bims-medebr 2026-02-01 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–02–01
twenty-one papers selected by
Regina F. Fernández, Johns Hopkins University

Advances in Cardiolipin Analysis: Applications in Central Nervous System Disorders and Nutrition Interventions.
Towards Simplification of Ketogenic Diet in Epilepsy: Effect of Caprylic (C8) and Capric (C10) Acid on the Mitochondrial Respiratory Chain in Murine Hippocampal Neurons In Vitro.
Molecular and biochemical insights into dysregulation of glycosphingolipid metabolism in a mouse model of lysosomal free sialic acid storage disorder.
Alterations in the brain lipidome of Alzheimer's disease donors with rare TREM2 risk variants.
GLUT1-DS Brain Organoids Exhibit Increased Sensitivity to Metabolic and Pharmacological Induction of Epileptiform Activity.
Cholinergic Phenotypes of Acetyl-CoA with ATP-Citrate Lyase Link.
The Role of Lipid Alteration in Multiple Sclerosis.
Loss of hepaCAM inhibits cholesterol biosynthesis and impairs learning and memory in mice.
Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.
Disrupted Vitamin D Signaling and Metabolism in Neurodevelopmental and Neurodegenerative Disorders.
OSBPL6 protects against demyelination and behavioral disorder via promoting cholesterol transport in oligodendrocyte.
Dodecanedioic Acid: Alternative Carbon Substrate or Toxic Metabolite?
Restoration of Interaction Between Fatty Acid Oxidation and Electron Transport Chain Proteins In Vitro by Addition of Recombinant VLCAD.
Introduction to the Neurophotonics Special Issue "Imaging Brain Metabolism and Neuroenergetics".
Microvascular endothelial metabolic dysfunction drives cerebral edema through bioenergetic failure after ischemia-reperfusion.
Metabolic Radiosensitization by Targeting Lactate Metabolism with Microfluidic Liposomal Nanocarriers.
Human Myelin Spheres for in Vitro Oligodendrocyte Maturation, Myelination and Neurological Disease Modeling.
Coenzyme A in Brain Biology and Neurodegeneration.
Myelin Lipid Reserves as a Conditional Metabolic Buffer: Implications for Alzheimer's Disease and Ischemic Stroke.
Dynamic instability in nanoscale lipid domains revealed by contact mode high speed AFM: effect of amyloid-β and cholesterol content.
Single-cell proteomic landscape of the developing human brain.

Biomolecules. 2026 Jan 01. pii: 71. [Epub ahead of print]16(1):

Advances in Cardiolipin Analysis: Applications in Central Nervous System Disorders and Nutrition Interventions.

Chen Dong, Depeng Lv, Yanyan Dong, Zuohan Zhang, Quancai Li, Zhen Chen.

  Cardiolipin (CL), a unique dimeric phospholipid predominantly enriched in the inner mitochondrial membrane, is a crucial determinant of mitochondrial structure and function. Its content, fatty acyl composition, and oxidation state are associated with mitochondrial bioenergetics, dynamics, and cellular signaling. Disruptions in CL metabolism are increasingly implicated in the pathogenesis of various central nervous system (CNS) disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, and traumatic brain injury. This narrative review summarizes recent advances in the analytical techniques employed for CL analysis. The principles and applications of mass spectrometry-based platforms, nuclear magnetic resonance, Fourier-transform infrared spectroscopy, atomic force microscopy-infrared spectroscopy, and fluorescent probes were discussed, with an emphasis on their strengths in revealing the structure, composition, dynamics, and spatial distribution of CL. Furthermore, the evidence of CL abnormalities in various CNS disorders was assessed, often showing decreased CL levels, loss of polyunsaturated species, and increased oxidation associated with mitochondrial dysfunction and neuronal apoptosis. Furthermore, the nutritional interventions for CL modulation were discussed, such as polyunsaturated fatty acids, polyphenols, carotenoids, retinoids, alkaloids, and triterpenoids, which summarize their potential health-beneficial effects in remodeling the CL acyl chain, preventing oxidation, and regulating mitochondrial homeostasis. Overall, this review provided insight into integrating CL analysis and dietary modulation in understanding CL-related pathologies in CNS disorders.

Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; antioxidants; lipidomics; mass spectrometry; molecular species; nutritional bioactive components; phospholipids; polyunsaturated fatty acids

DOI:  https://doi.org/10.3390/biom16010071
Nutrients. 2026 Jan 09. pii: 216. [Epub ahead of print]18(2):

Towards Simplification of Ketogenic Diet in Epilepsy: Effect of Caprylic (C8) and Capric (C10) Acid on the Mitochondrial Respiratory Chain in Murine Hippocampal Neurons In Vitro.

Miriam Rebekka Rühling, Hans Hartmann, Anibh Martin Das.

   BACKGROUND: Pharmacotherapy is the therapeutic mainstay in epilepsy, but in about 30% of patients, the epilepsy is pharmacoresistant. A ketogenic diet (KD) is an alternative therapeutic option. The mechanisms underlying the anti-seizure effect of KD are not fully understood. An enhanced energy metabolism may have a protective effect; C8 and C10 fatty acids were previously shown to activate mitochondrial function in vitro. In the present study, we investigated whether ß-hydroxybutyrate (HOB), C8, C10 or a combination of C8 and C10 fatty acids, which all increase under KD, could activate mitochondrial respiratory chain enzymes in murine hippocampal neurons (HT22).
METHODS: Cells were incubated for one week in the presence of the different metabolites. Respiratory chain enzyme activities as well as citrate synthase as a mitochondrial marker enzyme were determined spectrophotometrically in these cells. We observed that enzyme activities of complexes I and III, II and III, and IV (cytochrome c-oxidase) and V (ATP synthase) significantly increased in response to incubation with C8 and C10 fatty acids and a combination of both.
RESULTS: This activation of the respiratory chain enzymes was not inferior to an incubation with HOB, the key metabolite in KD. The activity of the mitochondrial marker enzyme citrate synthase increased under incubation with the fatty acids, showing that the mitochondrial content increased.
CONCLUSIONS: In murine hippocampal cells, C8, C10 and combined C8 and C10 fatty acids led to variable increases in activities of mitochondrial respiratory chain enzymes and citrate synthase. This indicates that both C8 and C10 fatty acids may be important for the antiepileptic effect of KD, as they enhance energy production.

Keywords:  ketogenic diet; medium-chain fatty acids; mitochondrial respiratory chain enzymes; pharmacoresistant epilepsy; ß-hydroxybutyrate

DOI:  https://doi.org/10.3390/nu18020216
Exp Neurol. 2026 Jan 22. pii: S0014-4886(26)00028-2. [Epub ahead of print] 115665

Molecular and biochemical insights into dysregulation of glycosphingolipid metabolism in a mouse model of lysosomal free sialic acid storage disorder.

Marya S Sabir, Mahin S Hossain, Laura Pollard, Petcharat Leoyklang, Marjan Huizing, William A Gahl, Frances M Platt, May Christine V Malicdan.

  Free sialic acid storage disorder (FSASD) is caused by pathogenic variants in SLC17A5, which encodes the lysosomal sialic acid exporter, sialin. FSASD is characterized by the accumulation of lysosomal free sialic acid, leading to either a severe, childhood-lethal form or a more slowly progressive neurodegenerative disorder associated with the p.Arg39Cys (p.R39C) variant, i.e., Salla disease. While dysregulated glycosphingolipid (GSL) metabolism has been observed in cellular models of FSASD, this study provides the first in vivo biochemical dissection of GSL metabolism in a knock-in mouse model harboring the Slc17a5 p.R39C variant. We employed an integrated multi-modal approach, including sialic acid quantification, exploratory untargeted lipidomics, HPLC-based GSL profiling, bulk transcriptomics, and 4-MU-based lysosomal enzyme activity assays in brain and peripheral tissues (liver and kidney). Exploratory untargeted lipidomic screening revealed region-dependent lipid alterations, with more pronounced changes in the cerebellum than in the forebrain. Pathway-level analyses indicated enrichment of lipid classes related to sphingolipid and GSL metabolism. Targeted biochemical analyses demonstrated that several GSL species accumulate predominantly in the brain, with minimal changes in peripheral tissues, whereas glucosylceramide levels were significantly reduced in all brain regions analyzed. Transcriptomic profiling identified dysregulation of several genes involved in GSL and sialic acid metabolism. Enzyme activity assays corroborated the transcriptomic findings, demonstrating increased activity of several lysosomal glycohydrolases, including neuraminidase 1/3/4 and β-hexosaminidase. Collectively, these findings highlight dysregulated GSL metabolism as a prominent biochemical consequence of sialin deficiency in vivo and highlight its putative role in FSASD neuropathology.

Keywords:  Gangliosides; Glycosphingolipids; Neuraminidase; Neurodegeneration; SLC17A5; Salla disease; Sialin

DOI:  https://doi.org/10.1016/j.expneurol.2026.115665
Brain Commun. 2026 ;8(1): fcaf452

Alterations in the brain lipidome of Alzheimer's disease donors with rare TREM2 risk variants.

Petroula Proitsi, Amera Ebshiana, Asger Wretlind, Jin Xu, Angela K Hodges, Cristina Legido-Quigley.

  Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a microglial receptor, sensitive to Phospholipids and Sphingomyelins, associated with neurodegeneration. Hypomorphic variants in the TREM2 gene significantly increase the risk of developing Alzheimer's disease (AD). The aim of this study was to characterize networks of lipids in post-mortem brain tissue from AD and Control donors, and to identify lipids associated with AD and impacted by dysfunctional TREM2. We studied human post-mortem brain tissue from the hippocampus and Brodmann area 9 (BA9) from 102 brains. Brain tissue from BA9 was available from n = 55 donors (14 Ad donors with a non-synonymous TREM2 risk variant [AD(TREM2+)], 20 Ad donors with no TREM2 risk variants [Ad(TREM2-)] and 21 Control donors), and brain tissue from the Hippocampus was available for n = 47 brain donors (7 Ad[TREM2+], 20 Ad[TREM2-] and 20 Control donors). Mass Spectrometry was performed to obtain lipidomic signatures spanning 99 lipid species that included the following lipid classes: Ceramides, Sphingomyelins, Phosphatidic acids, Phosphatidyl-cholines, Phosphatidyl-ethanolamines, Phosphatidyl-glycerols, Phosphatidyl-inositols, Phosphatidyl-serines and Triglycerides. Weighted gene co-expression network analysis (WGCNA) was used to identify highly correlated lipid modules and hubs in each brain region. Generalized least squares and linear regression analyses, adjusted for age at death, biological sex, number of Apolipoprotein E (APOE) ε4 alleles, and post-mortem delay, were used to assess the associations of lipid modules and hubs with AD and TREM2, in combined analyses across regions and in each region separately. Four lipid modules were relatively well-preserved between the two brain regions, and three of these modules were altered in AD donors and/or in AD TREM2 carriers. Levels of the BA9 'turquoise' module ('blue' hippocampus module), enriched in Sphingolipids and Phospholipids, were elevated in AD donors and particularly in AD TREM2 carriers [AD(TREM2+)]. The hub lipid of the BA9 'turquoise'/hippocampus 'blue' module, Phosphatidyl-serine [PS(32:1)], was increased in AD versus Control donors (beta = 0.677, 95% CI 0.28-1.08, P = 1.14E-03), and in AD(TREM2+) versus Control donors (beta = 1.00, 95% CI 0.53-1.48, P = 5.57E-03), whereas the strongest association was observed with Ceramide [Cer(d38:1)] increased in AD versus Control donors (beta = 0.929, 95% CI 0.46-1.40, P = 1.67E-04) and in AD(TREM2+) versus Controls donors (beta = 1.31, 95% CI 0.78-1.84, P = 4.35E-06). The consistent increase in TREM2 ligands such as Ceramides and Phosphatidyl-serines in the brains of AD donors, particularly TREM2 risk variants carriers, could reflect the presence of AD-associated damage signals in the form of stressed or apoptotic cells and damaged myelin.

Keywords:  Alzheimer's disease; TREM2; brain; lipidomics; lipids

DOI:  https://doi.org/10.1093/braincomms/fcaf452
Pharmaceuticals (Basel). 2026 Jan 07. pii: 105. [Epub ahead of print]19(1):

GLUT1-DS Brain Organoids Exhibit Increased Sensitivity to Metabolic and Pharmacological Induction of Epileptiform Activity.

Loïc Lengacher, Sylvain Lengacher, Pierre J Magistretti, Charles Finsterwald.

  Background/Objectives: Glucose Transporter 1 Deficiency Syndrome (GLUT1-DS) is a neurodevelopmental disorder caused by mutations in the gene encoding glucose transporter 1 (GLUT1), which leads to impaired glucose transport into the brain and is characterized by drug-resistant epilepsy. Limited glucose supply disrupts neuronal and astrocytic energy homeostasis, but how hypometabolism translates into network hyperexcitability remains poorly understood. Here, we used induced pluripotent stem cells (iPSCs)-derived brain organoids to examine how reduced metabolic substrate availability shapes epileptiform dynamics in human neuronal circuits from GLUT1-DS. Methods: Brain organoids were generated from a healthy donor or a GLUT1-DS patient and interfaced with multielectrode arrays (MEA) for recording of neuronal activity. A unified Python (v3.10)-based analytical pipeline was developed to quantify spikes, bursts, and power spectral density (PSD) across frequency bands of neuronal activity. Organoids were challenged with reduced glucose, pentylenetetrazol (PTZ), potassium chloride (KCl), and tetrodotoxin (TTX) to assess metabolic and pharmacological modulation of excitability. Results: GLUT1-DS organoids exhibited elevated baseline hyperexcitability compared to healthy control, characterized by increased spike rates, prolonged bursts, increased spikes per burst, and elevated PSD. Reduced glucose availability further amplified these features selectively in GLUT1-DS. Conclusions: Human brain organoids reproduce the pathological coupling between hypometabolism and hyperexcitability in GLUT1-DS. Our platform provides a mechanistic model and quantification tool for evaluating metabolic and anti-epileptic therapeutic strategies.

Keywords:  GLUT1-DS; astrocyte; brain organoid; epilepsy; glucose; hyperexcitability; hypometabolism; iPSCs; neuron

DOI:  https://doi.org/10.3390/ph19010105
Int J Mol Sci. 2026 Jan 13. pii: 782. [Epub ahead of print]27(2):

Cholinergic Phenotypes of Acetyl-CoA with ATP-Citrate Lyase Link.

Sylwia Gul-Hinc, Agnieszka Jankowska-Kulawy, Andrzej Szutowicz.

  Glycolysis-derived pyruvate is the almost exclusive source of acetyl-CoA for energy production in mitochondrial compartments of all types of neuronal and glial cells. Neurons utilize several times more glucose than glial cells due to their neurotransmitter functions. Cholinergic neurons that are responsible for cognitive functions require additional amounts of acetyl-CoA for acetylcholine-transmitter synthesis in their cytoplasmic compartment. It may be assured by preferential localization of ATP-citrate lyase (ACLY) in the cytoplasm of cholinergic neurons' perikaryons and axonal terminals. This thesis is supported by the existence of strong regional and developmental correlations of ATP-citrate lyase and choline acetyltransferase (ChAT) activities and ACh levels in the brain. Electrolytic or chemical lesions of cholinergic nuclei cause proportional loss of the above parameters in the respective cortical target areas. On the other hand, the regional activity of mitochondrial pyruvate dehydrogenase complex (PDHC), which synthesizes nearly the whole pool of neuronal acetyl-CoA, displays no correlation with cholinergic innervation. It makes cholinergic neurons highly susceptible to brain pathologies impairing energy metabolism. Therefore, the ACLY pathway, which provides acetyl units directly to the site of acetylcholine synthesis in cholinergic nerve terminals, plays a key role in the maintenance of cholinergic neurotransmission. On the other hand, in cholinergic motor neurons, various ACLY-protein complexes are involved not only in neurotransmission but also in axonal transport of cholinergic elements from the perikaryon to cholinergic neuro-muscular junctions. This review presents findings supporting this thesis.

Keywords:  ATP-citrate lyase; acetylcholine; choline acetyltransferase; cholinergic neuron; metabolic compartmentation; pyruvate dehydrogenase

DOI:  https://doi.org/10.3390/ijms27020782
Int J Mol Sci. 2026 Jan 14. pii: 812. [Epub ahead of print]27(2):

The Role of Lipid Alteration in Multiple Sclerosis.

Agnieszka Damiza-Detmer, Małgorzata Pawełczyk, Andrzej Głąbiński.

  Multiple sclerosis (MS) is traditionally recognized as a chronic immune-mediated disorder of the central nervous system (CNS), but increasing evidence suggests that systemic metabolic alterations may also contribute to its pathophysiology. Lipid abnormalities in MS have recently attracted renewed research interest, with studies focusing both on dysregulation of lipid signaling pathways and on alterations in standard lipid profile components, including total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), and non-HDL cholesterol. Although disturbances in serum lipid profiles are consistently reported in patients with MS, their origin remains unresolved. Emerging data indicate that dyslipidemia may stem from aberrant cholesterol metabolism within the CNS, secondary to demyelination and myelin sheath destruction, leading to the release of lipid-rich debris and subsequent systemic metabolic imbalance. These lipid changes appear to correlate with blood-brain barrier (BBB) dysfunction, suggesting a link between peripheral lipid metabolism and CNS inflammation. This review summarizes current knowledge on the mechanisms underlying dyslipidemia in MS, its potential impact on disease progression, and its relevance as a possible therapeutic or biomarker target in future translational studies.

Keywords:  HDL; LDL; cholesterol; dyslipidemia; lipid alteration; multiple sclerosis

DOI:  https://doi.org/10.3390/ijms27020812
Brain Res. 2026 Jan 26. pii: S0006-8993(26)00041-7. [Epub ahead of print] 150183

Loss of hepaCAM inhibits cholesterol biosynthesis and impairs learning and memory in mice.

Ziyu Qiu, Qiang Liu, Juan Zhang.

  Cholesterol is a major astrocyte-derived substance that reprograms neuronal lipid metabolism and regulates neuronal function upon uptake by neurons. However, the mechanisms controlling cholesterol biosynthesis and secretion in astrocytes remain poorly understood. Here, we show that hepaCAM, an astrocytic membrane protein, is essential for normal memory function in mice by maintaining synaptic protein levels and synaptic spine density. Mechanistically, hepaCAM promotes neuronal function by modulating SREBP2-dependent cholesterol biosynthesis in astrocytes and facilitating its subsequent secretion. Furthermore, we identify the interaction of hepaCAM and ClC-2 is required for hepaCAM's regulatory role in cholesterol biosynthesis. Knockdown of hepaCAM in the hippocampus leads to reduced synaptic protein levels, decreased spine density, and impaired memory in mice. Collectively, our findings demonstrate that astrocytic hepaCAM regulates memory function through modulation of the astrocytic cholesterol biosynthesis pathway.

Keywords:  Astrocyte; Cholesterol biosynthesis; HepaCAM; Memory function

DOI:  https://doi.org/10.1016/j.brainres.2026.150183
J Cell Biol. 2026 Apr 06. pii: e202501023. [Epub ahead of print]225(4):

Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.

Jill E Falk, Tobias Henke, Sindhuja Gowrisankaran, Simone Wanderoy, Himanish Basu, Sinead Greally, Judith Steen, Thomas L Schwarz.

Neuronal signaling requires large amounts of ATP, making neurons particularly sensitive to defects in energy homeostasis. Mitochondrial movement and energy production are therefore regulated to align local demands with mitochondrial output. Here, we report a pathway that arrests mitochondria in response to decreases in the ATP-to-AMP ratio, an indication that ATP consumption exceeds supply. In neurons and cell lines, low concentrations of the electron transport chain inhibitor antimycin A decrease the production of ATP and concomitantly arrest mitochondrial movement without triggering mitophagy. This arrest is accompanied by the accumulation of actin fibers adjacent to the mitochondria, which serve as an anchor that resists the associated motors. This arrest is mediated by activation of the energy-sensing kinase AMPK, which phosphorylates TRAK1. This mechanism likely helps maintain cellular energy homeostasis by anchoring energy-producing mitochondria in places where they are most needed.

DOI: https://doi.org/10.1083/jcb.202501023
ASN Neuro. 2026 Jan 19. 18(1): 2617453

Disrupted Vitamin D Signaling and Metabolism in Neurodevelopmental and Neurodegenerative Disorders.

Nasim Khatibi, Jessica L MacDonald.

  Vitamin D is a secosteroid hormone with myriad physiological functions, including pleiotropic effects in the central nervous system. Vitamin D deficiency has been linked to multiple neurodevelopmental and neurodegenerative diseases, including Rett syndrome, epilepsy, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Over the past decades, vitamin D supplementation has been used as a preventative measure or a therapeutic intervention, often with inconsistent or variable responses. We discuss the known association between vitamin D deficiency and neurological disorder occurrence or progression for these disorders. Further, we assess the underlying causes for disruptions in vitamin D levels and the potential mechanisms of vitamin D-mediated improvements. We discuss disruptions in the vitamin D metabolism pathway, signaling, and/or feedback homeostasis that could underpin individual responses to vitamin D supplementation in these disorders. We further discuss the intersection between the vitamin D and cholesterol synthesis pathways and neuroinflammation, and the complex interactions that could contribute to the broad impact of vitamin D on neurological disorders.

Keywords:  Alzheimer’s disease; Epilepsy; Inflammation; Metabolism; Multiple Sclerosis; Parkinson’s disease; Rett syndrome; Vitamin D

DOI:  https://doi.org/10.1080/17590914.2026.2617453
J Adv Res. 2026 Jan 26. pii: S2090-1232(26)00091-3. [Epub ahead of print]

OSBPL6 protects against demyelination and behavioral disorder via promoting cholesterol transport in oligodendrocyte.

Mengni Chang, Kaiqi Zhang, Ye Li, Xiao Chen, Tian Lan, Yan Zhu, Wenjing Wang, Changmin Wang, Xianghua Zhuang, Shihong Chen, Shuyan Yu.

   INTRODUCTION: Demyelination is associated with behavioral disorder and cognitive impairment in neuropsychiatric diseases, including major depressive disorder (MDD). However, the mechanism underlying myelin damage remains unclear, despite stress maybe a major risk factor.
OBJECTIVES: Here, we demonstrate that hippocampal neurons in the chronic stress-induced depressive mice are prone to demyelination due to disrupted cholesterol transport to myelin sheaths in oligodendrocyte.
METHODS AND RESULTS: Single-nucleus RNA sequencing of lipid metabolism-related signaling pathway revealed significant reduced levels of oxysterol binding protein-like 6 (OSBPL6) in hippocampal oligodendrocytes of depression mouse model. Consistently, specific knockdown of OSBPL6 in oligodendrocytes induced loss of myelin structure, while upregulating OSBPL6 or enhancing OSBPL6 transcription improved these impairments in depressive mice. Furthermore, restoring cholesterol transport with β-cyclodextrin decreased cholesterol accumulation, improved damaged myelin structure, and rescued depression-related behaviors in depressive mice.
CONCLUSIONS: These findings suggest that OSBPL6-mediated cholesterol homeostasis in oligodendrocytes can promote myelin production against chronic stress-induced cerebral demyelination and depression with behavioral disorders.

Keywords:  Cholesterol homeostasis; Demyelination; Depression; OSBPL6; Oligodendrocyte

DOI:  https://doi.org/10.1016/j.jare.2026.01.066
Biomolecules. 2025 Dec 30. pii: 57. [Epub ahead of print]16(1):

Dodecanedioic Acid: Alternative Carbon Substrate or Toxic Metabolite?

Igor Radzikh, Usua Oyarbide, Akshay Suresh Patil, Yana I Sandlers.

  Twelve-carbon dicarboxylic acid dodecanedioic acid (DODA) has gained recent interest as an alternative nutrient. However, little is known about DODA cellular metabolism. Our study presents novel data on DODA metabolism and its potential role as an alternative carbon substrate. Cells are readily oxidizing DODA as a primary carbon source, yielding acetyl-CoA and succinate and replenishing the Krebs cycle. Furthermore, cells treated with DODA are characterized by a distinct metabolic profile, whereas pathways associated with energy metabolism are highly impacted. We also found that DODA administration alters carbon substrate preferences for respiration, restricting overreliance on one substrate as a primary fuel. Consequently, by rebalancing cellular energy metabolism, DODA as a supplemental carbon source may have significant therapeutic implications in conditions that are characterized by energy deficiency and metabolic inflexibility.

Keywords:  alternative carbon substrate; anaplerosis; dicarboxylic acids; dodecanedioic acid; fatty acid oxidation

DOI:  https://doi.org/10.3390/biom16010057
Biomedicines. 2026 Jan 20. pii: 222. [Epub ahead of print]14(1):

Restoration of Interaction Between Fatty Acid Oxidation and Electron Transport Chain Proteins In Vitro by Addition of Recombinant VLCAD.

Yudong Wang, Gregory Varga, Meicheng Wang, Johan Palmfeldt, Shakuntala Basu, Erik Koppes, Andrew Jeffrey, Robert James Hannan, Grant Sykuta, Jerry Vockley.

  Background/Objectives: We have previously demonstrated that fatty acid oxidation (FAO) enzymes physically and functionally interact with electron transfer chain supercomplexes (ETC-SC) at two contact points. The FAO trifunctional protein (TFP) and electron transfer flavoprotein dehydrogenase (ETFDH) interact with the NADH+-binding domain of ETC complex I (com I) and the core 2 subunit of complex III (com III), respectively. In addition, the FAO enzyme very-long-chain acyl-CoA dehydrogenase (VLCAD) interacts with TFP. These interactions define a functional FAO-ETC macromolecular complex (FAO-ETC MEC) in which FAO-generated NADH+ and FADH2 can safely transfer electron equivalents to ETC in order to generate ATP. Methods: In this study, we use multiple mitochondrial functional studies to demonstrate the effect of added VLCAD protein on mutant mitochondria. Results: We demonstrate that heart mitochondria from a VLCAD knockout (KO) mouse exhibit disrupted supercomplexes, with significantly reduced levels of TFPα and TFPβ subunits, electron transfer flavoprotein a-subunit (ETFα), and NDUFV2 subunit of com I in the FAO-ETC MEC. In addition, the activities of individual oxidative phosphorylation (OXPHOS) enzymes are decreased, as is the transfer of reducing equivalents from palmitoyl-CoA to ETC (FAO-ETC flux). However, the total amount of these proteins did not decrease in VLCAD KO animals. These results suggest that loss of VLCAD affects the interactions of FAO and ETC proteins in the FAO-ETC MEC. Reconstitution of VLCAD-deficient heart mitochondria with recombinant VLCAD improved the levels of FAO-ETC MEC proteins and enzyme activities, as well as restoring FAO-ETC flux. It also reduced mitochondrial ROS levels, previously demonstrated to be elevated in VLCAD-deficient mitochondria. In contrast, incubation of VLCAD KO mitochondria with two VLCADs with mutations in the C-terminal domain of the enzyme (A450P and L462P) did not restore FAO-ETC MECs. Conclusions: These results suggest that VLCAD is a necessary component of the FAO-ETC MEC and plays a major role in assembly of the macro-supercomplex. These studies provide evidence that both the level of enzyme and its structural confirmation are necessary to stabilize the FAO-ETC MEC.

Keywords:  VLCAD deficiency; fatty acid oxidation; mitochondrial electron transfer chain supercomplex (ETC-SC); very-long-chain acyl-CoA dehydrogenase (VLCAD)

DOI:  https://doi.org/10.3390/biomedicines14010222
Neurophotonics. 2025 Jun;12(Suppl 2): S22801

Introduction to the Neurophotonics Special Issue "Imaging Brain Metabolism and Neuroenergetics".

Alberto L Vazquez, Ghazaleh Ashrafi, Prakash Kara.

The editorial introduces the articles in the Neurophotonics Special Issue on Imaging Brain Metabolism and Neuroenergetics.

DOI: https://doi.org/10.1117/1.NPh.12.S2.S22801
Theranostics. 2026 ;16(7): 3577-3598

Microvascular endothelial metabolic dysfunction drives cerebral edema through bioenergetic failure after ischemia-reperfusion.

Yi-Fan Zhou, Si-Bo Yang, Feng Zhang, Xiao-Di Sun, Bo-Hao Chang, Ya-Nan Li, Jie-Hong Wu, Hui-Juan Jin, Ming Huang, Sheng-Cai Chen, Hang Yang, Dong-Ya Zhu, Bijoy K Menon, Bo Hu.

  Aim: Despite major advances in recanalization therapy, poor functional outcomes after ischemic stroke remain common. The central challenge is not only restoring blood flow but also overcoming the bioenergetic failure that can persist during reperfusion. This study aims to identify the missing link by defining how a metabolic-epigenetic cascade drives microvascular energetic collapse, thereby elucidating mechanisms underlying sustained cerebral edema and the no-reflow phenomenon following ischemia-reperfusion. Methods: We analyzed serum samples from patients with acute ischemic stroke to evaluate associations among lactate/pyruvate (L/P) ratios, functional outcomes, and cerebral edema. High-resolution magnetic resonance imaging (MRI) and FITC-dextran extravasation test in transient middle cerebral artery occlusion (tMCAO) model were used to determine whether glycolytic inhibition reduced edema. Single-cell RNA sequencing characterized endothelial cell subpopulations after stroke, and molecular experiments examined the effects of lactate accumulation on histone H3K18 lactylation (H3K18la) and downstream ATF4-DDIT4 signaling. Mitochondrial function, electron transport chain (ETC) activity, and necroptosis-related pathways were assessed in endothelial cells. Results: An elevated L/P ratio was strongly correlated with poor neurological outcomes and was closely linked to ischemia-reperfusion-induced cerebral edema. Reducing glycolytic flux and lactate production attenuated edema formation. Single-cell sequencing identified a post-stroke hyper-glycolytic endothelial subset characterized by mitochondrial dysfunction and necroptosis activation, with greater expansion in aged tMCAO mice. Lactate accumulation increased H3K18la in endothelial cells and activated the ATF4-DDIT4 pathway, which further impaired mitochondrial and ETC function. These changes established a self-amplifying pathological loop -glycolysis/H3K18la/ATF4-DDIT4 - that intensified bioenergetic failure while promoting RIPK3-dependent necroptosis and inflammation. Conclusions: Aberrant lactate metabolism not only serves as a prognostic biomarker but also provides a mechanistic link between metabolic insufficiency and epigenetic dysregulation through histone lactylation. Targeting the feedback loop involving H3K18la and ATF4-DDIT4 offers a promising therapeutic approach to limit cerebral edema and improve functional outcomes after ischemic stroke.

Keywords:  cerebral edema after endovascular recanalization therapy; endothelial bioenergetic failure; histone lactylation; lactate metabolism; necroptosis

DOI:  https://doi.org/10.7150/thno.127083
ACS Biomater Sci Eng. 2026 Jan 28.

Metabolic Radiosensitization by Targeting Lactate Metabolism with Microfluidic Liposomal Nanocarriers.

Meabh Doherty, Jie Feng, Tongchuan Wang, Cancan Yin, Niall M Byrne, Sarah Chambers, Rayhanul Islam, Dimitrios A Lamprou, Jonathan A Coulter.

  Lactate, the main product of the Warburg effect, exerts both intrinsic effects on cancer cell metabolism and noncell autonomous effects that promote tumor development, metastasis, and treatment resistance. As such, glycolytic dependence in tumors is frequently associated with poor clinical outcomes. Targeting lactate metabolism has emerged as a promising strategy to enhance the efficacy of conventional therapies. Here, we investigate the therapeutic potential of targeting lactate metabolism via inhibiting MCT1, MCT4, and MPC in PC3 and FaDu tumor cell models. We confirmed lactate as a substrate that fuels mitochondrial respiration and supports cell survival under hypoxic conditions. Inhibition of lactate influx mediated by 7ACC2 reduced oxygen consumption, sensitizing tumor cells to radiation in both 2D-cell cultures and 3D-spheroid models. Encapsulation of 7ACC2 in DPPC liposomes using microfluidics preserved radiosensitizing activity in both systems, promoting reoxygenation, while overcoming the pharmacological limitations of the free drug. This liposomal formulation therefore represents a promising therapeutic approach to help mitigate hypoxia-induced radioresistance.

Keywords:  MCT1/4; MPC; hypoxia; lactate metabolism

DOI:  https://doi.org/10.1021/acsbiomaterials.5c02175
Stem Cell Rev Rep. 2026 Jan 28.

Human Myelin Spheres for in Vitro Oligodendrocyte Maturation, Myelination and Neurological Disease Modeling.

Karan Ahuja, Roya Ramezankhani, Xinyu Wang, Thibaut Burg, Giulia Amos, Katrien Neyrinck, Alessio Silva, Geethika Arekatla, Eleanor Eva Cassidy, Fatemeharefeh Nami, Joke Terryn, Keimpe Wierda, Katlijn Vints, Niels Vandamme, Suresh Poovathingal, Ivo Lambrichts, Johannes V Swinnen, Ludo Van Den Bosch, Lies De Groef, Lieve Moons, Catherine Verfaillie, Johan Neyts, Dirk Jochmans, Yoke Chin Chai.

Demyelinating diseases, such as multiple sclerosis, damage the protective myelin sheaths of the central nervous system. The development of effective therapies has been hampered by the lack of models that accurately replicate human myelin biology. Here we present a novel method to generate human myelin spheres (MyS) by coculturing of hPSC-derived neuronal and oligodendrocyte precursor cells, to create myelinated neurons. Using multimodal analyses including confocal and (electron)microscopy, single-nuclei transcriptomics, lipidomics, and electrophysiology, we demonstrate myelination in MyS as early as six weeks into coculture. These myelinated structures mature over time into multilamellar and compacted myelin sheaths with lipid compositions and transcriptomic profiles mirror the temporal dynamics of in vivo human oligodendrocyte development and neuronal myelination, resembling those of late fetal oligodendrocytes. By employing lysolecithin-induced demyelination and Rabies virus infection experiments, we demonstrate the potential of MyS as an innovative, physiologically relevant platform for studying myelin-related neurodegeneration and neuroinfection.

DOI: https://doi.org/10.1007/s12015-026-11061-4
Biomedicines. 2025 Dec 29. pii: 69. [Epub ahead of print]14(1):

Coenzyme A in Brain Biology and Neurodegeneration.

Dejun Zhang, Charlie Brett, Jason Cho, Tammaryn Lashley, Ivan Gout.

  Coenzyme A (CoA) biology has been extensively studied in health and disease due to the central role of CoA in numerous metabolic and signalling processes. CoA is essential for all living organisms, and its biosynthesis and homeostasis are tightly regulated by nutrient availability, mitogenic stimuli, and stress signals. Disruptions in CoA biosynthesis, caused by inborn mutations in genes encoding enzymes of the CoA biosynthetic pathway (such as PANK2 and CoASy), lead to neurodegeneration, indicating the critical role of CoA/CoA thioesters in the function and viability of neuronal cells. The molecular mechanisms linking CoA deficiency to neurodegeneration remain unknown, but recent studies have highlighted the involvement of disrupted metabolism and redox homeostasis. The antioxidant function of CoA, mediated by protein CoAlation, has recently emerged as a novel and important mechanism of redox regulation. This review highlights well-established principles of CoA in neuronal metabolism and summarises recent advances in our understanding of its role in adaptive responses to oxidative and metabolic stress. The identification of enzymes involved in the CoAlation/deCoAlation cycle, together with the development of novel analytical tools and methodologies, may provide new insights into the discovery of more effective diagnostic and therapeutic approaches for targeting neurodegenerative diseases.

Keywords:  Coenzyme A; neurodegeneration; redox regulation

DOI:  https://doi.org/10.3390/biomedicines14010069
Neuromolecular Med. 2026 Jan 30. 28(1): 7

Myelin Lipid Reserves as a Conditional Metabolic Buffer: Implications for Alzheimer's Disease and Ischemic Stroke.

Peibin Zou, Zhihai Huang, Yulan Zhang, Xuemei Zong, Quanguang Zhang.



Keywords:  Alzheimer disease; Beta oxidation; Ischemic stroke; Lipid metabolism; Metabolic buffering; Myelin; Oligodendrocytes; White matter energetics

DOI:  https://doi.org/10.1007/s12017-026-08905-0
Nanoscale Adv. 2025 Oct 08.

Dynamic instability in nanoscale lipid domains revealed by contact mode high speed AFM: effect of amyloid-β and cholesterol content.

Morgan Robinson, Loren Picco, Oliver D Payton, Nikolas Zelem, Charlotte Baur, Michael A Beazely, Mervyn J Miles, Zoya Leonenko.

Cellular membranes are an essential feature of life, the composition and structure of which is important in governing cellular processes and is linked to multiple disorders. Of particular interest is the role that the lipid membrane plays in amyloidogenic diseases such as Alzheimer's disease (AD), including the role of lipid composition and cholesterol in mediating amyloid toxicity. To mimic neuronal membranes, we used 3-component (DPPC/DOPC/Chol) and 5-component (DPPC/POPC/Chol/sphingomyelin/GM1) model membranes. Atomic force microscopy (AFM) is a key tool in studying the structures of lipid membranes and their interactions with amyloid. Recent advances in contact mode high-speed AFM (HS-AFM) have made it possible to capture dynamic processes at video rate. We used a unique custom-built contact mode HS-AFM to image model lipid membranes and study amyloid-β interactions in liquid. We demonstrate the advantage of using HS-AFM coupled with spatiotemporal variability analysis to capture the dynamic interaction of Aβ 1-42 monomers and oligomers with phase separated lipid bilayers to elucidate the role of nanoscale domains in amyloid-membrane interactions. We show that amyloid oligomer complexes induce greater dynamic instability than monomers, and that low cholesterol membranes are more susceptible to destabilization. Overall, we demonstrate the advantage of HS-AFM to image biological processes on biologically relevant soft samples and discuss tip-sample interactions at high-speed operation in contact mode on lipid membrane models in a liquid environment.

DOI: https://doi.org/10.1039/d5na00273g
Nat Biotechnol. 2026 Jan 27.

Single-cell proteomic landscape of the developing human brain.

Tianzhi Wu, Lihua Jiang, Tanzila Mukhtar, Li Wang, Ruiqi Jian, Cheng Wang, Tiffany Trinh, Arnold R Kriegstein, Michael Snyder, Jingjing Li.

Profiling protein abundance and dynamics at single-cell resolution in complex human tissues is challenging. Given the discordance between transcript and protein abundance observed in studies of the human cerebral cortex, we developed an optimized workflow that combines label-free single-cell mass spectrometry with precise sample preparation to resolve quantitative proteomes of individual cells from the developing human brain. Our method achieves deep proteomic coverage (~800 proteins per cell) even in small immature prenatal human neurons (diameter ~7-10 μm, ~50 pg protein), capturing major brain cell types and enabling proteome-wide characterization at single-cell resolution. We document extensive transcriptome-proteome discordance across cell types, particularly in genes associated with neurodevelopmental disorders. Proteins exhibit markedly higher cell-type specificity than their mRNA counterparts, underscoring the importance of proteomic-level analysis. By reconstructing developmental trajectories from radial glia to excitatory neurons at the proteomic level, we identify dynamic, stage-specific protein co-expression modules and pinpoint the intermediate progenitor-to-neuron transition as a genetically vulnerable phase associated with autism.

DOI: https://doi.org/10.1038/s41587-025-02980-7