bims-medebr 2026-03-22 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–03–22
twenty papers selected by
Regina F. Fernández, Johns Hopkins University

Lactate and cognition: a dual modulator.
Recent Updates on Lipid Landscapes in Neonatal and Adult Neurological Disorders: Advancing Mass Spectrometry and Lipidomics for Disease Insight: A Systematic Review.
Quantification and Localisation of New Brain Lipid Synthesis Using Deuterium Oxide and High Resolution Mass Spectrometry.
Metabolic dysfunction and mitochondrial failure in Alzheimer's disease: integrating pathophysiology, clinical evidence and emerging interventions.
Targeting the astrocytic metabolic cascade in Alzheimer's disease: mechanisms, challenges and opportunities.
3-Methylcrotonyl-CoA Carboxylase Expression Among Astrocytes and Neurons in the Human Brain and the Effect of Hyperglycemia on the Catabolic Flux of 13C6, 15N-Leucine in Cultured Astrocytes.
Mobile Powerhouses: Mitochondria Transfer via Tunnelling Nanotubes in Brain Health and Neurodegenerative Diseases.
Reduction in Synaptic Vesicle Protein Abundance but Increased Amounts of Nsg2 and Lpcat1 in Cerebral Cortices Without the Endosomal SNARE Proteins Vti1a and Vti1b.
"Not always the magic bullet"-Insufficient seizure control by ketogenic dietary therapies in Glut1 Deficiency Syndrome.
Neuronal loss of the pentose phosphate pathway in the living nervous system is causally linked to [NADPH] reduction and elevated oxidative stress.
Lipidomic remodeling of the brain and muscle in a zebrafish model of depression.
Neuronal mitochondrial dynamics: roles in brain disorders and therapeutic potential.
Oligodendrocyte-encoded lactate dehydrogenase A couples glycolysis to remyelination via protein lactylation.
Activated astrocytes increase dehydroascorbic acid uptake, changing intracellular metabolism and vitamin C recycling and emulating neuropathological conditions.
MitoTracker transfers from astrocytes to neurons independently of mitochondria.
Divergent white matter metabolic signature patterns indicate impending cognitive decline in aging and dementia.
Aging Inhibits Emergency Angiogenesis and Exacerbates Neuronal Damage by Downregulating DARS2.
Bioenergetic impairment in schizophrenia: role of mitochondrial signaling in synaptic dysfunction - a systematic review.
Neurometabolic Substrate Utilization Governs Oxidative Phosphorylation Conductance in Cortex and Hippocampus.
Decoding the mitochondrial metabolic engine for tumor metastasis and clinical therapeutic opportunities.

Front Mol Neurosci. 2026 ;19 1742681

Lactate and cognition: a dual modulator.

Wen Yang, Yu Xu, Kunhua Wang.

  Lactate, traditionally regarded as a byproduct of glycolysis, has emerged as a key metabolic substrate and signaling molecule in the brain. Through the astrocyte-neuron lactate shuttle, lactate provides an essential link between energy metabolism and neuronal function. Beyond its metabolic role, lactate influences synaptic plasticity, neuroinflammation, mitochondrial dynamics, and epigenetic regulation, thereby exerting multifaceted effects on cognitive processes. Accumulating evidence demonstrates that lactate acts as a double-edged regulator: under certain conditions, it promotes neuronal resilience and cognitive enhancement, whereas excessive accumulation or impaired transport may contribute to dysfunction. This review synthesizes current knowledge of lactate metabolism in the central nervous system, highlighting its physiological functions, bidirectional impact on cognition, and emerging role as both a biomarker and therapeutic target. A deeper understanding of lactate-mediated mechanisms may pave the way for novel strategies in the prevention and intervention of cognitive impairment. Clinically, lactate is best interpreted as a context-sensitive metabolic readout rather than a standalone disease-specific biomarker.

Keywords:  astrocyte–neuron lactate shuttle; cognition; epigenetic regulation; lactate; neuroinflammation; synaptic plasticity

DOI:  https://doi.org/10.3389/fnmol.2026.1742681
CNS Neurol Disord Drug Targets. 2026 Mar 11.

Recent Updates on Lipid Landscapes in Neonatal and Adult Neurological Disorders: Advancing Mass Spectrometry and Lipidomics for Disease Insight: A Systematic Review.

Santosh Kapil Kumar Gorti, Dilip Kumar Reddy, Hemanth Vikram Pr, Narasimha M Beeraka, Vladimir N Nikolenko, Padmanabha Reddy Y, Kirill V Bulygin, Jyothi Krishna, Allaka Satyavathi, Basappa Basappa.

   INTRODUCTION: The brain's complexity arises from intricate neural circuitry and dynamic molecular interactions. While genomics and proteomics have expanded understanding of brain pathology, lipidomics- particularly through metabolite and membrane lipid profiling-has emerged as a critical tool for elucidating phenotype-specific molecular mechanisms, especially those underlying neurodevelopmental and neurodegenerative disorders. Given the brain's high lipid content and the role of bioactive lipids in neural function, a deeper understanding of age-specific lipidomic landscapes is essential. </p> Methods: A comprehensive literature review was conducted using scientific databases such as PubMed, Scopus, and Web of Science. Key search terms included "lipidomics," "brain development," "neurodegeneration," "mass spectrometry," "neonatal brain," and "adult brain." Studies that applied advanced mass spectrometry techniques for brain lipid profiling, including LC-MS and GC-MS, were prioritized. The review focused on the identification, function, and clinical relevance of lipid species across age groups and neurological conditions. </p> Results: Distinct lipidomic profiles were observed between neonatal and adult brains. Neonatal brains were enriched in DHA-containing phospholipids, which are critical for synaptogenesis and neuronal growth. In adult brains, lipids such as sphingolipids and cholesterol showed higher abundance and functional diversity, contributing to membrane integrity, signal transduction, and neuroprotection. Alterations in lipid metabolism were linked to various neurological disorders, notably multiple sclerosis, Alzheimer's disease, and Parkinson's disease. The review also identified challenges in lipidomics data integration, standardization, and its application to clinical diagnostics. </p> Discussion: The findings highlight the critical importance of lipidomics in understanding brain development and neurodegeneration. Age-specific lipid signatures not only provide insights into the molecular basis of neurological disorders but also offer promising avenues for early diagnosis and therapeutic targeting. Despite advances in mass spectrometry and data analysis, challenges remain in integrating lipidomic data with other omics layers, necessitating further methodological and computational developments. Ultimately, lipidomics represents a transformative approach to decoding brain biology across the lifespan. </p> Conclusion: This review elucidates the pivotal role of lipidomics in revealing age-specific molecular signatures in the brain, with clear distinctions between neonatal and adult lipid profiles. In neonatal brains, DHA-enriched phospholipids are fundamental for neurodevelopmental processes such as synaptogenesis and myelination, whereas in adult brains lipid networks are more complex, supporting neuronal maintenance, signaling, and neuroprotection. Dysregulation of these lipid pathways is closely associated with the pathophysiology of neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, and Parkinson's disease. Advanced mass spectrometry technologies have facilitated high-resolution lipid profiling, enabling the identification of potential biomarkers and therapeutic targets. The broader implications of these findings are that lipidomics, when integrated with multi-omics approaches, can significantly enhance understanding of brain function and disease across the lifespan, ultimately informing the development of personalized diagnostic tools and age-specific therapeutic strategies for neurological disorders.

Keywords:  Lipidomics; adult brain; brain development; mass spectrometry; metabolomics integration; molecular mechanisms.; multiple sclerosis; neonatal brain; neurodegeneration; neurological disorders

DOI:  https://doi.org/10.2174/0118715273389633251202130742
Angew Chem Int Ed Engl. 2026 Mar 15. e24636

Quantification and Localisation of New Brain Lipid Synthesis Using Deuterium Oxide and High Resolution Mass Spectrometry.

Catherine Zhang, Jesse A Michael, Jonathan D Teo, Huitong Song, Mika T Westerhausen, Shadrack M Mutuku, Shane R Ellis, Anthony S Don.

  Myelin is the lipid-rich membrane that surrounds neuronal axons and is essential for neurological function in vertebrates. The development of therapeutics that stimulate myelin repair to treat demyelinating disorders such as multiple sclerosis is hampered by the inability to distinguish newly synthesised from pre-existing myelin. This study aimed to develop a method to quantify and localise new myelin lipid synthesis in the mouse brain. Deuterium oxide was administered for two weeks in the drinking water of mice fed normal chow, chow containing the demyelinating toxin cuprizone, or during spontaneous remyelination following cuprizone withdrawal. Liquid chromatography-tandem mass spectrometry and mass spectrometry imaging were used to quantify and localise the newly synthesised, deuterated lipids. While most glycerophospholipids were constitutively deuterated, deuteration of myelin-enriched sulfatides, hexosylceramides, and phosphatidylethanolamine plasmalogens was only apparent during remyelination. Most deuterium atoms were found in the fatty acyl chains, indicative of de novo lipid synthesis. Deuterated hexosylceramide and phosphatidylethanolamine plasmalogen species were localised primarily to the corpus callosum, the white matter tract that is most heavily affected by cuprizone. The method described herein provides the means to quantify and spatially profile dynamic lipid synthesis across diverse biological contexts, including understanding myelin homeostasis and preclinical evaluation of remyelinating therapeutics.

Keywords:  deuterium; lipid; mass spectrometry imaging; metabolism; remyelination

DOI:  https://doi.org/10.1002/anie.202524636
Front Neurol. 2026 ;17 1772036

Metabolic dysfunction and mitochondrial failure in Alzheimer's disease: integrating pathophysiology, clinical evidence and emerging interventions.

Xiaohua Xiao, Xueqin Yan, Chunhua Liang, Yunzhu Yang.

  Alzheimer's disease (AD) is a gradual and irreversible decline in the brain's ability to function which is not only signified by amyloid-beta plaques and neurofibrillary tangles but also by and metabolic and mitochondrial changes that have a negative impact on the classical neuropathological hallmarks. It is becoming increasingly clear that the central roles in the process of synaptic dysfunction, neuronal death and cognitive decline are played by the brain's impaired glucose utilization, insulin resistance, lipid metabolism alterations, and energy homeostasis disruption. Mitochondrial dysfunctions in AD comprising of oxidative phosphorylation defects, ATP production decrease, reactive oxygen species generation over and above the normal level, poor mitochondrial dynamics, and vacuolar-type H+-ATPase-mediated cell death are the factors that further worsen the situation and hence speed up the process of neuronal death and eventually, disease progression. The metabolic and mitochondrial disturbances have a two-way relationship with amyloid-beta and tau pathology, neuroinflammation, and oxidative stress, thus creating a self-sustaining cycle of neurodegeneration. Besides, clinical and neuroimaging studies, fluorodeoxyglucose positron emission tomography, cerebrospinal fluid biomarkers, and peripheral metabolic profiling all support the notion that metabolic impairment is an early and clinically relevant feature of AD very convincingly. Thus, the attention of the scientific community has turned more and more toward the approaches that use the metabolic and mitochondrial pathways as their target. The new treatments are coming, including insulin sensitizers, ketogenic and Mediterranean diets, mitochondrial-targeted antioxidants, exercise, metabolic modulators, and new drugs, all aimed at bringing back equilibrium to bioenergetics and letting neurons live longer. In this review, we have considered the current mechanistic insights, clinical evidence, and therapeutic advances related to metabolic dysfunction and mitochondrial failure in AD together and their potential as early biomarkers and modifiable targets for disease prevention and treatment that are highlighted.

Keywords:  Alzheimer's disease; brain energy metabolism; emerging interventions; insulin resistance; metabolic dysfunction; mitochondrial failure; neurodegeneration; oxidative stress

DOI:  https://doi.org/10.3389/fneur.2026.1772036
Front Aging Neurosci. 2026 ;18 1767811

Targeting the astrocytic metabolic cascade in Alzheimer's disease: mechanisms, challenges and opportunities.

Huawen Cao, Junyi Liang, Xiaohong Dong, Zhiqi Xia, Xiaoting Luo, Bin Liu.

  Alzheimer's disease (AD), a pressing global public health challenge, is underpinned by multifaceted pathogenic mechanisms. While traditional research has centered on amyloid-β deposition and tau hyperphosphorylation, emerging evidence reveals that metabolic perturbations play a pivotal role in the earliest phases of AD. As the principal regulators of energy homeostasis within the central nervous system, astrocytes orchestrate a multistep metabolic cascade-encompassing glucose uptake, glycolysis, mitochondrial oxidative metabolism, and the release of metabolic intermediates-to sustain neuronal energy supply and synaptic integrity. In the AD milieu, this astrocytic metabolic cascade becomes profoundly disrupted at every level. Such metabolic dysregulation not only compromises the neuroprotective functions of astrocytes but also directly accelerates synaptic degeneration, exacerbates Aβ and tau pathologies, and amplifies neuroinflammatory responses, collectively forming a core "metabolic-neurodegeneration" pathological axis. Here, we provide a comprehensive synthesis of the aberrant astrocytic metabolic cascade in AD, delineating its critical contributions to synaptic deterioration, proteinopathy progression, and inflammatory escalation. Building on these insights, we propose a conceptual model of an "astrocyte-centric metabolic collapse," highlighting metabolic derailment as a fundamental initiating and amplifying force in AD pathogenesis. Furthermore, we evaluate therapeutic strategies targeting key nodes of this cascade and discuss the challenges and opportunities inherent in modulating astrocytic metabolism. Through integrating the most recent advances, this review offers a refined understanding of astrocytic metabolic dysregulation in AD and examines its potential as a promising avenue for therapeutic intervention.

Keywords:  Alzheimer’s disease; amyloid-β metabolism; astrocytes; metabolic cascade; neuroinflammation; synaptic integrity; tau hyperphosphorylation

DOI:  https://doi.org/10.3389/fnagi.2026.1767811
Neurochem Res. 2026 Mar 19. pii: 113. [Epub ahead of print]51(2):

3-Methylcrotonyl-CoA Carboxylase Expression Among Astrocytes and Neurons in the Human Brain and the Effect of Hyperglycemia on the Catabolic Flux of 13C6, 15N-Leucine in Cultured Astrocytes.

Radovan Murín, Jakub Šofranko, Andrej Kováč, Markéta Murínová, Eduard Gondáš.

  Leucine is an essential amino acid which is imported into the brain parenchyma with high capacity. Animal studies have demonstrated that leucine plays a significant role in several cellular and physiological processes in brain parenchyma. In addition to its role in protein synthesis, leucine possesses signaling and regulatory functions. Furthermore, leucine catabolism may provide brain cells with amino nitrogen for the synthesis of glutamate and glutamine with an impact on sustaining glutamatergic and GABA-ergic neurotransmission. The entry of leucine's carbon skeleton into the intermediary metabolism of astrocytes yields the production of ketone bodies and acetyl-CoA. In order to investigate the metabolic capabilities of human astrocytes regarding leucine, we enriched their culture media with 13C₆,15N-leucine and conducted a metabolomic study using liquid chromatography-mass spectrometry (LC-MS) to identify and quantify isotopically labelled metabolites. Furthermore, we employed an antiserum against 3-methylcrotonyl-CoA carboxylase (MCC), the unique enzyme in the irreversible phase of leucine catabolism, to identify MCC-expressing cells both in culture and in situ. Our results indicate that cultured human astrocytes efficiently removed leucine from the medium, which was then enriched with several compounds containing nitrogen and/or carbon atoms derived from leucine. Among the released metabolites, glutamine and citrate were the most abundant. Leucine uptake was independent of glucose concentration; however, hyperglycemic conditions stimulated the capacity for the irreversible catabolism of the leucine-derived carbon skeleton. Immunoprobing with the MCC antiserum confirmed the mitochondrial expression of MCC in astrocytes in culture as well as in situ. In addition to astrocytes, immunofluorescent double-labelling revealed the colocalization of MCC with a neuronal marker in human brain sections. This study confirms that human astrocytes are capable of catabolizing leucine and incorporating leucine-derived atoms into the intermediary metabolism. The presence of MCC in cultured astrocytes underscores their ability to convert leucine into acetyl-CoA and ketone bodies. Additionally, MCC expression in astrocytes and neurons present in brain parenchyma suggests that these cells are enzymatically equipped to catabolize leucine into compounds entering their cellular metabolism.

Keywords:  3-methylcrotonyl-CoA carboxylase; Astrocyte; Brain; Citrate; Fluxomics; Glutamate; Glutamine; LC–MS; Leucine; Metabolism; Neuron

DOI:  https://doi.org/10.1007/s11064-026-04732-8
Eur J Neurosci. 2026 Mar;63(6): e70463

Mobile Powerhouses: Mitochondria Transfer via Tunnelling Nanotubes in Brain Health and Neurodegenerative Diseases.

Anna Henrich, Hannah Scheiblich.

  Mitochondria are central regulators of cellular metabolism, calcium homeostasis and survival. Owing to the brain's exceptional energy demand, mitochondrial dysfunction is tightly linked to neurodegenerative and neuroinflammatory disorders. Recent evidence challenges the traditional view of mitochondria as strictly cell-autonomous organelles, revealing that they can be exchanged between cells via intercellular transfer by extracellular vesicles, gap junctions or tunnelling nanotubes (TNTs) as part of an adaptive mechanism of metabolic support and signalling. Among the pathways mediating this intercellular exchange, TNTs-thin, actin-rich cytoplasmic bridges-have emerged as key conduits for mitochondrial transfer in the nervous system. TNTs enable bidirectional exchange of mitochondria between neurons, glia and vascular cells, thereby promoting bioenergetic recovery after injury and modulating immune and inflammatory responses. This review summarizes current evidence for TNT-mediated mitochondrial transfer in the brain and highlights the underlying molecular mechanisms that coordinate mitochondrial movement, including cytoskeletal dynamics, mitochondrial trafficking machinery and stress-induced signalling cascades. While mitochondrial donation can restore metabolic balance and promote neuroprotection, it may also facilitate the spread of pathological proteins, contributing to disease progression. Understanding the underlying molecular mechanism of TNT-mediated mitochondrial transfer provides a new framework for exploring metabolic communication and cellular resilience in the brain. By emphasizing emerging conceptual and mechanistic insights, we outline how advancing this field could pave the way for the development of innovative therapeutic strategies for neurodegenerative and neuroinflammatory disorders.

Keywords:  Miro1/2; actin dynamics; cell–cell connectivity; cytoskeletal remodelling; intercellular communication

DOI:  https://doi.org/10.1111/ejn.70463
Proteomics. 2026 Mar 20. e70117

Reduction in Synaptic Vesicle Protein Abundance but Increased Amounts of Nsg2 and Lpcat1 in Cerebral Cortices Without the Endosomal SNARE Proteins Vti1a and Vti1b.

Julia Gottschalk, Katharina Kotschnew, Julia Hahn, Thomas Patschkowski, Gabriele von Fischer von Mollard.

  Absence of the endosomal SNAREs vti1a and vti1b results in perinatal death and severe neuronal phenotypes in mice, while lack of one of these proteins results in minor phenotypes. Proteomic differences were investigated to obtain a deeper insight into processes in which vti1a and vti1b are involved. Here we applied a bottom-up shotgun proteomic approach to investigate the differences in wild-type, double heterozygous (DHET), vti1a-/- vti1b-/- double knockout (DKO), vti1a-/- knockout and vti1b-/- knockout cerebral cortices. Single deletions did not affect protein levels significantly. A total of 1725 proteins were detected of which 69 were less abundant and 191 proteins were more abundant in DKO cortices. Many less abundant proteins belonged to cellular components and reactome pathways synapse, synaptic vesicle cycle, vesicle mediated transport, L1CAM interaction, and cholesterol biosynthesis in pathway enrichment analysis. More abundant proteins were enriched in cellular components and Kyoto Encyclopaedia of Genes and Genomes (KEGG)-pathways such as spliceosome, ribosome, carbon metabolism, and ribonucleoprotein complex. Immunoblotting validated reduced expression levels of the tested synaptic vesicle proteins as well as increased amounts of lysophosphatidylcholine acyltransferase 1 (Lpcat1) and neuron-specific gene 2 (Nsg2), which is involved in postsynaptic AMPA-receptor recycling. These data indicate that the synapse and cell adhesion were strongly affected in DKO brains. STATEMENT OF SIGNIFICANCE OF THE STUDY: Distinct populations of neurons and glia cells are generated and organize into layers during brain development. Neurons develop an elaborate morphology to transmit information via axons and synapses to dendrites in receiving neurons. These neurites form via several specialized pathways of vesicle secretion and endocytosis. Fusion between these membranes requires members of the SNARE protein family. Double knockouts of the endosomal SNAREs vti1a and vti1b (DKO) result in perinatal lethality in mice with massive defects in the brain. In this study we compared the proteome of DKO brain cortices with double heterozygous controls to obtain insights into the molecular alterations and affected pathways. DKO brains contained lower amounts of synaptic proteins and proteins involved in cell adhesion, membrane trafficking and cholesterol biosynthesis. Several proteins of spliceosomes, ribosomes and carbon metabolism were more abundant in DKO brains, which may be a consequence of the reduced amounts of synaptic proteins or a shift in cell populations. Lysophosphatidylcholine acyltransferase 1 (Lpcat1) and neuron-specific gene 2 (Nsg2), which is involved in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) recycling, were confirmed to be more abundant by Western blotting. These data point to defects in trafficking especially in the synapse and in cell adhesion, which is required for neurite outgrowth.

Keywords:  SNARE; endosome; membrane traffic; neurodegeneration; proteome

DOI:  https://doi.org/10.1002/pmic.70117
Epilepsia Open. 2026 Mar 14.

"Not always the magic bullet"-Insufficient seizure control by ketogenic dietary therapies in Glut1 Deficiency Syndrome.

Joerg Klepper, Eva Runkel, Lucia Kiesel.

   OBJECTIVE: Ketogenic dietary therapies (KDTs) are the treatment of choice for Glut1 Deficiency Syndrome (Glut1DS), providing dietary ketones as an alternative fuel to the brain and effectively controlling seizures. Recent evidence indicates insufficient seizure control in Glut1DS patients despite adequate KDT and ketosis.
METHODS: Fifty-three patients, diagnosed with Glut1DS and treated by KDT, were followed in a single-center outpatient clinic from 2000 to 2023. Epilepsy, present in 44 patients, was analyzed for seizure control, EEG changes, and potential correlations to clinical and genetic features. Epilepsy response to KDT was defined as a >90% seizure reduction on KDT monotherapy.
RESULTS: On KDT monotherapy 27/44 (61%) patients became >90% seizure free, rated as responders. 17/44 were non-responders. Within this group, 10/17 patients responded to KDT plus antiseizure comedication. In 7 patients, KDT plus antiseizure comedication failed to control seizures. No correlations of seizure control to gender, age at start or type of KDT, or SLC2A1 variants were observed. In responders (n = 27), EEG epileptic activity, evident in 15/27 patients, improved on KDT in 5 patients. In non-responders (n = 17), EEG epileptic activity was evident in 14/17 and improved on KDT in 9 patients. EEG background slowing prior to KDT normalized in KDT in all responders (4/27), but in none of the non-responders (4/17).
SIGNIFICANCE: Epilepsy is a dominant feature of Glut1DS. KDT provides efficient seizure control, but failure to control epilepsy is more common than expected. KDT epilepsy response did not correlate with seizure type, clinical, or genetic features, emphasizing the complexity of this entity. Add-on antiseizure medication can be effective in some patients, without individual drug superiority. Epileptic activity on EEG did not prove a good marker for outcome, but reversible EEG background slowing on KDT might be predictive for favorable seizure control.
PLAIN LANGUAGE SUMMARY: Impaired glucose transport into the brain causes a brain energy crisis termed Glut1 Deficiency. Ketogenic diets mimic fasting, provide ketones as an alternative fuel, and effectively restore brain function. In our study, this worked for ca. 60% of patients. To our surprise, epilepsy persisted in about 40% of patients despite ketogenic diets for reasons unknown. Additional medication against epilepsy randomly helped in some patients. We analyzed many parameters without finding obvious explanations. Electrical brain activity improvement on ketogenic diets might be a future marker for efficient seizure control.

Keywords:  Glut1 deficiency; antiepileptic drugs; epilepsy; failure; ketogenic diet; seizure control

DOI:  https://doi.org/10.1002/epi4.70243
J Physiol. 2026 Mar 15.

Neuronal loss of the pentose phosphate pathway in the living nervous system is causally linked to [NADPH] reduction and elevated oxidative stress.

Stephan Müller, Nina Surina, Andrés Köhler-Solís, Ioannis Nellas, Astrid Fleige, Sebastian Görtz, Stefanie Schirmeier.

  Neurons are highly specialized cells that require large amounts of energy to function. Glial cells support neurons in many ways, including metabolically. In Drosophila, neuronal glycolysis has been found to be dispensable, as long as glial glycolysis is intact, a finding supporting a conservation of the astrocyte-neuron-lactate shuttle (i.e. ANLS)-hypothesis. Neurons use glia-derived lactate to fuel their highly oxidative metabolism. Nevertheless, they readily take up glucose. It has been hypothesized that neuronal glucose might be pre-dominantly metabolized through the pentose phosphate pathway (PPP) rather than glycolysis to produce reduction equivalents in the form of NADPH to cope with the oxidative stress caused by a highly oxidative metabolism and prevent oxidative damage. We show that knockdown of components of the PPP in all neurons in Drosophila induces mild neurodegeneration, which can be rescued by antioxidant feeding. To directly link a putative loss of neuronal NADPH to elevated reactive oxygen species (ROS), we generated fly lines expressing biosensors for NADPH and H2O2 and developed methods to image the sensors in Drosophila neurons. Panneuronal PPP knockdown results in reduced neuronal NADPH and elevated H2O2 levels in larval tissue. In addition, multiparametric live imaging of fully differentiated neurons in the adult Drosophila brain shows decreased NADPH levels and increased ROS stress upon PPP knockdown. Even though the phenotypic consequences of elevated ROS are mild, these data demonstrate that loss of PPP, reduced NADPH levels and increased oxidative stress are indeed functionally linked in living tissue. SIGNIFICANCE STATEMENT: The neuronal pentose phosphate pathway (PPP) has been linked to various phenotypes, including failures in long term memory formation (de Tredern et al., 2021). The PPP has long been postulated to play a neuro-protective role by providing reduction equivalents in the form of NADPH (Tang, 2019). However, studies directly linking the oxidative phase of the PPP to NADPH concentrations and subsequently reactive oxygen species (ROS) detoxification are missing. Here, we demonstrate the use of genetically encoded fluorescent metabolite indicators in Drosophila and reveal a causal link between PPP activity, NADPH and ROS concentrations. KEY POINTS: Neuronal pentose phosphate pathway (PPP) knockdown induces neurodegeneration that can be rescued by food-derived antioxidants. Neuronal PPP deficiency results in reduced neuronal NADPH levels in living tissue. Neuronal PPP deficiency results in elevated neuronal H2O2 levels in living tissue and oxidative stress.

Keywords:  NADPH; neurodegeneration; oxidative stress; pentose phosphate pathway; reactive oxygen species

DOI:  https://doi.org/10.1113/JP288582
J Affect Disord. 2026 Mar 16. pii: S0165-0327(26)00481-7. [Epub ahead of print]405 121630

Lipidomic remodeling of the brain and muscle in a zebrafish model of depression.

Bruno Pinto, Niedja Santos, Pedro Domingues, Helena Beatriz Ferreira, Marisa Pinho, Tânia Melo, Inês Domingues, M Rosário Domingues.

  Major depressive disorder (MDD) is a highly prevalent and disabling psychiatric condition, increasingly recognized as a systemic disorder involving central and peripheral pathophysiological alterations. In this study, we used a multidimensional approach using zebrafish (Danio rerio) exposed to an unpredictable chronic stress (UCS) protocol as a model of MDD, to unravel the plasticity of the lipidome in this mental disorder. Behavioral analyses revealed a reduction in sociability and locomotor activity in stressed animals, accompanied by significantly elevated cortisol levels. Fatty acid profiling demonstrated a decrease in n-3 (omega-3) polyunsaturated fatty acids (PUFA) and an increase in n-3 (omega-6) PUFA, which was more evident in the brain than in the muscle. After UCS, lipidomic analysis revealed a remodeling of the brain lipid profile, including the modulation of several phospholipid and sphingolipid species that may impact cell membrane properties and cause neuronal dysfunction. Some of these species have been previously correlated with neuroinflammation and impaired neurotransmission. An increase in plasmalogen phospholipids, well-known endogenous oxidant signaling molecules, suggests a dysregulation of the redox state. In muscle, lipidomic alterations were characterized by elevated levels of acylcarnitines, indicative of altered mitochondrial energy metabolism, and ceramides, well-known pro-inflammatory and pro-apoptotic molecules. This study highlights the relevance of lipidomic plasticity in the pathophysiology of MDD, associated with behavioral effects similar to MDD symptoms.

Keywords:  Behavior; Cortisol; Fatty acids; Lipidomics; Lipids; Unpredictable chronic stress

DOI:  https://doi.org/10.1016/j.jad.2026.121630
Acta Pharmacol Sin. 2026 Mar 16.

Neuronal mitochondrial dynamics: roles in brain disorders and therapeutic potential.

Xing-Xian Zhang, Jia-Min Du, Shen-Zhan Wang, Xin-Lei Mo, Xiang-Nan Zhang.

  Mitochondrial dynamics - processes that include fission, fusion, transport, and mitophagy - are essential for shaping mitochondrial form and function to meet neuronal homeostatic demands. Growing evidence links imbalances in these processes to the pathogenesis of multiple brain disorders. In this review we comprehensively summarize the molecular mechanisms that govern mitochondrial dynamics and clarify their roles in key neuronal functions, including synaptic transmission, vesicle recycling, and calcium buffering. We also examine how disruptions in mitochondrial dynamics drive synaptic dysfunction and neuronal injury, with specific implications for neurodegenerative and psychiatric disorders. Finally, we evaluate emerging therapeutic strategies that target mitochondrial dynamics - both pharmacological and genetic - and highlight their promise as novel therapies for brain disorders. This synthesis provides an in-depth perspective on mitochondrial dynamics in brain health and disease and aims to guide future research and drug development.

Keywords:  mitochondrial dynamics; neurodegenerations; neuron; neuropsychiatric disorders; therapeutic strategy

DOI:  https://doi.org/10.1038/s41401-025-01746-w
Neuron. 2026 Mar 16. pii: S0896-6273(26)00137-6. [Epub ahead of print]

Oligodendrocyte-encoded lactate dehydrogenase A couples glycolysis to remyelination via protein lactylation.

Ming-Yue Bao, Xiu-Qing Li, Qing-Qing Sun, Yan He, Yu-Jing Yin, Si-Han Li, Ruo-Yan Du, Gai-Xin Ma, Chen-Yu Feng, Bing Han, Rui Jia, Xuan Wang, Li-Bin Wang, Ya-Ping Yan, Xing Li, Yuan Zhang.

  Myelin injury, a hallmark of several neurological diseases, is highly sensitive to glucose metabolism disruptions. Here, we reveal that oligodendrocytes (OLs) within demyelinating lesions exhibit reduced glycolytic efficiency and lactate production compared with mature OLs. Administration of lactate, the product of glycolysis, or specific overexpression of lactate dehydrogenase A (LDHA), the enzyme in lactate production, in Olig1+ OLs significantly enhances remyelination. In contrast, conditional knockout of LDHA in the Olig1+ lineage or CNPase+ premyelinating OLs leads to severe neuropathy with dysmyelination in a development-dependent and cell-specific manner. Mechanistic insights show that OLs within demyelinating lesions undergo lactylation silencing, a lactate-induced epigenetic modification that impedes myelin restoration. Furthermore, lactylation of LDHA and carbonic anhydrase II (CAII) couples glycolysis with OL maturation. Our findings elucidate the metabolic interplay among glycolysis, lactylation, and OL maturation and provide novel enzymatic therapeutic perspectives for demyelinating disorders, for which effective therapies are currently lacking.

Keywords:  demyelinating disease; glycolysis; lactylation; oligodendrocyte; remyelination

DOI:  https://doi.org/10.1016/j.neuron.2026.02.032
Redox Biol. 2026 Feb 09. pii: S2213-2317(26)00072-8. [Epub ahead of print]92 104074

Activated astrocytes increase dehydroascorbic acid uptake, changing intracellular metabolism and vitamin C recycling and emulating neuropathological conditions.

Pedro Cisternas, Katterine Salazar, Eder Ramírez, Sebastián Elgueta, Isabelle de Lima, Valentina Muñoz, Francisco Nualart.

  Oxidative damage in neurodegenerative diseases activates astrocytes and perturbs antioxidant defenses. Vitamin C is the principal antioxidant in the brain. Ascorbic acid (AA, reduced form) is taken up by neurons via the sodium/vitamin C transporter 2 (SVCT2). Astrocytes take up only the oxidized form of vitamin C, dehydroascorbic acid (DHA), through glucose transporters (GLUT). AA is recycled between neurons and astrocytes, preserving antioxidant capacity and maintaining physiological DHA levels. We postulate that AA recycling modulates astrocyte energy and redox metabolism. We therefore examined the effects of AA and DHA accumulation on glycolysis, pentose phosphate pathway (PPP) activity, and glutathione (GSH) concentrations in activated astrocytes. Culture time negatively modulated DHA recycling. At 15 days in vitro (DIV), astrocytes efficiently took up physiological DHA and reduced it to AA, enhancing redox metabolism, stimulating PPP activity, and increasing intracellular GSH. At 30 DIV (cells positive for activation markers), astrocytes took up higher amounts of DHA but reduced it inefficiently; at this time point, the glycolytic rate was unchanged, PPP activity was inhibited, and GSH decreased. In both 15- and 30-DIV astrocytes, DHA stimulated lactate uptake. We propose that 30-DIV astrocytes constitute a cellular model of reactive astrocytes with impaired AA recycling, ultimately altering glycolytic and antioxidant function.

Keywords:  Apoptosis; Dehydroascorbic acid; Glucose transporters; Glutathione; Lactate; Oxidative stress; Pentose phosphate pathway; Reactive astrocytes; Vitamin C

DOI:  https://doi.org/10.1016/j.redox.2026.104074
Cell Rep Methods. 2026 Mar 13. pii: S2667-2375(26)00038-X. [Epub ahead of print] 101338

MitoTracker transfers from astrocytes to neurons independently of mitochondria.

Katriona L Hole, Rosalind Norkett, Emma Russell, Patrick Cottilli, Molly Strom, Jack H Howden, Nicola J Corbett, Janet Brownlees, Michael J Devine.

  The neuroprotective transfer of mitochondria from astrocytes to neurons has been primarily investigated by labeling astrocytic mitochondria with the dye MitoTracker. Here, we labeled astrocytic mitochondria with both a genetically encoded fluorophore (GFP) and MitoTracker dye and then imaged neurons immediately after co-culture with astrocytes or astrocyte-conditioned media (ACM). We report that MitoTracker transfers to neurons from both astrocytes and ACM, independently of mitochondrial transfer. Our observations provide an essential caveat to the use of this reagent and suggest that the investigation of astrocyte-neuron mitochondrial transfer, and other systems in which contact-independent transfer has been reported, requires the use of alternative labeling techniques.

Keywords:  CP: cell biology; CP: neuroscience; MitoTracker; astrocyte; intercellular mitochondrial transfer; mitochondria; neuron

DOI:  https://doi.org/10.1016/j.crmeth.2026.101338
Nat Commun. 2026 Mar 19.

Divergent white matter metabolic signature patterns indicate impending cognitive decline in aging and dementia.

Alzheimer’s Disease Neuroimaging Initiative

White matter (WM) is a key substrate for interregional neural communication and cognitive function but the role of WM glucose metabolism in cognitive aging has been understudied. Using multimodal neuroimaging (MRI, FDG-PET, amyloid-PET) from 3142 participants (15,287 visits) across two studies, we examined the contribution of WM to cognition and identified divergent WM signatures. Higher glucose metabolism in expected WM (EWM; corpus callosum and cingulum) was associated with better cognition, whereas increased metabolism in atypical WM (AWM; corona radiata) was linked to worse cognition, indicating a compensatory mechanism. EWM metabolism declined with aging, Alzheimer's disease (AD) progression (amyloid-β and APOE-ε4 carrier), and white matter hyperintensities, while AWM metabolism increased with aging and vascular risk but was partially weakened by AD neuropathology. Longitudinally, higher EWM and lower AWM metabolism predicted slower cognitive decline. Divergent WM metabolic patterns shed light on the dynamic role of WM in maintaining cognitive function. This study emphasizes the complementary information provided by WM metabolism for predicting future cognitive decline and identifying cognitive resilience.

DOI: https://doi.org/10.1038/s41467-026-70707-6
J Inflamm Res. 2026 ;19 527147

Aging Inhibits Emergency Angiogenesis and Exacerbates Neuronal Damage by Downregulating DARS2.

Dan Liu, Meilin Weng, Rui Wang, Wenchao Fu, Lijuan Zhang, Cheng Wang, Mingsen Liu, Tao Shen, Jirui Ren, Yinfei Song, Jiayu Li, Xianzhang Zeng.

   Background: Early vascular regeneration is important for the speedy recovery of neurological function following ischemic stroke. M2-like microglia polarization decreases and vascular regeneration weakens with aging. The function of mitochondrial respiratory chain is dependent on M2-like polarization in microglia. DARS2 gene is a marker for mitochondrial respiratory chain function, but its specific molecular mechanism affecting acute angiogenesis of microglia during ischemic stroke in elderly individuals remains unclear.
Methods: A murine model of middle cerebral artery occlusion (MCAO) was used to perform animal behavioral assessments, immunoblotting, tube formation and chick embryo chorioallantoic membrane assays. A D-galactose-induced cellular senescence model was established in BV2 cells.
Results: Aging significantly exacerbates acute brain injury 24 hours post-cerebral ischemia-reperfusion, with increased expression of M1-like microglial markers and a concomitant decrease in M2-like microglial markers. Additionally, aging can inhibit DARS2 protein expression, adversely affect angiogenesis and reduce brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor A (VEGFA) expression. In vitro, oxygen-glucose deprivation/reoxygenation and re-glucose (OGD/R) demonstrated that DARS2 gene knockout in young microglia replicates the phenotypic characteristics observed in aged microglia.
Conclusion: This study suggests that aging impedes M2-like microglial polarization by downregulating DARS2 expression in microglia, thereby impairing emergency angiogenesis during acute ischemic stroke and exacerbating neuronal damage.

Keywords:  DARS2; angiogenesis; ischemic stroke; microglia

DOI:  https://doi.org/10.2147/JIR.S527147
Front Cell Dev Biol. 2026 ;14 1740079

Bioenergetic impairment in schizophrenia: role of mitochondrial signaling in synaptic dysfunction - a systematic review.

Valerio Ricci, Giovanni Martinotti, Alessio Mosca, Giuseppe Maina.

   Background: Mitochondrial dysfunction represents a critical pathophysiological mechanism in schizophrenia, potentially linking bioenergetic impairment to synaptic dysfunction and cognitive deficits. Converging evidence suggests that deficits in oxidative phosphorylation may drive the synaptic pathology contributing to treatment-resistant cognitive and negative symptoms.
Objective: To systematically review the evidence linking mitochondrial bioenergetic dysfunction to synaptic impairment in schizophrenia, examining structural, functional, and molecular mechanisms across multiple methodological approaches.
Methods: Following PRISMA guidelines, we searched PubMed/MEDLINE, Embase, PsycINFO, and Web of Science from 2000 to 2025 for original research studies investigating mitochondrial function and synaptic dysfunction in schizophrenia. Two independent reviewers screened 2,224 articles, with 29 studies meeting inclusion criteria. Quality was assessed using the Newcastle-Ottawa Scale (median score 7/9).
Results: Twenty-nine studies representing 2,847 participants demonstrated consistent mitochondrial dysfunction across postmortem (n = 10), neuroimaging (n = 8), and molecular/cellular (n = 11) investigations. Postmortem studies revealed reduced complex I (18%-35%) and complex IV activity (22%-28%) in prefrontal cortex, with concurrent synaptic density reductions (27%). Neuroimaging studies demonstrated 20%-22% reductions in ATP synthesis rates correlating with cognitive deficits (r = 0.48) and negative symptoms (r = -0.42). First-episode antipsychotic-naïve patients exhibited comparable bioenergetic abnormalities, indicating primary pathophysiology rather than medication effects. Molecular studies identified impaired calcium homeostasis, oxidative stress (27%-35% glutathione reductions in synaptic compartments), and novel pseudogene regulatory mechanisms perpetuating complex I deficits. Peripheral biomarkers including platelet complex I activity and cell-free mitochondrial DNA showed disease specificity and correlation with cognitive impairment. Substantial methodological heterogeneity precluded meta-analysis but provided complementary evidence across analytical levels.
Conclusion: Mitochondrial bioenergetic impairment represents a core, potentially modifiable pathophysiological mechanism driving synaptic dysfunction in schizophrenia. Regional specificity (prefrontal cortex, hippocampus) and cell-type selectivity (pyramidal neurons) provide mechanistic insights into cognitive symptom profiles. Early presence and progressive worsening suggest critical intervention windows. Mitochondrial-targeted therapies merit investigation as novel approaches for treatment-resistant cognitive and negative symptoms.

Keywords:  bioenergetics; first-episode psychosis; mitochondrial dysfunction; oxidative phosphorylation; schizophrenia; synaptic dysfunction

DOI:  https://doi.org/10.3389/fcell.2026.1740079
J Neurophysiol. 2026 Mar 18.

Neurometabolic Substrate Utilization Governs Oxidative Phosphorylation Conductance in Cortex and Hippocampus.

Jessica R Hoffman, Junwon Heo, Briana L Clary, Tianyi Zheng, Kejie Rui, Nathan Gonsalves, Lohitash Karumbaiah, Luke J Mortensen, Jarrod A Call.

  Neurometabolism is increasingly recognized as a pathogenic contributor to neurodegenerative disease. However, commonly reported mitochondrial functional outcomes (e.g., respiration) often lack specificity with respect to energetic demand, carbon substrate utilization, and key bioenergetic parameters such as mitochondrial membrane potential. To address this limitation, the present study sought to determine whether oxidative phosphorylation conductance differs across brain regions and as a function of carbon substrate. Oxidative phosphorylation conductance was investigated in permeabilized frontal cortex and hippocampus of female and male C57BL/6J mice using pyruvate/malate substrate (PM, supporting complex I) or succinate with rotenone complex-I inhibition (SR, supporting complex II). Both mitochondrial volume (multiphoton microscopy) and abundance (flow cytometry) assessments showed no regional differences (p > 0.05 in both sexes). Mitochondria's ability to titer respiration to clamped energetic demands was lower with SR compared to PM in both sexes, regardless of brain region (p < 0.001). The production of ATP-to-respiration ratio (P/O ratio) was less at low energetic demands with SR compared to PM in males (p < 0.001) and less regardless of energetic demand with SR compared to PM in females (p < 0.05). This study, utilizing otherwise healthy, young brain tissue, demonstrates the necessity for greater precision in mitochondrial bioenergetic approaches to rigorously advance understanding of neurometabolism.

Keywords:  electron transport chain; metabolic function; neuroimaging

DOI:  https://doi.org/10.1152/jn.00026.2026
Life Sci. 2026 Mar 16. pii: S0024-3205(26)00135-9. [Epub ahead of print] 124326

Decoding the mitochondrial metabolic engine for tumor metastasis and clinical therapeutic opportunities.

Zixin Ye, Pai Zeng, Yujie Kang, Wenbin Liu, Hongde Li, Xiangjian Luo.

  Mitochondrial metabolic reprogramming, a recognized cancer hallmark, plays a pivotal role in malignant progression. These organelles serve as the cell's metabolic hubs, coordinating essential processes including OXPHOS, the TCA cycle, and FAO. This review delineates the significant alterations and functions of mitochondrial reprogramming in tumor metastasis, encompassing mechanisms such as energy restructuring and EMT promotion. Furthermore, mitochondrial dynamics exert profound effects on mitochondrial morphology and function, thereby reprogramming cellular metabolism to facilitate tumor metastasis. This review also explores the substantial mitochondrial metabolic changes within the TME and their interplay in optimizing energy utilization, forming the pre-metastatic niche, and sculpting an immunosuppressive milieu. Finally, it provides a critical evaluation of current and emerging therapeutic strategies targeting mitochondrial metabolism, including their use in combination regimens and the application of novel nano-delivery platforms.

Keywords:  Metastasis; Mitochondrial dynamics; Mitochondrial metabolism reprogramming; TME; Targeted therapy

DOI:  https://doi.org/10.1016/j.lfs.2026.124326