bims-medebr 2025-07-27 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–07–27
fifteen papers selected by
Regina F. Fernández, Johns Hopkins University

Measurement of brain glucose metabolism in obesity and diabetes.
Combined dietary omega-3 and omega-6 fatty acids protect against hyperglycemia-associated retinopathy in neonatal mice.
Isoflurane and urethane impact neuronal and astroglial metabolic activity differentially in mouse brain: An ex vivo 1H-[13C]-NMR study.
Embracing the Modern Biochemistry of Brain Metabolism.
Hypothalamic Astrocytes Exhibit Glycolytic Features Making Them Prone for Glucose Sensing.
Cerebrospinal fluid lipoprotein-mediated cholesterol delivery to neurons is impaired in Alzheimer's disease and involves APOE4.
The Influence of Schwann Cell Metabolism and Dysfunction on Axon Maintenance.
Signaling Mechanisms Underlying the Glioprotective Effects of Guanosine Against Glucose Deprivation-Induced Glial Dysfunction.
Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex.
The Evolution of Alzheimer's Disease: From Mitochondria to Microglia.
Quantitative analysis of targeted lipidomics in the hippocampus of APP/PS1 mice employing the UHPLC-MS/MS method.
Arachidonoyl-carnitine and arachidonoyl-coenzyme A are suitable substrates for mammalian ALOX isoforms.
Dissection of Neurochemical Pathways Across Complexity and Scale.
High altitude induces a shift from complex I to complex II in the brain mitochondria of newborn and adult mice.
Metabolic and Structural Alterations in the Motor System Following Spinal Cord Injury: An In-Vivo 1H-MR Spectroscopy Investigation.

Diabetologia. 2025 Jul 25.

Measurement of brain glucose metabolism in obesity and diabetes.

Janice J Hwang, Jason Bini, Renata Belfort-DeAguiar.

  The brain consumes a large amount of glucose to fuel its high metabolic demands. Understanding brain glucose metabolism is critical for understanding the brain's normal physiology and the pathological states of diabetes and obesity. However, accurately measuring brain glucose metabolism in humans presents significant challenges. Most studies depend on non-invasive neuroimaging techniques, such as positron emission tomography and magnetic resonance spectroscopy, which each have distinct advantages and limitations. This review outlines the primary neuroimaging modalities used to assess brain glucose metabolism, focusing on modalities and studies that have paired brain imaging with controlled physiological manipulations of circulating glucose and insulin levels, to examine how metabolic diseases influence brain glucose metabolism.

Keywords:  Brain metabolism; Diabetes; Hyperglycaemic clamp; Hyperinsulinaemic clamp; MRS imaging; Neuroimaging; Obesity; PET imaging; Review

DOI:  https://doi.org/10.1007/s00125-025-06491-7
Pharmacol Res. 2025 Jul 23. pii: S1043-6618(25)00302-0. [Epub ahead of print] 107877

Combined dietary omega-3 and omega-6 fatty acids protect against hyperglycemia-associated retinopathy in neonatal mice.

Myriam Boeck, Hitomi Yagi, Pia Lundgren, Aldina Pivodic, Anders K Nilsson, Yan Zeng, Chuck T Chen, Taku Kasai, Deokho Lee, Shen Nian, Victoria Hirst, Katherine Neilsen, Chaomei Wang, Jeff Lee, Mathew Yu, Andrew McCutcheon, Sasha A Singh, Masanori Aikawa, Richard P Bazinet, Zhongjie Fu, Ann Hellström, Lois Eh Smith.

  Retinopathy of prematurity (ROP) with early vessel loss (Phase I) followed by uncontrolled vessel growth (Phase II) causes visual impairment in premature infants. Although supplementation with omega-3 (n-3) docosahexaenoic acid (DHA) alone shows mixed results in preventing ROP, supplementation with both n-3 DHA and n-6 arachidonic acid (ARA) in early postnatal life reduces severe ROP by 50% (Mega Donna Mega study). In the Mega Donna Mega study, 146 (72.6%) of 201 included infants had at least one hyperglycemic episode during the first 14 days of life, which is a strong ROP risk factor. We therefore evaluated the protective effects and mechanisms of combined dietary n-3 DHA and n-6 ARA in a neonatal mouse model of hyperglycemia-induced suppression of retinal vascular development (Phase I ROP). At postnatal day (P)10, retinal vessel growth was improved in pups from mothers on diets enriched with 1%DHA+2%ARA versus 3%DHA. Lipid changes in pup plasma and RPE complex (retinal pigment epithelium with choroid and sclera) were in accordance with maternal diets' DHA and ARA levels indicating that milk lipids reflected maternal diets. Proteomic retinal analysis revealed increased abundances of proteins related to mitochondrial respiration and glucose metabolism with the combined diet. Inhibition of mitochondrial ATP synthase negated the protective effects of the combined diet. In conclusion, combined DHA+ARA oral maternal supplementation protects against hyperglycemia-induced retinopathy in mouse neonates (Phase I ROP model) through enhanced retinal metabolism, suggesting the potential of balanced lipid supplementation for ROP prevention.

Keywords:  ARA; DHA; postnatal hyperglycemia; retinal vasculature; retinopathy of prematurity

DOI:  https://doi.org/10.1016/j.phrs.2025.107877
Br J Pharmacol. 2025 Jul 23.

Isoflurane and urethane impact neuronal and astroglial metabolic activity differentially in mouse brain: An ex vivo 1H-[13C]-NMR study.

Sreemantula Arun Kumar, Akila Ramesh, Pooja Gautam, Anant Bahadur Patel.

   BACKGROUND AND PURPOSE: Isoflurane and urethane are among the most routinely used anaesthetics to immobilise rodents in functional studies. However, the quantitative significance of their impacts on neuronal and astroglial activity is not very clear. This study evaluated the impacts of isoflurane and urethane on the metabolic activity of glutamatergic neurons, GABAergic neurons and astrocytes in different brain regions.
EXPERIMENTAL APPROACH: Male C57BL/6 mice were anaesthetised with either isoflurane (1.5%) or urethane (1.5 g kg-1, intraperitoneal), and administered [1,6-13C2]glucose or [2-13C]acetate intravenously for 10 or 15 min, respectively. The brain metabolism was arrested using Focussed Beam Microwave Irradiation, and the 13C labelling of neurometabolites in the brain tissue extracts was measured ex vivo using 1H-[13C]-nuclear magnetic resonance (NMR) spectroscopy.
RESULTS: The levels of aspartate and succinate were decreased, while alanine increased in the studied brain regions in mice exposed to isoflurane compared to awake mice. The labelling of GluC4/C3, GABAC2 and GlnC4 from [2-13C]acetate was decreased in the isoflurane group when compared with awake, suggesting that isoflurane suppresses the astroglial metabolic activity, particularly in the subcortical region. There was a severe reduction in the 13C labelling of brain amino acids from [1,6-13C2]glucose in all the brain regions in isoflurane and urethane groups of mice, indicating a severe impact of both anaesthetics on the metabolic activity of glutamatergic and GABAergic neurons.
CONCLUSIONS AND IMPLICATIONS: These findings demonstrate that isoflurane and urethane differentially reduce excitatory and inhibitory synaptic transmissions in the brain. Notably, isoflurane shifts cerebral metabolism towards anaerobic respiration.

Keywords:  GABA; acetate; cerebral metabolic rate; glucose; glutamate; glutamine; neurotransmission

DOI:  https://doi.org/10.1111/bph.70113
J Neurochem. 2025 Jul;169(7): e70166

Embracing the Modern Biochemistry of Brain Metabolism.

Juan P Bolaños, Cristina M Alberini, Angeles Almeida, L Felipe Barros, Gilles Bonvento, Anne-Karine Bouzier-Sore, Ralf Dringen, Giles E Hardingham, Johannes Hirrlinger, Pierre J Magistretti, Giovanni Marsicano, Klaus-Armin Nave, Rosa C Paolicelli, Luc Pellerin, Pierre-Yves Plaçais, Thomas Preat, Nathalie Rouach, Ivan Ruminot, Aiman S Saab, Carmen Sandi, Stefanie Schirmeier, Avital Schurr, Jimena Sierralta, Maite Solas, Vanja Tepavcevic, Bruno Weber, Eduardo R Zimmer.

This editorial challenges the long-held neuron-centered view of brain metabolism, relying on ample evidence that it is a cooperative, multicellular process. Astrocytes, oligodendrocytes, and other glia play active roles providing lactate, antioxidant support, and substrate shuttles that fuel neuronal function and memory. Despite mounting data, some critics persist in refuting intercellular metabolic exchange, often guided more by entrenched creeds than concrete evidence, slowing constructive, hypothesis-driven discourse and delaying clinical and neuroprotective advances. The authors call for a rigorous research agenda: cell-type-specific manipulations, advanced biosensors, imaging and biomarkers, and integration with behavior and electrophysiology. They urge redirecting focus from outdated dogma to physiology-driven exploration of glia-neuron metabolic partnerships.

DOI: https://doi.org/10.1111/jnc.70166
Glia. 2025 Jul 24.

Hypothalamic Astrocytes Exhibit Glycolytic Features Making Them Prone for Glucose Sensing.

Sarah Geller, Nadège Zanou, Sylviane Lagarrigue, Tamara Zehnder, Cathy Gouelle, Tania Santoro, Cendrine Repond, Paola Bezzi, Francesca Amati, Anne-Karine Bouzier-Sore, Ariane Sharif, Luc Pellerin.

  In the hypothalamus, detection of energy substrates such as glucose is essential to regulate food intake and peripheral energy homeostasis. Metabolic interactions between astrocytes and neurons via lactate exchange have been proposed as a hypothalamic glucose-sensing mechanism, but the molecular basis remains uncertain. Mouse hypothalamic astrocytes in vitro were found to exhibit a stronger glycolytic phenotype in basal conditions than cortical astrocytes. It was associated with higher protein expression levels of the Pyruvate Kinase Isoform M2 (Pkm2) and its more prominent nuclear localization. In parallel, hypothalamic astrocytes also expressed higher levels of the monocarboxylate transporter Slc16a3 (Mct4), which were dependent on Pkm2 expression. The stronger Mct4 expression in hypothalamic versus cortical astrocytes is an intrinsic characteristic, as it was also present after their direct isolation from adult mouse tissue. The high lactate release capacity of hypothalamic astrocytes was demonstrated to depend on the expression of Mct4, but not Mct1. Unlike cortical astrocytes, hypothalamic astrocytes in culture do not respond to glutamate with enhanced glycolysis, but instead, they modulate their lactate production according to glucose concentrations in an AMPK-dependent manner, an effect observed in both mouse and human hypothalamic astrocytes in vitro. Our study shows that hypothalamic and cortical astrocytes are geared to have distinct glycolytic responses to glucose and glutamate, respectively. These results reveal a metabolic specialization of astrocytes in order to fulfill distinct area-specific functions: glucose-sensing in the hypothalamus versus activity-dependent neuronal energetic supply in cortical regions.

Keywords:  Mct1; Mct4; Pkm2; astrocytes; glucose; hypothalamus; lactate

DOI:  https://doi.org/10.1002/glia.70066
J Lipid Res. 2025 Jul 21. pii: S0022-2275(25)00127-0. [Epub ahead of print] 100865

Cerebrospinal fluid lipoprotein-mediated cholesterol delivery to neurons is impaired in Alzheimer's disease and involves APOE4.

Carla Borràs, Marina Canyelles, David Santos, Noemí Rotllan, Estefanía Núñez, Jesús Vázquez, Daniel Maspoch, Mary Cano-Sarabia, Qi Zhao, Maria Carmona-Iragui, Sònia Sirisi, Alberto Lleó, Juan Fortea, Daniel Alcolea, Francisco Blanco-Vaca, Joan Carles Escolà-Gil, Mireia Tondo.

  In the central nervous system, apolipoprotein (APO)E-containing lipoprotein particles mediate the transport of glial-derived cholesterol to neurons, which is essential for neuronal membrane remodeling and maintenance of the myelin sheath. We aimed to examine cholesterol transport via lipoprotein particles in cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients compared to control individuals. Additionally, we explored the ability of reconstituted HDL containing different APOE isoforms to regulate cholesterol transport. We evaluated the capacity of CSF lipoprotein particles to facilitate radiolabeled unesterified cholesterol efflux from A172 human glioblastoma astrocytes and to deliver cholesterol to SH-SY5Y human neuronal cells. The CSF lipoprotein proteome was analyzed by LC-MS/MS. Reconstituted HDL nanoparticles were prepared by combining phospholipids and cholesterol with human APOE3 or APOE4, followed by radiolabeling with unesterified cholesterol. Our results showed that cholesterol efflux from astrocytes to CSF were similar between AD patients and controls, both under baseline conditions and after activation of ABCA1 and ABCG1. However, CSF lipoprotein-mediated neuronal cholesterol uptake was significantly reduced in the AD group. LC-MS/MS analysis identified 239 proteins associated with CSF lipoproteins in both groups, with no major alterations in proteins linked to cholesterol metabolism. However, 27 proteins involved in non-cholesterol-related processes were differentially expressed. Notably, synthetic reconstituted HDL particles containing APOE4 exhibited reduced capacity to deliver cholesterol to neurons compared to those with APOE3. These findings indicate that CSF lipoproteins from patients with AD demonstrate impaired cholesterol delivery to neurons. Our study highlights APOE4 as a critical contributor to abnormal neuronal cholesterol uptake in AD pathophysiology.

Keywords:  APOE; Alzheimer's Disease; CSF lipoprotein; Cholesterol

DOI:  https://doi.org/10.1016/j.jlr.2025.100865
Glia. 2025 Jul 25.

The Influence of Schwann Cell Metabolism and Dysfunction on Axon Maintenance.

Rose Follis, Vishwanath V Prabhu, Bruce D Carter.

  Schwann cells are the glial cells in the peripheral nervous system responsible for the production of myelin, which is essential for rapid, saltatory conduction in nerves. However, it has become increasingly recognized that Schwann cells are also key regulators of neuron viability and function, especially for sensory neurons. Neurons and Schwann cells form a tightknit, interdependent couple with complex mechanisms of communication that are only beginning to be understood. There is growing evidence that Schwann cell metabolism profoundly influences axons through the release of a variety of metabolites. These glial cells serve as energy depots for axon function, supplying lactate and/or pyruvate during repeated firing and after injury. Lipid metabolism in Schwann cells, which is critical for myelin production, also affects axon viability, such that disruptions in the production or breakdown of lipids can lead to axon dysfunction and subsequent degeneration. Here, we discuss emerging concepts on the mechanisms by which Schwann cell metabolites influence neuron activity and survival, with particular focus on how dysfunction of lipid metabolism can lead to axon degeneration and the development of peripheral neuropathy.

Keywords:  Schwann cell; axon; myelin

DOI:  https://doi.org/10.1002/glia.70071
Neurochem Res. 2025 Jul 21. 50(4): 240

Signaling Mechanisms Underlying the Glioprotective Effects of Guanosine Against Glucose Deprivation-Induced Glial Dysfunction.

Larissa Daniele Bobermin, Caio César Ramalho Bezerra, Júlia Krebs-Rosa, Vanessa-Fernanda Da Silva, Izaviany Schmitz, Rômulo Rodrigo de Souza Almeida, Fernanda Becker Weber, Nikoli Zasso, Aline Longoni, Adriano Martimbianco de Assis, Carlos-Alberto Gonçalves, Diogo Onofre Souza, André Quincozes-Santos.

  Glucose is a critical energy substrate for brain function; therefore, hypoglycemia or compromised glucose metabolism can lead to cognitive impairment and an increased risk for neurodegenerative and neuropsychiatric disorders. Astrocytes are glial cells that act as key regulators of brain glucose metabolism, thus representing important cellular targets for neuroprotection during glucose deprivation. Guanosine, a guanine-based purine, has shown neuroprotective properties in various central nervous system (CNS) disorders. As such, this study aimed to evaluate the potential glioprotective effects of guanosine in a glucose deprivation model, using C6 astroglial cells and focusing on redox imbalance, inflammatory and trophic responses, as well as putative signaling mechanisms associated with these effects. C6 astroglial cells were cultured under normal glucose conditions and subjected to glucose deprivation (culture medium without glucose), with or without guanosine (100 µM) for 12 h. Cytokine levels, oxidative stress markers, mitochondrial function, and NFκB, Nrf2/HO-1, and PI3K/Akt signaling were assessed via ELISA, RT-PCR, colorimetric and fluorescence assays. Glucose deprivation induced glial dysfunction, particularly changes in inflammatory response, redox homeostasis, and cytoprotective/survival signaling pathways. Guanosine prevented glucose deprivation-induced NFκB activation, reducing inflammatory markers (e.g., TNF-α, IL-1β) and restoring S100B secretion. Guanosine also upregulated Nrf2/HO-1 expression, improved antioxidant enzyme activities, mitigated oxidative stress, and preserved mitochondrial membrane potential. Additionally, guanosine restored PI3K/Akt expression and modulated glial-derived factors, including GDNF and TGF-β. By modulating the NFκB, Nrf2/HO-1, and PI3K/Akt pathways, guanosine offers a promising glioprotective strategy to mitigate astrocytic damage during hypoglycemia, potentially reducing CNS injury and associated neurodegeneration.

Keywords:  Astroglial cells; Glucose deprivation; Guanosine; Inflammatory response; Redox imbalance

DOI:  https://doi.org/10.1007/s11064-025-04498-5
Nat Commun. 2025 Jul 21. 16(1): 6700

Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex.

Yingyuan Sun, Yaru Wang, Zheng Xing, Dongyu Li, Rong Wang, Baozhi Chen, Ning Zhou, Alyssa Ayala, Benjamin P Tu, Xiaofeng Qi.

The Mitochondrial Pyruvate Carrier (MPC) bridges cytosolic and mitochondrial metabolism by transporting pyruvate into mitochondria for ATP production and biosynthesis of various essential molecules. MPC functions as a heterodimer composed of MPC1 and MPC2 in most mammalian cells. Here, we present the cryogenic electron microscopy (cryo-EM) structures of the human MPC1-2 complex in the mitochondrial intermembrane space (IMS)-open state and the inhibitor-bound in the mitochondrial matrix-open state. Structural analysis shows that the transport channel of MPC is formed by the interaction of transmembrane helix (TM) 1 and TM2 of MPC1 with TM2 and TM1 of MPC2, respectively. UK5099, a potent MPC inhibitor, shares the same binding site with pyruvate at the matrix side of the transport channel, stabilizing MPC in its matrix-open conformation. Notably, a functional W82F mutation in MPC2 leads to the complex in an IMS-open conformation. Structural comparisons across different conformations, combined with yeast rescue assays, reveal the mechanisms of substrate binding and asymmetric conformational changes in MPC during pyruvate transport across the inner mitochondrial membrane (IMM) as well as the inhibitory mechanisms of MPC inhibitors.

DOI: https://doi.org/10.1038/s41467-025-61939-z
Ageing Res Rev. 2025 Jul 21. pii: S1568-1637(25)00184-9. [Epub ahead of print] 102838

The Evolution of Alzheimer's Disease: From Mitochondria to Microglia.

Feng-Ge Yang, Yu-Lin Liang, Xu Wang, Jun-Ting Wang, Wei Gao, Qiu-Yan Ye, Xue-Yuan Li, Yu Yang, Hong-Lin Li.

  Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder worldwide. Recent studies highlights that mitochondrial dysfunction drives alterations in microglial function, serving as a pivotal mechanism in the pathogenesis and progression of AD. Increasingly, there is evidence that mitochondrial dysfunction encompasses energy metabolism deficits, heightened oxidative stress, impaired mitochondrial dynamics, disrupted autophagy, and calcium homeostasis imbalances. These impairments modulate microglial activation states, precipitating exacerbated neuroinflammation, altered phagocytic capacity, and increased cellular apoptosis, collectively contributing to microglial dysfunction. This paper presents a narrative review on the relationship between mitochondrial dysfunction and AD, elucidating the impact of mitochondrial impairment on microglia. It summarizes therapeutic strategies that target mitochondria to modulate microglial function, aiming to prevent and treat AD. The goal is to provide new perspectives and insights for AD research and treatment, contributing to improving patients' quality of life and prognosis.

Keywords:  Alzheimer's disease; Microglial cell polarization; Mitochondrial dysfunction; Mitophagy; Neuroinflammation; Therapeutic strategies

DOI:  https://doi.org/10.1016/j.arr.2025.102838
Front Aging Neurosci. 2025 ;17 1561831

Quantitative analysis of targeted lipidomics in the hippocampus of APP/PS1 mice employing the UHPLC-MS/MS method.

Shiyu Xiao, Xuemeng Wei, Bing Han, Xiaoqian Shi, Congzhen Wei, Rumeng Liang, Jingna Sun, Zheng Zhang, Zhengang Han, Li Shen.

   Background: Alzheimer's disease (AD) is marked by the pathological features of amyloid-β plaque accumulation, as well as intracellular neurofibrillary tangles formation in the patients' brain. Aberrant lipid metabolism is increasingly recognized as one of the important contributors to AD.
Purpose: The main goal of this research was to conduct quantitative detection of targeted lipidomics in hippocampal tissue of APPSwe/PS1dE9 mice in order to identify lipid metabolic biomarkers of early-onset AD mice.
Methods: Our approach departs from conventional lipid detection methods, employing a highly accurate quantificational Ultra High Performance Liquid Chromatography Tandem Mass Spectrometry (UHPLC-MS/MS) technique to analyze targeted lipid biomarkers. The innovative method was utilized to detect targeted lipids in the hippocampus of AD and wild-type mice. Statistical method was performed by Student's t-test and multivariate analysis. Differential metabolites were identified through fulfilling the standard of Variable Importance in Projection surpassing one and the significance probability lower than 0.05 thresholds.
Results: Both groups utilized identical methodologies and adhered strictly to standardized treatment protocols. Sphingolipids (SPs), Glycerophospholipids (GPs), Glycolipids, Glycerides (GLs), Sterol Lipids (STs), and Free Fatty Acid (FA) were identified as prominent lipids exhibiting alterations in the hippocampus of AD models. Regarding glycolipid and glycerolipid composition, monogalactosyldiacylglycerols (MGDGs) and Triacylglycerols (TGs) constituted a significant proportion (p < 0.05, VIP > 1). Among glycerophospholipids, phosphatidylethanolamines (PEs) and phosphatidylcholines (PCs) emerged as significant constituents (p < 0.05, VIP > 1). Furthermore, hexosylceramides (HexCers) and ceramides (Cers) in the AD model's hippocampus, the prominent sphingolipids in the hippocampus of AD mice, existed as the two primary changed lipid metabolites. The levels of some TGs in GLs and CEs in STs showed a significant elevation (p < 0.05, VIP > 1). In contrast, most kinds of MGDGs, HexCers, Cers, PEs and FA (18:2) demonstrated a notable decrease in the hippocampus of AD group (p < 0.05, VIP > 1).
Conclusion: The present research represents the important quantitative identification of distinct lipid biomarker profiles within the hippocampal portion of 7.5-month-aged AD mice. It encompasses glycolipid, GLs, GPs, SPs, STs, and FAs using a targeted HPLC-MS method for quantification. These findings suggest potential diagnostic lipid biomarkers in hippocampus of early-onset AD mice related to cellular membrane integrity, atherosclerosis, oxidative stress damage, and inflammation.

Keywords:  APP/PS1 mice; Alzheimer’s disease; UHPLC-MS; hippocampus; targeted lipidomics

DOI:  https://doi.org/10.3389/fnagi.2025.1561831
J Lipid Res. 2025 Jul 17. pii: S0022-2275(25)00123-3. [Epub ahead of print] 100861

Arachidonoyl-carnitine and arachidonoyl-coenzyme A are suitable substrates for mammalian ALOX isoforms.

Xin Chen, Sahanawaz Parvez, Hannah F Wiegand, Liuhui Wu, Sabine Stehling, Astrid Borchert, Junlin Yang, Polamarasetty Aparoy, Hartmut Kuhn.

  Lipoxygenases (ALOX) convert free polyenoic fatty acids to bioactive mediators, which induce phenotypic alterations in target cells. However, the intracellular concentrations of free fatty acids are very low since these compounds are either rapidly esterified with coenzyme-A. The acyl-CoA esters are subsequently used for re-acylation via the Lands cycle or they are trans-esterified to acyl carnitines for mitochondrial import. Whether acyl carnitines and acyl-CoA derivatives might also serve as ALOX substrates has not been explored. In the present study, we prepared six different wildtype mammalian ALOX-isoforms and a selected enzyme mutant, incubated the recombinant proteins in vitro with free arachidonic acid, arachidonoyl-carnitine and arachidonoyl-coenzyme A and quantified the amounts of primary oxygenation products. We found that for most ALOX-isoforms arachidonoyl-carnitine was oxygenated with a similar rate as free arachidonic acid and that the chemical structures of the primary oxygenation products were identical. In contrast, arachidonoyl-coenzyme A was oxygenated with a 3-5-fold lower rate but here again highly specific patterns of primary oxygenation products were formed. In silico docking studies and molecular dynamics simulations suggested that free arachidonic acid and arachidonoyl-carnitine are similarly aligned at the active site of rabbit ALOX15 but binding of arachidonoyl-coenzyme A was sterically hindered because of the bulkiness of the CoA moiety. Taken together, our data indicate that acyl carnitines and fatty acid coenzyme A esters are suitable lipoxygenase substrates and that these compounds are oxygenated to isoform-specific patterns of primary oxygenation products.

Keywords:  acyl carnitines; coenzyme A; eicosanoids; lipid peroxidation; lipoxygenases; oxidative stress

DOI:  https://doi.org/10.1016/j.jlr.2025.100861
J Neurochem. 2025 Jul;169(7): e70160

Dissection of Neurochemical Pathways Across Complexity and Scale.

Alice Abbondanza, Nawon Kim, Ricardo A S Lima-Filho, Azin Amin, Roberta G Anversa, Felipe Borges Almeida, Pablo L Cardozo, Giovanna Carello-Collar, Emma V Carsana, Royhaan O Folarin, Sara Guerreiro, Olayemi K Ijomone, Sodiq K Lawal, Isadora Matias, Smart I Mbagwu, Sandra A Niño, Bolanle F Olabiyi, Sunday Y Olatunji, Tosin A Olasehinde, Waralee Ruankham, William N Sanchez, Carina Soares-Cunha, Paula A Soto, Jazmín Soto-Verdugo, Nathan R Strogulski, Weronika Tomaszewska, Cármen Vieira, Adriano Chaves-Filho, Michael A Cousin, Ago Rinken, Tyler J Wenzel.

  The field of Neurochemistry spent decades trying to understand how the brain works, from nano to macroscale and across diverse species. Technological advancements over the years allowed researchers to better visualize and understand the cellular processes underpinning central nervous system (CNS) function. This review provides an overview of how novel models, and tools have allowed Neurochemistry researchers to investigate new and exciting research questions. We discuss the merits and demerits of different in vivo models (e.g., Caenorhabditis elegans, Drosophila melanogaster, Ratus norvegicus, and Mus musculus) as well as in vitro models (e.g., primary cells, induced pluripotent stem cells, and immortalized cells) to study Neurochemical events. We also discuss how these models can be paired with cutting-edge genetic manipulation (e.g., CRISPR-Cas9 and engineered viral vectors) and imaging techniques, such as super-resolution microscopy and new biosensors, to study cellular processes of the CNS. These technological advancements provide new insight into Neurochemical events in physiological and pathological contexts, paving the way for the development of new treatments (e.g., cell and gene therapies or small molecules) that aim to treat neurological disorders by reverting the CNS to its homeostatic state.

Keywords:   C. elegans ; Drosophila ; biosensors; gene therapy; iPSCs; super‐resolution microscopy

DOI:  https://doi.org/10.1111/jnc.70160
J Exp Biol. 2025 Jul 22. pii: jeb.250422. [Epub ahead of print]

High altitude induces a shift from complex I to complex II in the brain mitochondria of newborn and adult mice.

Maud Demarest, Fernanda Aliaga-Raduan, Christian Arias-Reyes, Marcelino Gonzales, Edith M Schneider Gasser, Jorge Soliz, Vincent Joseph.

  Species living at high altitude (HA) often exhibit optimized oxygen utilization at adulthood, however, the plasticity of metabolic pathways during postnatal development remains unclear. Because mice, but not rats are commonly found at HA, we investigated mitochondrial oxygen consumption rates (OCR) in the cerebral cortex across postnatal development and at adulthood at sea level (SL, Quebec, Canada) under normoxia or hypoxia (13.5% O2), and at HA (La Paz, Bolivia, 3600m) after 50 generations of residency. At postnatal day 7 (P7), 14 (P14), 21 (P21) and in adults (P60-90), fresh tissue samples were used to assess mitochondrial OCR under states of proton LEAK (OCRLEAK(N)) and oxidative phosphorylation (OXPHOS) using substrates for complex I (N pathway - OCRN), complex II (S pathway - OCRS), and complexes I+II (NS pathways - OCRNS). Our results showed 1) At HA, rats exhibit higher OCR at P7, P14, and at adulthood compared to their SL counterparts, and 2) HA residency induces a shift from the N pathway to the S pathway at all ages in mice. Finally, these responses were absent in SL animals exposed to postnatal hypoxia, highlighting the importance to study HA-living species. These findings emphasize key metabolic shifts, with implications for understanding responses to hypoxia in species showing divergent success at HA.

Keywords:  Brain cortex; High altitude; Mitochondria; Postnatal development; Rodents.

DOI:  https://doi.org/10.1242/jeb.250422
J Neurosci Res. 2025 Jul;103(7): e70071

Metabolic and Structural Alterations in the Motor System Following Spinal Cord Injury: An In-Vivo 1H-MR Spectroscopy Investigation.

Simon Schading-Sassenhausen, Anna Lebret, Kadir Şimşek, Pauline Gut, Sabrina Imhof, Björn Zörner, Roland Kreis, Patrick Freund, Maryam Seif.

  Spinal cord injury (SCI) disrupts spinal tracts and neuronal pathways, including those in the primary motor cortex (M1) and the lumbar cord enlargement (LCE) involved in motor control. This study sought to determine whether metabolite concentrations deviate between SCI and healthy controls (HC) in M1 and LCE using proton magnetic resonance spectroscopy (1H-MRS) and structural MRI, and if these correlate with clinical impairment. Sixteen chronic SCI (mean age: 54.7 ± 14.8y) and 19 HCs (mean age: 53.2 ± 18.8y) underwent 1H-MRS to quantify metabolites along with T1- and T2*-weighted MRI to assess tissue structural changes. Associations between metabolic and structural changes and clinical impairment were also assessed. Patients showed significant atrophy in both white matter of the LCE (HC: 37.7 ± 4.7 mm2, SCI: 33.9 ± 3.7 mm2, Δ = -10.1%, p = 0.015) and gray matter (HC: 20.9 ± 2.1 mm2, SCI: 19.4 ± 1.5 mm2, Δ = -7.2%, p = 0.022). Total N-acetylaspartate (tNAA) with respect to total creatine (tCr) was reduced in M1 of SCI (HC: 1.94 ± 0.21, SCI: 1.77 ± 0.14, ∆ = -8.8%, p = 0.006) and in the LCE (HC: 2.48 ± 0.76, SCI: 1.81 ± 0.80, ∆ = -27.0%, p = 0.02). In conclusion, reduced tNAA/tCr in both the atrophied LCE and M1 suggests widespread neuronal changes including cell atrophy and/or cell loss after injury. These findings provide in vivo evidence for retrograde and trans-synaptic neurodegeneration, which may underline the atrophy observed in the motor system in SCI. Ultimately, this highlights the potential for metabolic and structural biomarkers to improve the monitoring of subtle neurodegeneration following SCI and to enhance future regenerative treatment strategies.

Keywords:  1H‐MR spectroscopy; lumbar cord; motor dysfunction; spinal cord injury

DOI:  https://doi.org/10.1002/jnr.70071