Biology subjects

Morozova, K.

Publications and source records attributed to Morozova, K..

6 recordsLinked to original sources

bioRxiv2026

Bayesian Network Analysis Identifies PREX1 as a Master Regulator of Cytoskeletal Disruption in Inflammatory Bowel Disease

BackgroundInflammatory bowel diseases are complex multifactorial and polygenic conditions with incompletely understood etiology. Transcriptomic and metabolomic studies reveal hundreds of genes and metabolites associated with the inflammatory dowel diseases (IBD), while about 240 genetic loci are associated with these diseases. IBD are accompanied by numerous epithelial lesions including epithelial cells damage and barrier dysfunction. Recent studies suggest that cytoskeleton dysregulation underlies these aspects of IBD. We have previously shown that the disruption of cortical actin filaments and microvilli degeneration are characteristic of Muc2 mouse IBD model. MethodsWe used transmission electron microscopy to evaluate ultrastructural defects in the intestinal epithelium of IBD patients. A probabilistic graphical model (Bayesian network) was employed in order to identify the key gene network hierarchy that might define cytoskeletal architecture among other regulatory events in IBD. The Bayesian network was based on preselected key node genes from open access transcriptomic data obtained in patients with Crohns disease. ResultsElectron microscopy of IBD patients demonstrated disruption of the brush border ultrastructure, similar to the microvillar defects previously described in Muc2 colitis model mice. We highlighted a list of genes contributing to actin polymerization and bundling, of which PREX1 were further confirmed using the transcriptome data obtained from Muc2 mice. ConclusionOur study underscores the utility of Bayesian network analysis in complex cellular phenotypes that helped to identify potential target genes responsible for cortical cytoskeleton and microvilli disruption upon chronic intestinal inflammation.

bioinformatics↗

bioRxiv2026

F-actin dynamics couples sphingolipid metabolism to epithelial barrier integrity in chronic colitis

BackgroundIntestinal barrier dysfunction is a hallmark of inflammatory bowel diseases (IBD). This condition causes intoxication and immune hyperactivation. Understanding the events underlying epithelial barrier disruption during chronic inflammation is key to developing barrier-restoring therapies. Filamentous actin (F-actin) is essential for maintaining polarity and junctional integrity. However, the contribution of F-actin dynamics to IBD-associated barrier dysfunction remains unclear. ObjectiveWe aimed to examine actin cytoskeleton integrity during chronic colitis across mouse models and human patients and identify potential regulators of cytoskeleton dynamics. DesignF-actin and junctional proteins were analyzed in three models of chronic colitis (Muc2 KO, DSS-induced colitis, adoptive transfer colitis) using confocal microscopy. Claudin-3 interactors were identified by immunoprecipitation and proteomics. Intestinal organoids were used to assess the effect of F-actin disruption on barrier integrity. Metabolomic and gene expression analyses identified candidate pathways, further validated by chemical inhibition. Biopsies from patients with ulcerative colitis (UC) were examined using transmission electron microscopy and confocal microscopy. ResultsDisrupted actin dynamics emerged as a critical driver of epithelial barrier dysfunction in chronic colitis. An imbalance between polymeric and monomeric actin impaired barrier integrity in vivo and in 3D organoids. Immunoprecipitation identified actin and associated factors as the primary interactors of claudin-3 with reduced interaction during inflammation. Ceramide metabolism was revealed as a potential regulator of F-actin and intestinal barrier. In UC patients, we confirmed concurrent disruption of junctions and F-actin. ConclusionsF-actin dysregulation contributes to barrier dysfunction in IBD and targeting its modulators, including ceramide biosynthesis, represents a novel therapeutic strategy. WHAT IS ALREADY KNOWN ON THIS TOPICO_LIEpithelial damage and increased paracellular permeability are key characteristics of inflammatory bowel diseases. C_LIO_LIParacellular permeability is partially attributed to the downregulation of junction proteins but this mechanism does not explain all clinical observations. C_LIO_LIIn the Muc2 KO mouse model of chronic colitis, F-actin organization and membrane localization of tight junction protein claudin-3 are disrupted, although protein expression levels remain unchanged. C_LI WHAT THIS STUDY ADDSO_LIF-actin dynamics is impaired in the intestinal epithelium across three different mouse models of chronic colitis and IBD patients. C_LIO_LIDisruption of F-actin dynamics leads to impaired membrane localization of tight and adherens junction proteins and increased intestinal epithelial permeability in vivo and in colonic organoids. C_LIO_LIInhibition of ceramide biosynthesis rescues F-actin polymerization and intestinal barrier integrity in mouse chronic colitis models. C_LI HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYO_LITargeting F-actin dynamics is a promising approach to improve gut epithelial integrity. C_LIO_LI"Ceramide-F-actin-junction" axis is proposed as one of the mechanisms behind epithelial barrier disruption in colitis. Therapeutic targeting of this axis represents a promising path for restoring gut integrity. C_LI

cell biology↗

bioRxiv2026

Cell type-specific proximity labeling of organ secretomes reveals energy balance-dependent proteomic remodeling.

Intercellular communication is critical for maintaining organismal metabolic homeostasis. Here, we present a new method enabling temporally controlled, cell type-specific labeling of secreted and membrane proteins in key metabolic tissues. The method employs a genetically encoded proximity-labeling strategy by targeting a Cre-dependent TurboID ligase to the endoplasmic reticulum (ER) in ES cell-derived mice. Expression of TurboID in liver, adipose tissue, and spleen enabled the characterization of organ-specific ER proteomes at baseline and in response to fasting, inflammation, and dietary obesity, revealing tissue-and perturbation-specific changes and augmenting our understanding of how the proteomes of individual tissues change to regulate systemic energy balance. This comprehensive resource represents an important advance toward understanding both how cell-to-cell communication changes in response to energy homeostasis and how it contributes to these alterations. This method is broadly applicable and provides a means for identifying biomarkers and therapeutic targets across a wide range of tissues.

physiology↗

bioRxiv2024

Cerebral perfusion and metabolic response of astrocytes and neurons during locomotion

The hemodynamic response links neural oxidative metabolism changes to increased cerebral blood flow during brain activity1. Although Roy and Sherrington introduced this concept over a century ago (1890), the exact cellular mechanisms remain unclear. This study demonstrates how local blood supply increases correlate with the metabolic response of individual brain cells during locomotion. Using Raman microspectroscopy, we observed an elevation in oxygen saturation levels (sO2) in cortical venules but not in arterioles, which were already near saturation. The increased sO2 in the venules was accompanied by vasodilation, indicating blood oversupply in the local brain area, a phenomenon known as functional hyperemia. We then analyzed the metabolic response of individual neurons and astrocytes to locomotion. In neurons, the levels of reduced cytochromes of c and b types [cyt c,b (Fe2+)] rapidly decreased at the onset of locomotion. This suggests an increase in the activity of the mitochondrial respiratory chain (electron transport chain, ETC) in response to heightened energy demands in these cells2. In contrast, because astrocytes rely less on oxidative phosphorylation for their energy metabolism than neurons3, we did not observe an initial decrease in reduced cytochromes in these cells. However, as locomotion continued, the cyt c,b (Fe2+) levels steadily increased in both cell types. In neurons, this led to a slow recovery from the initial drop, while in astrocytes, the increase exceeded baseline levels. Consequently, we observed an overload of electrons in the astrocytic ETC. The distinct responses of astrocytic and neuronal mitochondria to locomotion may reflect differences in the organization of the ETC in the two cell types4. Furthermore, astrocytes may shift to glycolysis under increased neuronal activity5,6. This difference also resulted in hydrogen peroxide (H202) production in astrocytic mitochondria but not neuronal mitochondria. Since H202 is a signaling molecule critical for cognitive function in the brain7, we speculate that astrocytic mitochondria act as signaling hubs during exercise.

neuroscience↗

bioRxiv2022

Aging impairs astrocytes in the human cerebral cortex

How aging affects cellular components of the human brain active milieu remains largely unknown. We analyzed astrocytes and neurons in the neocortical access tissue of younger (22 - 50 years) and older (51 - 72 years) adult patients who underwent glioma resection. Aging decreased the amount of reduced mitochondrial cytochromes in astrocytes but not neurons. The total amount of protein was decreased in astrocytes and increased in neurons. Aged astrocytes showed morphological dystrophy quantified by the decreased length of branches, decreased volume fraction of leaflets, and shrinkage of the anatomical domain. Dystrophy correlated with the loss of gap junction coupling between astrocytes and increased input resistance. Aging was accompanied by the upregulation of glial fibrillary acidic protein (GFAP) and downregulation of membrane-cytoskeleton linker Ezrin associated with leaflets. No significant changes in neuronal excitability or spontaneous inhibitory postsynaptic signaling were observed. Thus, brain aging is associated with the impaired morphological presence and mitochondrial malfunction of astrocytes, but not neurons.

neuroscience↗

bioRxiv2021

A high-fat diet changes astrocytic metabolism to enhance synaptic plasticity and promote exploratory behavior

A high-fat diet (HFD) is generally considered to negatively influence the body, the brain, and cognitive abilities. On the other hand, fat and fatty acids are essential for nourishing and constructing brain tissue. Astrocytes are central for lipolysis and fatty acids metabolism. Here we show that exposure of young mice to one month of HFD elevates lipid content and increases the relative amount of reduced cytochromes in astrocytes but not in neurons. Metabolic changes were paralleled with an enlargement of astrocytic territorial domains due to an increased outgrowth of branches and leaflets. Astrocyte remodeling was associated with an increase in expression of ezrin and with no changes in glial fibrillary acidic protein (GFAP), glutamate transporter-1 (GLT-1), and glutamine synthetase (GS). Such physiological (non-reactive) enlargement of astrocytes in the brain active milieu promoted glutamate clearance and long-term potentiation. These changes translated into improved exploratory behavior. Thus, dietary fat intake is not invariably harmful and might exert beneficial effects depending on the biological context. In BriefA high-fat diet stimulates the metabolism and growth of astrocytes, which improves glutamate clearance, synaptic plasticity, and exploratory behavior in young mice. Thus, dietary fat arguably is an essential component of the diet for children and young adults, supporting the optimal development of the brain. HighlightsO_LIExposure of young mice to a high-fat diet elevated lipid content and increased amount of reduced cytochromes in astrocytes but not in neurons. C_LIO_LIMetabolic changes were paralleled with an enlargement of astrocytic territorial domains due to an increased outgrowth of branches and leaflets. C_LIO_LIAstrocytic enlargement was associated with increased expression of ezrin but not GFAP, hence was not reactive but physiological C_LIO_LIExpansion of astrocytes in the brain active milieu improved glutamate clearance and long-term potentiation. C_LIO_LIThe high-fat diet improved exploratory behavior in young mice. C_LI

neuroscience↗