Biology subjects

Rosenhek-Goldian, I.

Publications and source records attributed to Rosenhek-Goldian, I..

6 recordsLinked to original sources

bioRxiv2025

Extracellular Vesicles Mediate Glucose Regulation by GLUT4-Overexpressing Engineered Muscle Tissue in T2D Mice

1Type 2 diabetes (T2D) is characterized by impaired glucose uptake in skeletal muscle and adipose tissues, which contributes to systemic hyperglycemia. GLUT4 is a crucial component in insulin-stimulated glucose uptake and its expression as well as translocation are impaired in T2D onset. This study explored the role of extracellular vesicles (EVs) derived from GLUT4-overexpressing engineered muscle constructs (G4OE-EMC) in glucose metabolism. G4OE-EMC-derived EVs enhanced glucose uptake and insulin sensitivity both in vitro, when tested on wild-type (WT) engineered muscle constructs, and in vivo using the diet-induced obesity (DIO) mouse model. Proteomic and transcriptomic analyses revealed that the EVs were enriched in IGF1 and contained reduced levels of miRNAs, such as miR-122-5p, miR-16-5p, and miR-486-5p, which target IGF1R. The multi-omic approach used here suggests a mechanism whereby G4OE-EMC-derived EVs enhance glucose metabolism via IGF1 signaling and miRNA-mediated regulation of IGF1R expression, offering a potential therapeutic strategy for T2D.

bioengineering↗

bioRxiv2025

Persistent ECM Scarring Reprograms Intestinal Stem Cells to Drive Chronic Inflammation

Tissue regeneration is conventionally viewed as a return to homeostasis. Here, we uncover that the extracellular matrix (ECM) in the colon undergoes a lasting pathological reprogramming following inflammation, forming a remodeled niche--modECM--that persistently disrupts intestinal stem cell (ISC) identity. Using temporal multi-omics, biomechanical profiling, and spatial fate mapping in murine colitis models, we show that modECM, characterized by Collagen XVIII accumulation and immune-driven proteolysis, redirects ISCs toward a wound-associated, squamous-like epithelial state with pro-inflammatory transcriptional signatures. Ex vivo, modECM alone reprograms ISC fate by suppressing Wnt signaling and activating immune recruitment pathways. In vivo, modECM-rich zones sustain T cell infiltration and KRT14 epithelial cell emergence from Lgr5 progenitors. This aberrant epithelial program is mirrored in inflamed rectal biopsies from ulcerative colitis patients. Our findings redefine the ECM as a long-lived instructive compartment that encodes injury memory and promotes maladaptive regeneration, positioning it as a potential therapeutic target in chronic inflammatory disease.

immunology↗

bioRxiv2025

Non-Invasive Mechanical-Functional Analysis of Individual Liver Mitochondria by Atomic Force Microscopy

Mitochondria play a pivotal role in energy production, signaling, and apoptosis. Yet, probing their functional state at the single-organelle level without invasive labels remains a major challenge. Here, we introduce a novel, label-free approach that leverages Atomic Force Microscopy (AFM) beyond its traditional imaging role, transforming it into a powerful tool for functional analysis of individual, isolated mitochondria. By immobilizing mouse liver mitochondria on polylysine-coated mica, we achieved nanoscale resolution of mitochondrial mechanical properties including height, height fluctuation power spectra, and Youngs modulus, under different respiratory states. Strikingly, fluctuations in mitochondrial height fluctuations below 20 Hz showed robust correlation with the mitochondria membrane potential ({Delta}{Psi}m), a cornerstone of mitochondrial function. This relationship allows AFM to sensitively detect changes in the mitochondria bioenergetic status. Applying this method to mitochondria from liver-specific MTCH2 liver-conditional knockout mice, a model of mitochondrial malfunction, we confirmed AFMs diagnostic potential. The technique reliably distinguished malfunctional mitochondria, mirroring and adding new insights beyond conventional fluorescence assays. By bridging nanomechanics and mitochondrial bioenergetics, this approach paves the way for non-invasive, high-resolution diagnostics at the single-organelle level, holding promise to monitor the actual functional state of mitochondria in clinical settings.

biophysics↗

bioRxiv2023

Sound-mediated nucleation and growth of amyloid fibrils

Mechanical energy, specifically in the form of ultrasound, can induce pressure variations and temperature fluctuations when applied to an aqueous media. These conditions can both positively and negatively affect protein complexes, consequently altering their stability, folding patterns, and self-assembling behavior. Despite much scientific progress, our current understanding of the effects of ultrasound on the self-assembly of amyloidogenic proteins remains limited. In the present study, we demonstrate that when the amplitude of the delivered ultrasonic energy is sufficiently low, it can induce refolding of specific motifs in protein monomers, which is sufficient for primary nucleation; this has been revealed by MD. These ultrasound-induced structural changes are initiated by pressure perturbations and are accelerated by a temperature factor. Furthermore, the prolonged action of low-amplitude ultrasound enables the elongation of amyloid protein nanofibrils directly from natively folded monomeric lysozyme protein, in a controlled manner, until it reaches a critical length. Using solution X-ray scattering, we determined that nanofibrillar assemblies, formed either under the action of sound or from natively fibrillated lysozyme, share identical structural characteristics. Thus, these results provide insights into the effects of ultrasound on fibrillar protein self-assembly and lay the foundation for the potential use of sound energy in protein chemistry. Significance StatementUnderstanding how and why proteins form amyloid fibrils is crucial for research into various diseases, including neurodegeneration. Ultrasound is routinely used in research settings as a tool for generating amyloid seeds (nucleation sites) from mature fibrils, which accelerate the rate of fibril growth. However, ultrasound can have various effects on aqueous media including temperature, extreme shear, and free radicals. Here we show that when the ultrasound parameters are precisely adjusted, they can be utilized as a tool for amyloid growth directly from the natively folded monomers. Thus, it is possible to induce minor changes in the folding of proteins, which trigger nucleation and accelerate amyloid growth. This knowledge lays the foundation for the potential use of sound in protein chemistry.

biochemistry↗

bioRxiv2022

Yeast Mitochondrial Derived Vesicles (MDVs) have membrane potential and contain a functional ATP synthase

Vesicular transport is a means of communication. While cells can communicate between each other via secretion of extracellular vesicles, less is known regarding organelle-to organelle communication, in particularly in the case of mitochondria. Mitochondria are responsible for the production of energy and for essential metabolic pathways in the cell, as well as fundamental processes such as apoptosis and aging. Here we show that functional mitochondria, isolated from Saccharomyces cerevisiae release vesicles, independent of the fission machinery. We were then able for the first time to isolate these Mitochondrial Derived Vesicles (MDVs) and found that they are relatively uniform in size, of about 100nm and carry selective protein cargo including enrichment of ATP synthase subunits. Remarkably, we further found that these MDVs harbor a functional ATP synthase complex. Moreover, we demonstrate that these vesicles have a membrane potential, produce ATP, and seem to fuse with naive mitochondria. Our findings reveal a possible delivery mechanism of ATP producing vesicles, which can potentially regenerate ATP deficient mitochondria and may participate in organelle to organelle communication.

cell biology↗

bioRxiv2022

LIS1 RNA-binding orchestrates the mechanosensitive properties of embryonic stem cells in AGO2-dependent and independent ways

Lissencephaly-1 (LIS1) is associated with neurodevelopmental diseases and is known to regulate the activity of the molecular motor cytoplasmic dynein. Here we show that LIS1 is essential for the viability of mouse embryonic stem cells (mESCs), and it regulates the physical properties of these cells. LIS1 dosage substantially affects gene expression, and we uncovered an unexpected interaction of LIS1 with RNA and RNA-binding proteins, most prominently the Argonaute complex. We demonstrate that LIS1 overexpression partially rescued the expression of extracellular matrix (ECM) and mechanosensitive genes conferring stiffness to Argonaute null mESCs. Collectively, our data transforms the current perspective on the roles of LIS1 in post- transcriptional regulation underlying development and mechanosensitive processes.

cell biology↗