bims-medebr 2025-06-01 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–06–01
fifteen papers selected by
Regina F. Fernández, Johns Hopkins University

Mitochondria: the hidden engines of traumatic brain injury-driven neurodegeneration.
Myelin Lipid Composition in the Central Nervous System Is Regionally Distinct and Requires Mechanistic Target of Rapamycin Signaling.
Deciphering the brain glucose metabolism: A gateway to innovative stroke therapies.
Hypoxia-ischemia and sexual dimorphism: modeling mitochondrial dysfunction using brain organoids.
Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy.
Clinical Use of Hypertonic Lactate - Current Evidence and Emerging Perspectives.
Neurogenin 2-induced central neurons from iPSC-established patients with NPC display attenuated neurite outgrowth while accumulating cholesterol.
Deficiency in the conserved ECHS1 gene causes Leigh syndrome by impairing mitochondrial respiration efficiency and suppressing ADRB2-PKA signaling.
The Ferroptosis-Mitochondrial Axis in Depression: Unraveling the Feedforward Loop of Oxidative Stress, Metabolic Homeostasis Dysregulation, and Neuroinflammation.
Lipid metabolism in health and disease: Mechanistic and therapeutic insights for Parkinson's disease.
Effects of lauric acid on cognitive impairment in a scopolamine-induced Alzheimer's disease-like rat model.
Metabolic flux analysis of glioblastoma neural stem cells reveals distinctive metabolic phenotypes in ketogenic conditions.
From Obesity to Mitochondrial Dysfunction in Peripheral Tissues and in the Central Nervous System.
Rab11a-dependent recycling of Glut3 inhibits seizure-induced neuronal disulfidptosis by alleviating glucose deficiency.
SLC35A2 loss-of-function variants affect glycomic signatures, neuronal fate and network dynamics.

Front Cell Neurosci. 2025 ;19 1570596

Mitochondria: the hidden engines of traumatic brain injury-driven neurodegeneration.

Olusola A Olatona, Sydney P Sterben, Sahan B S Kansakar, Aviva J Symes, Volha Liaudanskaya.

  Mitochondria play a critical role in brain energy metabolism, cellular signaling, and homeostasis, making their dysfunction a key driver of secondary injury progression in traumatic brain injury (TBI). This review explores the relationship between mitochondrial bioenergetics, metabolism, oxidative stress, and neuroinflammation in the post-TBI brain. Mitochondrial dysfunction disrupts adenosine triphosphate (ATP) production, exacerbates calcium dysregulation, and generates reactive oxygen species, triggering a cascade of neuronal damage and neurodegenerative processes. Moreover, damaged mitochondria release damage-associated molecular patterns (DAMPs) such as mitochondrial DNA (mtDNA), Cytochrome C, and ATP, triggering inflammatory pathways that amplify tissue injury. We discuss the metabolic shifts that occur post-TBI, including the transition from oxidative phosphorylation to glycolysis and the consequences of metabolic inflexibility. Potential therapeutic interventions targeting mitochondrial dynamics, bioenergetic support, and inflammation modulation are explored, highlighting emerging strategies such as mitochondrial-targeted antioxidants, metabolic substrate supplementation, and pharmacological regulators of mitochondrial permeability transition pores. Understanding these mechanisms is crucial for developing novel therapeutic approaches to mitigate neurodegeneration and enhance recovery following brain trauma.

Keywords:  bioenergetics; brain injury; metabolism; mitochondria; neurodegeneration

DOI:  https://doi.org/10.3389/fncel.2025.1570596
Glia. 2025 May 26.

Myelin Lipid Composition in the Central Nervous System Is Regionally Distinct and Requires Mechanistic Target of Rapamycin Signaling.

Marie L Mather, Angelina V Evangelou, Jennifer N Bourne, Wendy B Macklin, Teresa L Wood.

  Cholesterol is highly enriched in the myelin sheath and is often dysregulated in neurodegenerative diseases affecting myelin integrity. Despite the prominence of promyelinating drugs targeting sterol synthesis and our increasing knowledge of oligodendrocyte heterogeneity, few studies have defined regional differences in lipid metabolism across the CNS. Previous analyses revealed that spinal cord oligodendroglia have a higher capacity for endogenous cholesterol biosynthesis compared to brain oligodendroglia. Our current findings reveal that, in contrast to spinal cord oligodendroglia, brain oligodendroglia have a higher capacity to uptake and respond to extracellular lipoproteins. Moreover, brain myelin has lower lipid concentrations compared to spinal cord myelin. Comparisons between spinal cord and subregions of the brain revealed that myelin lipid content is correlated to average axon diameter such that regions with smaller diameter axons, such as corpus callosum and cortical gray matter, have myelin with lower cholesterol and phospholipid content compared to regions containing higher diameter axons, including spinal cord and brain stem. When differentiated on synthetic nanofibers in vitro, spinal cord oligodendrocytes maintained a higher cholesterol content compared to brain oligodendrocytes irrespective of fiber diameter but displayed fiber diameter-dependent changes in fatty acid content. Establishment and maintenance of regional differences in myelin composition are supported by the mechanistic target of rapamycin (mTOR) signaling, as deletion of mTOR in oligodendroglia abolishes regional differences in myelin lipid content, with the greatest decreases in spinal cord and brain stem. These data highlight multiple differences in brain and spinal cord lipid metabolism, which result in regionally distinct myelin composition.

Keywords:  astrocyte; cholesterol; myelin; oligodendrocyte

DOI:  https://doi.org/10.1002/glia.70042
J Cereb Blood Flow Metab. 2025 May 29. 271678X251346277

Deciphering the brain glucose metabolism: A gateway to innovative stroke therapies.

Didier F Pisani, Nicolas Blondeau.

  Stroke is the leading cause of physical disability and death among adults in most Western countries. Consecutive to a vascular occlusion, cells face a brutal reduction in supply of oxygen and glucose and thus an energy failure, which in turn triggers cell death mechanisms. Among brain cells, neurons are the most susceptible to ischemia because of their high metabolic demand and low reservoir of energy substrates. In neurons, glycolysis uses glucose coming from blood or from glycogen stored in astrocytes, underlying the deep astrocyte-neuron metabolic cooperation. During ischemia, both the aerobic and anaerobic pathways and thus energy production are compromised, which disrupts proper cell functioning, notably Na+/K+ ATPase and mitochondria. This results in altered Ca2+ homeostasis and overproduction of ROS, the latter being further exacerbated during the reperfusion phase. Consequently, glucose metabolism in the different brain cell populations plays a central role in injury and recovery after stroke, and has recently emerged as a promising target for therapeutic intervention. In this context, the overall objective of this article is to review the interconnections between stroke and brain glucose metabolism and to explore how its targeting may offer new therapeutic opportunities in addressing the global stroke epidemic.

Keywords:  Cerebral ischemia; glycolysis; neuroprotective agents; oxidative stress; pentose phosphate pathway; reperfusion

DOI:  https://doi.org/10.1177/0271678X251346277
Cell Biosci. 2025 May 24. 15(1): 67

Hypoxia-ischemia and sexual dimorphism: modeling mitochondrial dysfunction using brain organoids.

Romane Gaston-Breton, Clémence Disdier, Henrik Hagberg, Aloïse Mabondzo.

  Hypoxic-ischemic encephalopathy (HIE) is a leading cause of neurodevelopmental morbidities in full-term infants. There is strong evidence of sexual differences in hypoxic-ischemic (HI) injury where male neonates are at higher risk as they are subject to more pronounced neurological deficits and death than females. The cellular and molecular mechanisms underlying these sexual discrepancies in HI injury are poorly understood. Mitochondrial dysregulation has been increasingly explored in brain diseases and represents a major target during HI events. In this review, we discuss (1) different mitochondrial functions in the central nervous system (2), mitochondrial dysregulation in the context of HI injury (3), sex-dependent mitochondrial pathways in HIE and (4) modeling of mitochondrial dysfunction using human brain organoids. Gaining insight into these novel aspects of mitochondrial function will offer valuable understanding of brain development and neurological disorders such as HI injury, paving the way for the discovery and creation of new treatment approaches.

Keywords:  Brain organoid; Hypoxic-ischemic encephalopathy; Mitochondria; Sexual differences

DOI:  https://doi.org/10.1186/s13578-025-01402-0
Genes (Basel). 2025 May 17. pii: 590. [Epub ahead of print]16(5):

Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy.

Pierre Bougnères, Catherine Le Stunff.

   BACKGROUND: X-ALD is a white matter (WM) disease caused by mutations in the ABCD1 gene encoding the transporter of very-long-chain fatty acids (VLCFAs) into peroxisomes. Strikingly, the same ABCD1 mutation causes either devastating brain inflammatory demyelination during childhood or, more often, progressive spinal cord axonopathy starting in middle-aged adults. The accumulation of undegraded VLCFA in glial cell membranes and myelin has long been thought to be the central mechanism of X-ALD.
METHODS: This review discusses studies in mouse and drosophila models that have modified our views of X-ALD pathogenesis.
RESULTS: In the Abcd1 knockout (KO) mouse that mimics the spinal cord disease, the late manifestations of axonopathy are rapidly reversed by ABCD1 gene transfer into spinal cord oligodendrocytes (OLs). In a peroxin-5 KO mouse model, the selective impairment of peroxisomal biogenesis in OLs achieves an almost perfect phenocopy of cerebral ALD. A drosophila knockout model revealed that VLCFA accumulation in glial myelinating cells causes the production of a toxic lipid able to poison axons and activate inflammatory cells. Other mouse models showed the critical role of OLs in providing energy substrates to axons. In addition, studies on microglial changing substates have improved our understanding of neuroinflammation.
CONCLUSIONS: Animal models supporting a primary role of OLs and axonal pathology and a secondary role of microglia allow us to revisit of X-ALD mechanisms. Beyond ABCD1 mutations, pathogenesis depends on unidentified contributors, such as genetic background, cell-specific epigenomics, potential environmental triggers, and stochasticity of crosstalk between multiple cell types among billions of glial cells and neurons.

Keywords:  VLCFA; X-adrenoleukodystrophy; cerebral demyelination; neuroinflammation; oligodendrocytes; peroxisomes; spinal cord axonopathy

DOI:  https://doi.org/10.3390/genes16050590
J Clin Endocrinol Metab. 2025 May 29. pii: dgaf321. [Epub ahead of print]

Clinical Use of Hypertonic Lactate - Current Evidence and Emerging Perspectives.

Mette Glavind Bülow Pedersen, Jens Hohwü Voigt, Esben Søndergaard, Niels Møller, Nikolaj Rittig.

   CONTEXT: Lactate has traditionally been viewed as a metabolic byproduct associated with metabolic acidosis, exercise-induced fatigue, and cancer metabolism. However, accumulating evidence highlights its valuable role as an alternative fuel and a key signaling molecule. Hypertonic sodium lactate infusions have gained interest for their potential therapeutic applications, particularly in neurology and cardiology. This review examines the established and potential clinical uses of exogenous hypertonic lactate treatment.
EVIDENCE ACQUISITION: A literature search was conducted in PubMed and Medline using the keywords: hypertonic lactate, half-molar sodium lactate, sodium lactate, and exogenous lactate.The search was limited to human studies investigating hypertonic sodium lactate solutions with a lactate concentration ≥500 mmol/L as an intervention. Case reports, pediatric studies, preclinical research, and studies in psychiatric populations were excluded.
EVIDENCE SYNTHESIS: Infusion of hypertonic lactate has demonstrated promising effects across several clinical settings, serving as an alternative fuel for the brain that supports up to 20% of cerebral energy metabolism. In patients with traumatic brain injury (TBI), lactate treatment increases cerebral glucose availability, reduces intracranial pressure, and enhances cognitive recovery. In the heart, lactate infusion increases cardiac output, stroke volume, and ejection fraction, potentially benefiting heart failure patients. Hypertonic lactate infusions are generally well tolerated, with minor electrolyte changes as the most common side effect.
CONCLUSIONS: Lactate is emerging as a therapeutic agent beyond its traditional role in metabolism. Hypertonic sodium lactate infusions have potential therapeutic benefits within neurology and cardiology, but large-scale trials are required to evaluate efficacy, optimize dosing, and assess long-term safety.

Keywords:  clinical application; hypertonic lactate; sodium lactate

DOI:  https://doi.org/10.1210/clinem/dgaf321
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 May 26. pii: S1388-1981(25)00047-2. [Epub ahead of print] 159639

Neurogenin 2-induced central neurons from iPSC-established patients with NPC display attenuated neurite outgrowth while accumulating cholesterol.

Miki Igarashi, Takashi Miyajima, Chen Wu, Takeo Iwamoto, Yoshikatsu Eto.

  Niemann-Pick disease type C (NPC) is a lysosome disease hallmarked by autosomal recessive mutations in the NPC1 or NPC2 genes. It results in the accumulation of unesterified cholesterol in the late endosome/lysosome compartment, and then induces progressive neurodegeneration in affected individuals. Previous studies have primarily used fibroblasts derived from NPC patients to examine the cellular pathology and test therapeutic agents. However, the neurodegenerative aspect of the disease should be clarified using an in vitro system that recapitulates the cellular mechanisms underlying the neuronal defects. In this study, we generated iPSCs from NPC patients, and differentiated them into neurons to examine the pathological and biological defects in NPC neurons. Five iPSCs (3 NPC and 2 healthy individuals) carrying a doxycycline-inducible NGN2 (iPSCsTetON:NGN2) were generated, and edited cells efficiently differentiated into cortical neurons by 15 days. Although the standard differentiated culture method did not show any phenotypic features in NPC neurons, human-derived low-density lipoprotein (LDL) treatment exhibited cellular pathological features, including the accumulation of unesterified cholesterol and impaired neurite outgrowth. Miglustat, a drug approved for NPC in several countries, promoted neurite outgrowth and reduced unesterified cholesterol accumulation in LDL-treated NPC neurons. Using our model, two drugs among an FDA-approved drug library attenuated the pathological defects by LDL treatment. Collectively, our results indicate that neurons of NPC patients fail neurite extension due to suboptimal cholesterol transport to the membrane. This will be a valuable tool for NPC research to identify the pathological mechanisms of neuronal degeneration and to discover new therapeutics.

Keywords:  Cholesterol; Lysosome; NPC; Neuron; iPSC

DOI:  https://doi.org/10.1016/j.bbalip.2025.159639
Biochim Biophys Acta Mol Basis Dis. 2025 May 28. pii: S0925-4439(25)00278-9. [Epub ahead of print] 167930

Deficiency in the conserved ECHS1 gene causes Leigh syndrome by impairing mitochondrial respiration efficiency and suppressing ADRB2-PKA signaling.

Baojiang Wang, Yueyuan Qin, Yantao Bao, Shiguo Chen, Junge Zheng, Sheng Lin, Kaifeng Zheng, Shan Duan.

  Deficiency in the short-chain enoyl-CoA hydratase 1 (ECHS1) gene causes Leigh Syndrome (LS), a rare inherited metabolic disorder. Despite LS that arises as a result of inborn errors of energy metabolism, the specific contributions of ECHS1 deficiency to energy metabolism processes, developmental delay, and its mediated signaling mechanism remain unclear. Here, we identify a novel compound heterozygous variant [c.724G > A (p.Glu242Lys) and c.865G > A (Asp289Asn)] in the ECHS1 gene from a family of Han Chinese descent, with the affected individual displaying typical LS symptoms. The ECHS1 variants exhibit reduced 2-enoyl-CoA hydratase activity, resulting in a restricted ATP production rate, but the cellular ATP levels remains unchanged. ECHS1 deficiency also decreases cell viability and proliferation. Mechanistically, ECHS1 interacts with ADRB2, and its variants suppress the ADRB2/protein kinase A (PKA) signaling. Treatment with PKA signaling agonists or overexpression of PKA subunits in ECHS1-deficient cells can rescue the ATP production rate and restore cell viability. Additionally, the mitochondrial E3 ligase MUL1 mediates the ubiquitylation and degradation of ECHS1 protein variants. In conclusion, our study suggests that ECHS1 deficiency impairs mitochondrial respiratory efficiency, thereby lowering the ATP production rate, and reveals a promising therapeutic approach by targeting ADRB2/PKA signaling to combat ECHS1 deficiency-induced LS.

Keywords:  ADRB2; Developmental delay; ECHS1 deficiency; Leigh syndrome; Mitochondrial respiration; Neurodegenerative conditions

DOI:  https://doi.org/10.1016/j.bbadis.2025.167930
Antioxidants (Basel). 2025 May 20. pii: 613. [Epub ahead of print]14(5):

The Ferroptosis-Mitochondrial Axis in Depression: Unraveling the Feedforward Loop of Oxidative Stress, Metabolic Homeostasis Dysregulation, and Neuroinflammation.

Xu Liu, Qiang Luo, Yulong Zhao, Peng Ren, Yu Jin, Junjie Zhou.

  Emerging evidence links ferroptosis-mitochondrial dysregulation to depression pathogenesis through an oxidative stress-energy deficit-neuroinflammation cycle driven by iron overload. This study demonstrates that iron accumulation initiates ferroptosis via Fenton reaction-mediated lipid peroxidation, compromising neuronal membrane integrity and disabling the GPx4 antioxidant system. Concurrent mitochondrial complex I/IV dysfunction impairs ATP synthesis, creating an AMPK/mTOR signaling imbalance and calcium dyshomeostasis that synergistically impair synaptic plasticity. Bidirectional crosstalk emerges: lipid peroxidation derivatives oxidize mitochondrial cardiolipin, while mitochondrial ROS overproduction activates ACSL4 to amplify ferroptotic susceptibility, forming a self-reinforcing neurodegenerative loop. Prefrontal-hippocampal metabolomics reveal paradoxical metabolic reprogramming with glycolytic compensation suppressing mitochondrial biogenesis (via PGC-1α/TFAM downregulation), trapping neurons in bioenergetic crisis. Clinical data further show that microglial M1 polarization through cGAS-STING activation sustains neuroinflammation via IL-6/TNF-α release. We propose a "ferroptosis-mitochondrial fragmentation-metabolic maladaptation" triad as mechanistic subtyping criteria for depression. Preclinical validation shows that combinatorial therapy (iron chelators + SIRT3 agonists) rescues neuronal viability by restoring mitochondrial integrity and energy flux. This work shifts therapeutic paradigms from monoaminergic targets toward multimodal strategies addressing iron homeostasis, organelle dynamics, and metabolic vulnerability-a framework with significant implications for developing neuroprotective antidepressants.

Keywords:  depression; disorder of energy metabolism; ferroptosis; iron dysregulation; lipid metabolism disorders; mitochondrial dysfunction; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox14050613
Chin Med J (Engl). 2025 May 26.

Lipid metabolism in health and disease: Mechanistic and therapeutic insights for Parkinson's disease.

Bingqing Qin, Yuan Fu, Ana-Caroline Raulin, Shuangyu Kong, Han Li, Junyi Liu, Chunfeng Liu, Jing Zhao.

   ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons and the accumulation of Lewy bodies, leading to motor and nonmotor symptoms. While both genetic and environmental factors contribute to PD, recent studies highlight the crucial role of lipid metabolism disturbances in disease progression. Altered lipid homeostasis promotes protein aggregation and oxidative stress, with significant changes in lipid classes such as sphingolipids and glycerolipids observed in patients with PD. These disturbances are involved in key pathological processes, such as α-synuclein aggregation, organelle dysfunction, lipid-mediated neuroinflammation, and impaired lipid homeostasis. This review examines the relationship between lipid species and PD progression, focusing on the physiological roles of lipids in the central nervous system. It explores the mechanistic links between lipid metabolism and PD pathology, along with lipid-related genetic risk factors. Furthermore, this review discusses lipid-targeting therapeutic strategies to mitigate PD progression, emphasizing the potential of lipid modulation for effective treatment development.

Keywords:  Cholesterol; Fatty acids; Glycerophospholipids; Lipid metabolism; Lipoproteins; Parkinson’s disease; Sphingolipids

DOI:  https://doi.org/10.1097/CM9.0000000000003627
Nutr Neurosci. 2025 May 26. 1-11

Effects of lauric acid on cognitive impairment in a scopolamine-induced Alzheimer's disease-like rat model.

Fajemidagba Grace Ayobami, Oluwadare Joshua Ogundipe, Ajibade Adewale Emmanuel, Idowu Olumayowa Kolawole.

  Background: Alzheimer's disease (AD) is a multi-factorial type of dementia that poses a social and medical burden in that no effective treatment has been achieved yet. Impaired brain glucose metabolism is one of the major pathophysiological factors linked to its onset and progression. Lauric acid (LA) is a triglyceride with medium chain that can produce ketone body utilize by the brain as an alternative energy source.Objective: Therefore, the present study was carried out with the purpose of evaluating the effect of LA on cognitive impairments in scopolamine-induced AD-like rat model.Methods: Forty-two male Wistar rats were divided into six groups to receive normal saline, scopolamine, scopolamine with Donepezil, and scopolamine with varied doses of LA for a period of 21 days. Morris water maze (MWM) and Elevated Plus Maze (EPM) tests were performed to evaluate cognitive performance. After, brains were harvested and processed to assay for the level of malondialdehyde (MDA), reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), acetylcholinesterase (AChE) and interleukin-6 (IL-6). Histological analyses using Haematoxylin and eosin staining was also performed.Results: The LA-treated groups demonstrated memory retention in the MWM and EPM tests, and showed increased levels of CAT, SOD, and GSH similar to the Donepezil group, in contrast to the scopolamine only group while MDA levels, IL-6, and AChE activity were reduced in the LA treated groups contrasted to scopolamine only group. LA reduces oxidative stress, neuroinflammation, and AChE activity, which indicates a possible ability of LA to protect against AD.

Keywords:  Alzheimer’s disease; cognition; dementia; donepezil‌; lauric acid; scopolamine

DOI:  https://doi.org/10.1080/1028415X.2025.2508775
Sci Rep. 2025 May 28. 15(1): 18736

Metabolic flux analysis of glioblastoma neural stem cells reveals distinctive metabolic phenotypes in ketogenic conditions.

Anna Rushin, Aleezeh Shaikh, Callie Hardin, Loic P Deleyrolle, Matthew E Merritt.

  Glioblastomas (GBM) are the most prevalent primary brain tumors, affecting 5 in every 100,000 people. GBMs optimize proliferation through adaptive cellular metabolism, frequently exploiting the Warburg effect by increasing aerobic glycolysis and glucose utilization to facilitate rapid cell growth. This disproportionate reliance on glucose has driven interest in using the ketogenic diet (KD) as a treatment for GBM. In this study, we explored metabolic flux in three primary human GBM cell samples using a media simulating a KD. Flux analysis using a detailed metabolic modeling approach revealed three unique metabolic phenotypes in the patient GBMs that correlated with cell viability. Notably, these phenotypes are apparent in the flux modeling, but were not evidenced by changes in the metabolite pool sizes. This variability in metabolic flux may underlie the inconsistent results observed in preclinical and clinical studies using the KD as a treatment paradigm.

Keywords:  Cancer biology; Glioblastoma; Isotopic analysis; Ketogenesis; Metabolism

DOI:  https://doi.org/10.1038/s41598-025-02124-6
Biomolecules. 2025 Apr 29. pii: 638. [Epub ahead of print]15(5):

From Obesity to Mitochondrial Dysfunction in Peripheral Tissues and in the Central Nervous System.

Francesca Marino, Lidia Petrella, Fabiano Cimmino, Amelia Pizzella, Antonietta Monda, Salvatore Allocca, Roberta Rotondo, Margherita D'Angelo, Nadia Musco, Piera Iommelli, Angela Catapano, Carmela Bagnato, Barbara Paolini, Gina Cavaliere.

  Obesity is a condition of chronic low-grade inflammation affecting peripheral organs of the body, as well as the central nervous system. The adipose tissue dysfunction occurring under conditions of obesity is a key factor in the onset and progression of a variety of diseases, including neurodegenerative disorders. Mitochondria, key organelles in the production of cellular energy, play an important role in this tissue dysfunction. Numerous studies highlight the close link between obesity and adipocyte mitochondrial dysfunction, resulting in excessive ROS production and adipose tissue inflammation. This inflammation is transmitted systemically, leading to metabolic disorders that also impact the central nervous system, where pro-inflammatory cytokines impair mitochondrial and cellular functions in different areas of the brain, leading to neurodegenerative diseases. To date, several bioactive compounds are able to prevent and/or slow down neurogenerative processes by acting on mitochondrial functions. Among these, some molecules present in the Mediterranean diet, such as polyphenols, carotenoids, and omega-3 PUFAs, exert a protective action due to their antioxidant and anti-inflammatory ability. The aim of this review is to provide an overview of the involvement of adipose tissue dysfunction in the development of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and multiple sclerosis, emphasizing the central role played by mitochondria, the main actors in the cross-talk between adipose tissue and the central nervous system.

Keywords:  Alzheimer’s disease; Parkinson’s disease; adipose tissue; mitochondria; multiple sclerosis; neurodegenerative disorders; obesity

DOI:  https://doi.org/10.3390/biom15050638
Cell Biosci. 2025 May 28. 15(1): 69

Rab11a-dependent recycling of Glut3 inhibits seizure-induced neuronal disulfidptosis by alleviating glucose deficiency.

Sijun Li, Junrui He, Huimin Kuang, Xiaojuan Wang, Muhua Zhou, Dongmei Li, Baoren Kang, Honghu He, Lina He, Wei Lin, Yuan Lv.

  Seizures can trigger neuronal glucose deficiency, thereby inducing disulfidptosis. Disulfidptosis is a novel cell death mechanism characterized by the abnormal accumulation of disulfide caused by glucose deficiency. However, the mechanism underlying disulfidptosis caused by glucose deficiency in seizures remains elusive. Rab11a-dependent recycling of glucose transporter 3 (Glut3) is closely related to glucose metabolism in neurons, which may contribute to neuronal disulfidptosis after seizures by abnormal glucose metabolism. So here we introduced a well-established in vitro model of seizures to evaluate cell survival, glucose levels, disulfidptosis biomarkers, Glut3 and Rab11a expression, the recycling ratio of Glut3, and the protein complex of Glut3-Rab11a. Cell survival rates and glucose levels were lower in the in vitro model of seizures, accompanied by elevated levels of disulfidptosis markers. Moreover, the surface expression and the recycling ratio of Glut3, as well as the protein complex of Glut3-Rab11a, were positively correlated with Rab11a expression. Lastly, Rab11 overexpression improved cell survival rates, increased glucose levels, and decreased the levels of disulfidptosis biomarkers in the in vitro model of seizure. Rab11a-dependent recycling of Glut3 inhibited seizure-induced neuronal disulfidptosis by alleviating glucose deficiency.

Keywords:  Disulfidptosis; Glucose; Neurons; Recycling; Seizures

DOI:  https://doi.org/10.1186/s13578-025-01396-9
Brain. 2025 May 26. pii: awaf198. [Epub ahead of print]

SLC35A2 loss-of-function variants affect glycomic signatures, neuronal fate and network dynamics.

Dulcie Lai, Paulina Sosicka, Damian J Williams, MaryAnn E Bowyer, Andrew K Ressler, Sarah E Kohrt, Savannah J Muron, Peter B Crino, Hudson H Freeze, Michael J Boland, Erin L Heinzen.

  SLC35A2 encodes a UDP-galactose transporter essential for glycosylation of proteins and galactosylation of lipids and glycosaminoglycans. Germline genetic SLC35A2 variants have been identified in congenital disorders of glycosylation and somatic SLC35A2 variants have been linked to intractable epilepsy associated with malformations of cortical development. However, the functional consequences of these pathogenic variants on brain development and network integrity remain unknown. In this study, we use an isogenic human induced pluripotent stem cell-derived neuron model to comprehensively interrogate the functional impact of loss of function variants in SLC35A2 through the integration of cellular and molecular biology, protein glycosylation analysis, neural network dynamics, and single cell electrophysiology. We show that loss of function variants in SLC35A2 result in disrupted glycomic signatures and precocious neurodevelopment, yielding hypoactive, asynchronous neural networks. This aberrant network activity is attributed to an inhibitory/excitatory imbalance as characterization of neural composition revealed preferential differentiation of SLC35A2 loss of function variants towards the GABAergic fate. Furthermore, electrophysiological recordings of synaptic activity and gene expression differences suggest network phenotypes are driven by changes occurring at the synapse. Our study is the first to provide mechanistic insight regarding the early development and functional connectivity of SLC35A2 loss-of-function variant harboring human neurons, providing important groundwork for future exploration of potential therapeutic interventions.

Keywords:  epilepsy; glycosylation; human stem cells; neural network; neurodevelopment

DOI:  https://doi.org/10.1093/brain/awaf198