bims-medebr 2025-08-10 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–08–10
eleven papers selected by
Regina F. Fernández, Johns Hopkins University

Sex-Specific recurrent insulin-induced hypoglycemia (RIIH) effects on ventromedial hypothalamic nucleus astrocyte metabolic sensor expression and glycogen metabolism.
Lipid and Lipoprotein Metabolism in Microglia: Alzheimer's Disease Mechanisms and Interventions.
Blood and Neuronal Extracellular Vesicle Mitochondrial Disruptions in Schizophrenia.
Modulating the serine metabolism in human differentiated astrocytes: an integrated multi omics approach.
Erratum: Analysis of mitochondrial Complex I activity and ATP hydrolysis capacity of ATP synthase in developing rat brains using frozen tissues.
The significance of glycemic variability in conjunction with lactate metabolism levels in the clinical assessment of neonatal hypoxic-ischemic encephalopathy.
Strategies to rescue mitochondria in Parkinson's disease: The significance of mitochondrial transfer.
Microglia-to-neuron signaling increases lipid droplet metabolism, enhancing neuronal network activity.
Effect of Hyperbaric Oxygen Treatment on Lipid Metabolism and Neurovascular Microenvironment in an Apolipoprotein E Knockout Mouse Model.
Microglia-neuron crosstalk via Hex-GM2-MGL2 maintains brain homeostasis.
ATP allosterically regulates an acyl-CoA oxidase.

Neuroscience. 2025 Aug 01. pii: S0306-4522(25)00825-5. [Epub ahead of print]

Sex-Specific recurrent insulin-induced hypoglycemia (RIIH) effects on ventromedial hypothalamic nucleus astrocyte metabolic sensor expression and glycogen metabolism.

Sushma Katakam, Subash Sapkota, Madhu Babu Pasula, Rami Shrestha, Rajesh Yadav, Karen P Briski.

  Brain astrocytes support neuron energy stability by maintaining an energy reserve and by catabolizing glucose to the transferrable oxidizable fuel L-lactate. Astrocyte-neuron metabolic coupling shapes ventromedial hypothalamic nucleus (VMN) counterregulatory neurotransmission. VMN astrocyte involvement in recurring insulin-induced hypoglycemia (RIIH)-associated sex-specific acclimation of these neurochemical signals is unclear. Current research implemented combinatory in situ immunocytochemistry/laser-catapult-microdissection/Western blotting and micropunch-dissection/HPLC-electrospray ionization-mass spectrometry methods to investigate whether RIIH alters VMN astrocyte glucose sensing and glycogen metabolism according to sex. Data disclose distinctive effects of single and repetitive hypoglycemia exposure on glucose transporter-2, glucokinase, and total/phosphorylated 5'-AMP-activated protein kinase protein profiles in dorsomedial (dm) versus ventrolateral (vl) VMN astrocytes. Acute hypoglycemia down-regulated VMNdm and VMNvl astrocyte glycogen synthase protein; in each sex, this inhibitory response was abolished (VMNdm) or persisted (VMNvl) during RIIH. Singular hypoglycemia respectively up- or down-regulated glycogen phosphorylase-brain (GPbb) and -muscle type (GPmm) proteins in female VMN astrocytes, responses that were correspondingly amplified by or refractory to RIIH. Male astrocytes exhibited RIIH-associated habituation of VMNdm GPbb (inhibitory) and GPmm (stimulatory) responses to hypoglycemia. Acute hypoglycemia amplified (male) or decreased (female) glycogen levels in each VMN division. RIIH exacerbated (VMNdm) or normalized (VMNvl) glycogen augmentation in males, yet reversed glycogen diminution in the female VMNdm, not VMNvl. Results show that RIIH elicits VMN division-specific adjustments in male and female astrocyte glucose and energy sensing functions and tissue glycogen content. Further research is needed to examine whether precedent hypoglycemia-associated acclimation of VMNdm and/or VMNvl astrocyte glucose handling controls sex-specific counterregulatory neurotransmission and hormone secretion during RIIH.

Keywords:  Astrocyte; Glycogen; LC-ESI-MS; Laser-catapult-microdissection; Recurrent insulin-induced hypoglycemia; Ventromedial hypothalamic nucleus

DOI:  https://doi.org/10.1016/j.neuroscience.2025.07.042
J Lipid Res. 2025 Aug 04. pii: S0022-2275(25)00134-8. [Epub ahead of print] 100872

Lipid and Lipoprotein Metabolism in Microglia: Alzheimer's Disease Mechanisms and Interventions.

Kayla G Sprenger, Emma E Leitzke, John T Melchior, Kimberley D Bruce.

  Alzheimer's disease (AD) presents a significant challenge owing to its widespread prevalence and complex neuropathogenesis, affecting millions worldwide. Current therapeutic strategies that predominantly target amyloid-beta accumulation are insufficient, particularly for ApoE4 carriers. Alterations in lipid composition are well-documented in AD, characterized by reductions in phospholipids and sulfatides, along with increases in cholesterol, cholesteryl esters, and triglycerides. Microglia, the brain's resident immune cells, link dysfunctional lipid processing to AD neuropathogenesis. For example, genetic studies have pointed to microglial lipid and lipoprotein processing gene variants as some of the strongest risk factors for AD. In addition, microglial dysfunction, characterized by lipid droplet accumulation, increased cholesterol and triglyceride levels, and altered lipid transport, may exacerbate the pathological hallmarks of AD, such as amyloid-beta and tau accumulation. Conversely, emerging studies have shown that strategies aimed at inhibiting lipid-droplet accumulation in microglia, reducing triglyceride synthesis, and promoting the activity of lipoprotein receptors expressed by microglia can improve cell functions and markers of AD pathology. This review dissects the interplay between microglial lipid metabolism and AD, highlighting the significance of lipid transport and trafficking within the central nervous system. Given the intrinsic link between microglial metabolism and AD progression, emerging and potential therapeutic strategies aimed at altering lipid handling and improving microglial function are explored. This review provides a comprehensive examination of emerging literature, detailing the current state of knowledge on microglial lipid metabolism, its genetic underpinnings, and the potential for novel interventions targeting these mechanisms to ameliorate AD pathology.

Keywords:  Alzheimer’s disease; Microglia; apolipoproteins; lipids; lipoproteins

DOI:  https://doi.org/10.1016/j.jlr.2025.100872
bioRxiv. 2025 Jul 31. pii: 2025.07.30.667452. [Epub ahead of print]

Blood and Neuronal Extracellular Vesicle Mitochondrial Disruptions in Schizophrenia.

A Ankeeta, Ashutosh Tripathi, Bindu Pillai, Yizhou Ma, Joshua J Chiappelli, Jessica N Jernberg, Keiko Kunitoki, Xiaoming Du, Si Gao, Bhim M Adhikari, Consuelo Walss-Bass, Giselli Scaini, Peter Kochunov, Anilkumar Pillai, L Elliot Hong.

The high energy demand of the human brain obligates robust mitochondrial energy metabolism, while mitochondrial dysfunctions have been linked to neuropsychiatric disorders including schizophrenia spectrum disorders (SSD). However, in vivo assessments that can directly inform brain mitochondrial functioning and its etiopathophysiological path to SSD remain difficult to obtain. We hypothesized that system and brain mitochondrial dysfunctions in SSD may be indexed by elevated cell-free mitochondrial DNA (cf-mtDNA) levels in the blood and in neuronal extracellular vesicles (nEVs). We also explored if these mtDNA marker elevations were associated brain metabolites as measured by magnetic resonance spectroscopy (MRS). We examined blood cf-mtDNA in 58 SSD patients and 33 healthy controls, followed by assessing nEV mtDNA and metabolite levels using MRS in a subgroup of patients and controls. We found that people with SSD had significantly elevated cf-mtDNA levels in both the blood (p=0.0002) and neuronal EVs (p=0.003) compared to controls. These mtDNA abnormalities can be linked back to brain lactate+ levels such that higher blood and nEV mtDNA levels were significantly associated with higher lactate+ levels measured at the anterior cingulate cortex (r=0.53, 0.53; p=0.008, 0.03, respectively) in SSD patients. Furthermore, higher developmental stress and trauma were significantly associated with higher cf-mtDNA levels in both the blood and neuronal EVs in SSD patients (r=0.29, 0.49; p=0.01, 0.03, respectively). In conclusion, if replicated and fully developed, blood and neuronal EV-based cell free mtDNA may provide a clinically accessible biomarker to more directly evaluate the mitochondrial hypothesis and the abnormal bioenergetics pathways in schizophrenia.

DOI: https://doi.org/10.1101/2025.07.30.667452
Front Cell Neurosci. 2025 ;19 1616911

Modulating the serine metabolism in human differentiated astrocytes: an integrated multi omics approach.

Farida Tripodi, Elisa Maffioli, Silvia Sacchi, Valentina Rabattoni, Zoraide Motta, Claudia Bearzi, Gabriella Tedeschi, Loredano Pollegioni, Paola Coccetti.

   Introduction: Astrocytes are the major source of L-serine (L-Ser) in the brain: the glycolytic intermediate D-3-phosphoglycerate is converted into L-Ser through the phosphorylated pathway (PP) made up of three enzymes, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT) and phosphoserine phosphatase (PSP), recently proposed to generate a metabolic assembly named serinosome. In the central nervous system, L-Ser is used for a number of functions, including the synthesis of glycine (Gly) and D-serine (D-Ser), the two key NMDAR co-agonists.
Methods: Here, we used iPSC-derived human astrocytes as a cellular model to evaluate the impact on cell metabolism of the overexpression of each of the three enzymes of the PP as GFP-tagged proteins.
Results: The subcellular cytosolic localization of PP enzymes remains unchanged compared to endogenous proteins, while the complex formation is increased in all cases. Notably, among the factors involved, the overexpression of PHGDH appears to play a pivotal role in promoting the serinosome assembly and/or stabilization, highlighting the critical importance of this multi-domain protein. Particularly, the overexpression of each enzyme of the PP alters the cellular metabolism in a specific way. The L-Ser and Gly levels increase more in PHGDH overexpressing cells, in agreement with the known kinetics of the PP. A consistent increase in the TCA cycle, as well as in mitochondrial activities, serine-glycine-one carbon pathway, asparagine, arginine, purine and pyrimidines metabolism is also observed.
Discussion: Peculiar alterations are observed when each enzyme of the PP is overexpressed, strongly supporting the use of human iPSC-derived astrocytes overexpressing the PP pathway enzymes as a valuable cellular model for understanding how Ser glial metabolism occurs in a non-tumor system under both physiological and pathological conditions.

Keywords:  human differentiated astrocytes; metabolism; metabolomics; phosphorylated pathway; proteomics; serinosome

DOI:  https://doi.org/10.3389/fncel.2025.1616911
MicroPubl Biol. 2025 ;2025

Erratum: Analysis of mitochondrial Complex I activity and ATP hydrolysis capacity of ATP synthase in developing rat brains using frozen tissues.

[This corrects the article DOI: 10.17912/micropub.biology.001641.].

DOI: https://doi.org/10.17912/micropub.biology.001787
Sci Rep. 2025 Aug 08. 15(1): 29072

The significance of glycemic variability in conjunction with lactate metabolism levels in the clinical assessment of neonatal hypoxic-ischemic encephalopathy.

Lili Zhang, Chuanhua Wang, Qi Jia, Hui Li, Fudong Wang, Lijun Jiang.

  The disruption of cerebral cellular energy metabolism represents the initial phase in the pathogenesis of neonatal hypoxic-ischemic encephalopathy (HIE). This study aimed to investigate the significance of glycemic variability (GV) and lactate (LAC) metabolic levels for early assessment of HIE. A retrospective study was conducted on asphyxiated neonates admitted to our hospital from January 2018 to January 2024. Neonates ultimately diagnosed with HIE were categorized into the HIE group, while those excluded from the HIE diagnosis were allocated to the control group. GV was assessed using the difference between maximum and minimum (max-min), standard deviation (SD), and coefficient of variation (CV). Lactate clearance rate (LCR) was used as an indicator of lactate metabolism. We found that GLU CV and LCR were independent risk factors for brain injury following asphyxia. The combination of GLU CV and LCR demonstrated a sensitivity of 84.2% and specificity of 78.6% in predicting HIE, and achieved a sensitivity of 90.0% and specificity of 61.1% in predicting moderate-severe HIE. Early monitoring of GV and LAC levels can serve as valuable indicators for predicting neonatal HIE and assessing disease severity.

Keywords:  Asphyxia; Glycemic variability; Hypoxic-ischemic encephalopathy; Lactate clearance rate; Lactic acid; Newborn

DOI:  https://doi.org/10.1038/s41598-025-14871-7
Ageing Res Rev. 2025 Aug 05. pii: S1568-1637(25)00202-8. [Epub ahead of print]112 102856

Strategies to rescue mitochondria in Parkinson's disease: The significance of mitochondrial transfer.

Junhan Liang, Zhaoqin Su, Gongmeiyue Su, Madiha Rasheed, Shiyi Tang, Hafsa Sunniya, Mohamed Maazouzi, Yaoyuan Cui, Junxiao Wang, Xuezhe Wang, Jing Yang, Mingchao Ding, Zhao Li, Yulin Deng.

  Parkinson's disease (PD) is a common neurodegenerative disorder characterized by dopaminergic neuronal degeneration and pathological α-synuclein accumulation. Mitochondrial dysfunction is a central feature in PD pathogenesis, contributing to impaired bioenergetics, oxidative stress, neuroinflammation, and defective organelle communication. This review synthesizes the current understanding of mitochondrial quality control mechanisms, including fission, fusion, mitophagy, and biogenesis, and their disruption in PD. Particular emphasis is placed on the role of intercellular mitochondrial transfer as a compensatory mechanism. Emerging evidence suggests that mitochondria can be transferred between neurons and glial cells through tunneling nanotubes, extracellular vesicles, and gap junctions, offering protective effects by restoring metabolic function and attenuating cellular stress. We examine the molecular mediators of these transfer pathways, the influence of PD-associated mutations, and the bidirectional dynamics between donor and recipient cells. Additionally, we explore translational strategies, including mitochondrial transplantation, bioengineered mitochondria, and stem cell-based delivery systems. While preclinical models demonstrate promising therapeutic outcomes, clinical translation faces challenges, including targeting specificity, mitochondrial viability, and immune compatibility. By integrating mechanistic insights with therapeutic developments, this review highlights mitochondrial transfer as a novel and promising approach in the future treatment of PD, potentially addressing longstanding limitations in conventional neuroprotective strategies.

Keywords:  Future therapies; Mitochondria transfer; Mitochondrial dysfunction; Parkinson’s disease; Quality control

DOI:  https://doi.org/10.1016/j.arr.2025.102856
bioRxiv. 2025 Aug 03. pii: 2025.08.03.668224. [Epub ahead of print]

Microglia-to-neuron signaling increases lipid droplet metabolism, enhancing neuronal network activity.

Ana P Verduzco Espinoza, Na Na, Loraine Campanati, Priscilla Ngo, Kristin Kay Baldwin, Hollis Tremaine Cline.

Microglia regulate neuronal circuit plasticity. Disrupting their homeostatic function has detrimental effects on neuronal circuit health. Neuroinflammation contributes to the onset and progression of neurodegenerative diseases, including Alzheimers disease, with several microglial activation genes linked to increased risk for these conditions. Inflammatory microglia alter neuronal excitability, inducing metabolic strain. Interestingly, expression of APOE4, the strongest genetic risk factor for Alzheimers disease, affects both microglial activation and neuronal excitability, highlighting the interplay between lipid metabolism, inflammation, and neuronal function. It remains unclear how microglial inflammatory state is conveyed to neurons to affect circuit function and whether APOE4 expression alters this intercellular communication. Here, we use a reductionist model of human iPSC-derived microglial and neuronal monocultures to dissect how the APOE genotype in each cell-type independently contributes to microglial regulation of neuronal activity during inflammation. Conditioned media from LPS-stimulated microglia increased neuronal network activity, assessed by calcium imaging, with APOE4 microglial conditioned media driving higher neuronal firing rates than APOE3 conditioned media. Both APOE3 and APOE4 neurons increase network activity in response to conditioned media treatments, while APOE4 neurons uniquely increase presynaptic puncta with APOE4 microglial conditioned media. Conditioned media-derived exosomes from LPS-stimulated microglia can mediate increases to network activity. Lastly, increased network activity is accompanied by increased lipid droplet metabolism and blocking lipid droplet metabolism abolishes network activity. These findings illuminate how microglia-to-neuron communication drives inflammation-induced changes in neuronal circuit function, demonstrate a role for neuronal lipid droplets in network activity, and support a potential mechanism through which APOE4 increases neuronal excitability.

DOI: https://doi.org/10.1101/2025.08.03.668224
J Integr Neurosci. 2025 Jul 28. 24(7): 39656

Effect of Hyperbaric Oxygen Treatment on Lipid Metabolism and Neurovascular Microenvironment in an Apolipoprotein E Knockout Mouse Model.

Guoying Dong, Yuxiao Liu, Huijun Liu, Chen Qiao, Xia Chen, Linxiao Wang.

   BACKGROUND: Dyslipidemia during midlife represents a significant risk factor for neuropathological alterations associated with cognitive decline. Given the currently incurable nature of dementia, implementation of preventive strategies and early therapeutic interventions prior to disease progression are paramount. Emerging evidence suggests that hyperbaric oxygen (HBO) therapy exhibits neuroprotective properties in various neurological conditions. However, whether HBO treatment modulates lipid metabolism dysregulation and subsequent neurodegeneration remains unanswered. This investigation aimed to elucidate the therapeutic potential of HBO treatment in ameliorating cerebral dysfunction and metabolic perturbations using apolipoprotein E (ApoE)-deficient (ApoE-/-) mice.
METHODS: ApoE-/- mice received HBO treatment for 10 consecutive days, and then behavioral assessment tests were performed. Serum and brain tissue were collected to measure oxidative stress levels and inflammatory factors.
RESULTS: Compared with ApoE-/- group, cognitive declines was significantly reversed in mice of the ApoE-/-+HBO mice. The blood lipid profiles of ApoE-/- mice were also improved after HBO treatment, accompanied by a reduction in body weight. Moreover, HBO treatment was found to ameliorates neuronal injury and amyloid-β deposition in the hippocampus of ApoE-/- mice. Further studies have revealed that the benefits of HBO treatment occurred through the reduction of inflammatory factors and attenuation of oxidative stress.
CONCLUSIONS: These findings indicate that HBO treatment effectively improves the intracerebral microenvironment of ApoE-/- mice, providing a novel regulatory mechanism of protection against dyslipidemia-associated brain deficits by HBO treatment.

Keywords:  apolipoprotein E; cognitive dysfunction; dyslipidemias; hyperbaric oxygenation; inflammation

DOI:  https://doi.org/10.31083/JIN39656
Nature. 2025 Aug 06.

Microglia-neuron crosstalk via Hex-GM2-MGL2 maintains brain homeostasis.

Maximilian Frosch, Takashi Shimizu, Emile Wogram, Lukas Amann, Lars Gruber, Ayelén I Groisman, Maximilian Fliegauf, Marius Schwabenland, Chintan Chhatbar, Sabrina Zechel, Hendrik Rosewich, Jutta Gärtner, Francisco J Quintana, Joerg M Buescher, Thomas Blank, Harald Binder, Christine Stadelmann, Johannes J Letzkus, Carsten Hopf, Takahiro Masuda, Klaus-Peter Knobeloch, Marco Prinz.

As tissue resident macrophages of the central nervous system (CNS) parenchyma, microglia perform diverse essential functions during homeostasis and perturbations1. They primarily interact with neurons via synaptic engulfment and through the rapid elimination of apoptotic cells and nonfunctional synapses2. Here, by combining unbiased lipidomics and high resolution spatial lipid imaging, deep single-cell transcriptome analysis and novel cell type-specific mutants, we identified a previously unknown mode of microglial interaction with neurons. During homeostasis, microglia deliver the lysosomal enzyme β-hexosaminidase (Hex) to neurons for the degradation of the ganglioside GM2 that is integral to maintaining cell membrane organization and function. Absence of Hexb, encoding the β subunit of Hex, in both mice and patients suffering from neurodegenerative Sandhoff disease leads to a massive accumulation of GM2 derivatives in a characteristic spatiotemporal manner3. In mice, neuronal GM2 gangliosides subsequently engage the macrophage galactose-type lectin (MGL)2 receptor on microglia via N-acetylgalactosamine (GalNAc) residues, leading to lethal neurodegeneration. Notably, replacement of microglia with peripherally derived microglia-like cells (MLCs) is able to break this degenerative cycle and fully restore CNS homeostasis. Our results reveal a novel mode of bidirectional microglia-neuron communication centred around GM2 ganglioside turnover, identify a novel microgliopathy and offer novel therapeutic avenues for these maladies.

DOI: https://doi.org/10.1038/s41586-025-09477-y
Nat Commun. 2025 Aug 08. 16(1): 7318

ATP allosterically regulates an acyl-CoA oxidase.

David H Perez, Arup Mondal, Weijie Xu, Valentina Baredes, Hannah E Connell, Alberto Perez, Rebecca A Butcher.

ATP is an important allosteric regulator of many enzymes, but these enzymes typically utilize ATP or other nucleotides as substrates. Acyl-CoA oxidase (ACOX) enzymes are central players in peroxisomal fatty acid metabolism, as well as in secondary metabolism in nematodes and plants. These dimeric enzymes have been shown to bind to ATP at unusual sites that are buried at the dimer interface. Here, we show that ATP stimulates the activity of an ACOX enzyme by increasing the binding affinity of the enzyme for its FAD cofactor. The effect of ATP is highly specific as other nucleotides do not stimulate the activity of the enzyme and mutation of the ATP binding site blocks the effect. We use X-ray crystallography and molecular dynamics simulations of the apo dimeric enzyme to identify an unprecedented mechanism whereby ATP can reach its binding site through a shift in an α-helix bundle. An allosteric network connects the ATP and FAD binding sites, enabling ATP to enhance FAD binding affinity and thus enzymatic activity. In summary, the binding of ACOX enzymes to FAD is allosterically controlled by ATP, potentially providing a link between ATP levels and primary and secondary metabolism.

DOI: https://doi.org/10.1038/s41467-025-61905-9