for the following purposes: (1) identifying potential biomarkers of onset and disease progression; (2) identifying novel mechanisms of disease progression; and (3) assessing treatment prognosis and outcome. Reproducible and efficient extraction of metabolites is imperative to the success of any metabolomics investigation. Unlike other OMICS techniques, the composition of the metabolome can be negatively impacted by the preparation, processing, and handling of these samples. The proper choice of data collection, preprocessing, and processing protocols are similarly important to the design of an effective metabolomics experiment. Likewise, correctly applying univariate and multivariate statistical methods is essential for providing biologically relevant insights. In this chapter, we have outlined a detailed metabolomics workflow that addresses these issues. A step-by-step protocol from preparing neuronal cells and metabolomic tissue samples to their metabolic analyses using nuclear magnetic resonance, mass spectrometry, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), and chemometrics is presented.

Keywords:  Chemometrics; MALDI imaging; Mass Spectrometry; Metabolomics; NMR; Neurodegeneration; Parkinson’s disease

DOI:  https://doi.org/10.1007/978-1-0716-4534-5_24
Nat Protoc. 2025 Jun 12.

High-spatial-resolution mass spectrometry imaging of biological tissues using a microfluidic probe.

Li-Xue Jiang, Xiangtang Li, Matthias Polack, Detlev Belder, Julia Laskin.

Nanospray desorption electrospray ionization (nano-DESI) is a liquid extraction-based ambient ionization mass spectrometry imaging (MSI) technique that enables quantitative molecular mapping of biological samples in their native state with high spatial resolution. To facilitate the wider adoption of nano-DESI MSI by the scientific community, we have developed a robust and user-friendly microfluidic probe (MFP). The probe has been used to achieve high spatial resolution of 8-10 µm and up to 10-fold improvement in the experimental throughput, enabling imaging of large tissue sections with cellular resolution. Here, we provide detailed instructions for designing, fabricating and operating MFPs. In addition, we describe a complete workflow for nano-DESI MSI, covering every step from probe assembly to data acquisition and analysis. Although the fabrication of MFPs requires expertise in microfluidics and can take a few days, the process can be outsourced to qualified companies for manufacturing. Once the MFP is fabricated, the entire imaging workflow can be completed in several hours, depending on the sample size. For example, a sample with an area of 1 cm² can be analyzed in <10 h at a spatial resolution of 10 µm. The exceptional performance and ease of use of these probes will make high-resolution nano-DESI MSI more accessible to the scientific community.

DOI: https://doi.org/10.1038/s41596-025-01188-y