Search Results (209)

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic ciliopathy resulting from loss-of-function mutations in the PKD1 and PKD2 genes, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC1 and PC2 regulate mechanosensation, calcium signaling, and key pathways controlling tubular epithelial structure and function. Loss of PC1/PC2 disrupts calcium homeostasis, elevates cAMP, and activates proliferative cascades such as PKA–B-Raf–MEK–ERK, mTOR, and Wnt, driving cystogenesis via epithelial proliferation, impaired apoptosis, fluid secretion, and fibrosis. Recent evidence also implicates novel signaling axes in ADPKD progression including, the Hippo pathway, where dysregulated YAP/TAZ activity enhances c-Myc-mediated proliferation; the stimulator of interferon genes (STING) pathway, which is activated by mitochondrial DNA release and linked to NF-κB-driven inflammation and fibrosis; and the TWEAK/Fn14 pathway, which mediates pro-inflammatory and pro-apoptotic responses via ERK and NF-κB activation in tubular cells. Mitochondrial dysfunction, oxidative stress, and maladaptive extracellular matrix remodeling further exacerbate disease progression. A refined understanding of ADPKD’s complex signaling networks provides a foundation for precision medicine and next-generation therapeutics. This review gathers recent molecular insights and highlights both established and emerging targets to guide targeted treatment strategies in ADPKD. Full article

Mechanosensitive ion channels such as OSCA1.2 enable cells to sense and respond to mechanical forces by translating membrane tension into ionic flux. While lipid rearrangement in the inter-subunit cleft has been proposed as a key activation mechanism, the contributions of other domains to OSCA gating remain unresolved. Here, we combined the genetic encoding of the photoactivatable crosslinker p-benzoyl-L-phenylalanine (BzF) with functional Ca²⁺ imaging and molecular dynamics simulations to dissect the roles of specific residues in OSCA1.2 gating. Targeted UV-induced crosslinking at positions F22, H236, and R343 locked the channel in a non-conducting state, indicating their functional relevance. Structural analysis revealed that these residues are strategically positioned: F22 interacts with lipids near the activation gate, H236 lines the lipid-filled cavity, and R343 forms cross-subunit contacts. Together, these results support a model in which mechanical gating involves a distributed network of residues across multiple channel regions, allosterically converging on the activation gate. This study expands our understanding of mechanotransduction by revealing how distant structural elements contribute to force sensing in OSCA channels. Full article

The multi-domain muscle protein titin provides elasticity and mechanosensing functions to the sarcomere. Titin’s PEVK domain is intrinsically disordered due to the presence of a large number of prolines and highly charged residues. Although PEVK does not have canonical actin-binding motifs, it has been shown to bind F-actin. Here, we explored whether the PEVK domain may also affect actin assembly. We cloned the middle, 733-residue-long segment (called PEVKII) of the full-length PEVK domain, expressed in E. coli and purified by using His- and Avi-tags engineered to the N- and C-termini, respectively. Actin assembly was monitored by the pyrene assay in the presence of varying PEVKII concentrations. The structural features of PEVKII-associated F-actin were studied with atomic force microscopy. The added PEVKII enhanced the initial and log-phase rates of actin assembly and the peak F-actin quantity in a concentration-dependent way. However, the critical concentration of actin polymerization was unaltered. Thus, PEVK accelerates actin polymerization by facilitating its nucleation. This effect was highlighted in the AFM images of F-actin–PEVKII adsorbed to the supported lipid bilayer. The sample was dominated by radially symmetric complexes of short actin filaments. PEVK’s actin polymerization-modulating effect may, in principle, have a function in regulating sarcomeric actin length and turnover. Altogether, titin’s PEVK domain is not only a non-canonical actin-binding protein that regulates sarcomeric shortening, but one that may modulate actin polymerization as well. Full article

In this perspective, we highlight the relevance of the FA-Hippo signaling pathway and its regulation of the Yes-associated protein (YAP) and the transcriptional coactivator with a PDZ-binding domain (TAZ) as main players in the process of implants integration. The modulation and responses of YAP/TAZ triggered by substrate and ECM stiffness are of particular interest in the construction of materials used for medical implants. YAP/TAZ nuclear localization and activity respond to the substrate stiffness by several mechanisms that involve the canonical and non-canonical Hippo signaling and independently of the Hippo cascade. YAP/TAZ regulate the expression of genes involved in several mechanisms of relevance for implant integration such as the proliferation and differentiation of cell precursors and the immune response to the implant. The influence of substrate stiffness on the regulation of the immune response is not completely understood and the progress in this field can contribute to the designing of an adequate implant design. Though the use of nano-biomaterials has been proved to contribute to implant success, the relationship between grain size and stiffness of the material has not been explored in the biomedical field; filling these gaps in the knowledge of biomaterials will highly contribute to the design of biomaterials that could take advantage of the cells sensing and response to the stiffness at the implant interface. Full article

Spindle orientation (SO) plays a critical role in tissue morphogenesis, homeostasis, and tumorigenesis by ensuring accurate division plane positioning in response to intrinsic and extrinsic cues. While SO has been extensively linked to cell shape sensing and cortical forces, the interplay between shape- and force-sensing mechanisms remains poorly understood. Here, we reveal that SO is governed by two parallel mechanisms that ensure redundancy and adaptability in diverse cellular environments. Using live-cell imaging of cultured cells, we demonstrate that the long prometaphase axis (LPA) is a superior predictor of SO compared to the long interphase axis, reflecting adhesive geometry and force distribution efficiently at prometaphase. Importantly, we uncover a pivotal role for focal adhesion kinase (FAK) in mediating cortical mechanosensing to regulate SO in cells undergoing complete metaphase rounding. We show that in cells with complete metaphase rounding, FAK-dependent force sensing aligns the spindle with the major force vector, ensuring accurate division. Conversely, in cells retaining shape anisotropy during mitosis, a FAK-independent shape-sensing mechanism drives SO. These findings highlight a dual regulatory system for SO, where shape sensing and force sensing operate in parallel to maintain division plane fidelity, shedding light on the mechanisms that enable cells to adapt to diverse physical and mechanical environments. Full article

Mechanical forces are increasingly recognised as fundamental regulators of cellular function, complementing classical biochemical cues to direct development, tissue homeostasis, and disease progression. Cells detect external and internal forces via mechanosensor proteins and adapt their cytoskeletal architecture, leading to changes in cell behaviour. Biomaterials and biodevices come to the aid of tailoring biomaterials’ properties in terms of chemical/physical properties and, by emulating dynamical forces, e.g., shear stress and cell swelling, they may enlighten mechanobiological processes. Additionally, emerging technologies expand the experimental toolkit for probing mechanobiological phenomena in complex, customisable settings. Central to these processes are mechanotransducer proteins and membrane–organelle networks that convert mechanical deformation into biochemical signals, orchestrating downstream transcriptional and post-translational modifications. This review highlights how through bridging material engineering and cellular mechanics, mechanobiology provides a unified framework to understand how physical forces shape tissues and drive pathologies. The continued integration of advanced biomaterials, dynamic biodevices, and multiscale analytical methods promises to uncover new mechanistic insights and inform the development of mechanotherapeutic strategies. Full article

During periods of exercise, the primary cause of metabolic acidosis is the accumulation of lactate from anaerobic metabolism, whereas a transient increase in CO₂ triggers a mild respiratory acidosis through the production of carbonic acid (H₂CO₃). The combined effects of these reactions result in a slight acidifying shift in arterial blood pH. Proton-sensing G protein-coupled receptors (including GPR68, GPR4, GPR132, and GPR65) represent the primary receptors within the body for detecting alterations in extracellular proton concentrations. These receptors have been demonstrated to possess potential roles in mechanosensation, intestinal inflammation, oncoimmunological interactions, hematopoiesis, as well as inflammatory and neuropathic pain. Recent studies have shown that the activation or inhibition of these receptors modulates a number of arterial functions, including angiogenesis, arterial relaxation, and arterial inflammation. It is well established that moderate exercise has a beneficial effect on the regulation of arterial function. This study examines the effect of exercise on proton concentrations in the microenvironment of the organism and its influence on proton-sensing G protein-coupled receptors located on cell membranes, as well as possible mechanisms involved in the regulation of arterial function. The objective is to present novel perspectives for the exploration of potential drug targets for the prevention and treatment of arterial dysfunction and the development of exercise regimens. Full article

Cilia are evolutionarily conserved, microtubule-based organelles characterized by their ultrastructures and diverse functional roles, including developmental signaling, mechanosensation, and fluid propulsion. They are widely distributed across cell surfaces and play crucial roles in cell cycle regulation and tissue homeostasis. Despite advances in studying their molecular regulation and functions, demonstrating the precise ultrastructure of cilia remains a challenge. Recent novel microscopy techniques, such as super-resolution microscopy and volume electron microscopy, are revolutionizing our understanding of their architecture and mechanochemical signaling. By integrating findings from different methodologies, this review highlights how these advances bridge basic research and clinical applications and provide a comprehensive understanding of the structural organization, functional mechanisms, and dynamic changes of cilia. Full article

Caveolae are distinctive, flask-shaped structures within the cell membrane that play critical roles in cellular signal transduction, ion homeostasis, and mechanosensation. These structures are composed of the caveolin protein family and are enriched in cholesterol and sphingolipids, creating a unique lipid microdomain. Caveolae contribute to the functional regulation of various ion channels through both physical interactions and involvement in complex signaling networks. Ion channels localized within caveolae are involved in critical cellular processes such as the generation and propagation of action potentials, cellular responses to mechanical forces, and regulation of metabolism. Dysregulation of caveolae function has been linked to the development of various diseases, including cardiovascular disorders, neurodegenerative diseases, metabolic syndrome, and cancer. This review summarizes the ion channel function and regulation in caveolae, and their pathological implications, offering new insights into their potential as therapeutic targets for ion channel-related diseases. Full article

Bone is a highly mechanosensitive tissue, where mechanical signaling plays a central role in maintaining skeletal homeostasis. Mechanotransduction regulates the balance between bone formation and resorption through coordinated interactions among bone cells. Key mechanosensing structures—including the extracellular/pericellular matrix (ECM/PCM), integrins, ion channels, connexins, and primary cilia, translate mechanical cues into biochemical signals that drive bone adaptation. Disruptions in mechanotransduction are increasingly recognized as an important factor in osteoporosis. Under pathological conditions, impaired mechanical signaling reduces bone formation and accelerates bone resorption, leading to skeletal fragility. Defects in mechanotransduction disrupt key pathways involved in bone metabolism, further exacerbating bone loss. Therefore, targeting mechanotransduction presents a promising pharmacological strategy for osteoporosis treatment. Recent advances have focused on developing drugs that enhance bone mechanosensitivity by modulating key mechanotransduction pathways, including integrins, ion channels, connexins, and Wnt signaling. A deeper understanding of mechanosignaling mechanisms may pave the way for novel therapeutic approaches aimed at restoring bone mass, mechanical integrity, and mechanosensitive bone adaptation. Full article

The International CCN Society has been organizing workshops and conferences for the past two decades to advance our understanding of the biology and pathophysiology of the cellular communication network (CCN) proteins. The 12th CCN Workshop broadened the scope of discussions, introducing topics like CCN-dependent and -independent signaling networks involved in brain development, cellular senescence, efferocytosis, neurobiology, and the application of DNA-fabricated origami structures. This expansion proved fruitful and should continue in future events. Fostering collaborations across various fields has created a dynamic environment for innovative ideas, driving substantial progress to tackle both basic scientific questions and clinically relevant challenges. Three standout presentations sparked significant discussions and highlighted key advancements in these areas. These include the work of Li-Jen Lee (Neurobiology and Cognitive Science Center, National Taiwan University) on the involvement of the CCN2 protein in depressive and aggressive behaviors in mice; the studies of Anna Zampetaki (King’s College London British Heart Foundation Centre, School of Cardiovascular & Metabolic Medicine and Sciences) and Brahim Chaqour (University of Pennsylvania, Perelman School of Medicine, Dept of Molecular Ophthalmology) on the metabolome and mechanosensing in iPSC-derived human blood vessel organoids and in the microvasculature of genetically modified mice, and the talk of Björn Högberg (Karolinska Institutet, Department of Medical Biochemistry and Biophysics) on the promises of DNA origami. We believe that these examples illustrate better future directions, as they offer an opportune moment to pursue initiatives that broaden the focus of the CCN Workshops and other projects like ARBIOCOM (website link included below) that support collaboration among research societies, educational institutions, and private biomedical industries, all working together to further our understanding of biosignaling and cellular communication networks for the development of new drug discovery methods and disease treatments. Full article

von Willebrand factor (vWF) is a large glycoprotein in the circulation system, which senses hydrodynamic force at vascular injuries and then recruits platelets in assembling clots. How vWF mechanosenses shear flow for molecular unfolding is an important topic. Here, a Förster resonance energy transfer (FRET) biosensor was developed to monitor vWF conformation change to hydrodynamic force. The vWF-based biosensor is anchored on the cell surface, in which the A2 domain is flanked with a FRET pair. With 293T cells seeded into microfluidic channels, 2.8 dyn/cm² of shear force (i.e., 28 μN/cm², or 264.1/s in shear rate) induced a remarkable FRET change (~60%) in 30 min. A gradient micro-shear below 2.8 dyn/cm² demonstrated FRET responses positively related to flow magnitudes, with 0.14 dyn/cm² (1.4 μN/cm²) inducing an obvious change (~16%). The FRET increases indicate closer positioning of A2’s two terminals in vWF or the addition of a more parallel orientation of the FRET pair, supported with the high FRET of the A2-only-based biosensor, which probably resulted from flow-induced A2 dissociation from vWF intramolecular binding such as that in A1/A3 domains. Interestingly, gradient flow increases from 2.8 to 28 dyn/cm² led to decreasing FRET changes, suggesting the second-level unfolding in the A2 domain. The LOCK-vWF biosensor with bridged A2 two terminals or an A2-only biosensor could not sense the shear, indicating a structure-flexible A2 and large vWF molecules that are important in the mechanosensation. In conclusion, the developed vWF-based biosensor demonstrated the high mechanosensation of vWF with two-level unfolding to shear force: the dissociation of the A2 domain from vWF intramolecular binding under a micro-shear, and then the unfolding of A2 in vWF under a higher shear; the FRET response to shear force at a very low scale may support the observed clot formation at microvascular wounds. This study provides new insights into the vWF’s mechanosensitive feature for its physiological functions and implicated disorders. Full article

Background/Objectives: Human-driven selection has shaped modern horse breeds into highly specialized athletes, particularly in racing. Arabian horses, renowned for their endurance, provide an excellent model for studying molecular adaptations to exercise. This study aimed to identify genes commonly influenced by physical exertion in the gluteus medius muscle and whole blood of Arabian horses during their first year of race training. Methods: RNA sequencing of sixteen pure-breed Arabian horses was used to analyze transcriptomic changes at three key training stages. Differentially expressed genes (DEGs) were identified to explore their role in endurance and metabolic adaptation. Results: Seven genes—RCHY1, PIH1D1, IVD, FABP3, ANKRD2, USP13, and CRYAB—were consistently deregulated across tissues and training periods. These genes are involved in muscle remodeling, metabolism, oxidative stress response, and protein turnover. ANKRD2 was associated with mechanosensing and muscle adaptation, FABP3 with fatty acid metabolism, and USP13 with ubiquitination-related pathways crucial for muscle recovery and energy regulation. The transcriptomic overlap between muscle and blood suggests potential systemic biomarkers for athletic performance and endurance. Conclusions: Our findings highlight the importance of multi-tissue transcriptomic profiling in understanding exercise-induced molecular adaptations. The identified genes warrant further investigation as potential molecular markers for monitoring training progression and athletic potential in endurance horses. This study contributes to the growing field of equine sports genetics and may offer translational insights into human sports performance. Full article

The carotid sinus and the carotid body are major peripheral chemo- and baro(mechano)receptors that sense changes in arterial wall pressure and in oxygen, carbon dioxide, and pH in arterial blood. Recently, it was demonstrated that the PIEZO1 and PIEZO2 mechanoreceptor/mechanotransducers are responsible for the baroreflex in the murine aortic arch (aortic sinus). Furthermore, some experimental evidence suggests that the carotid body could participate in mechanosensing. In this study, we used immunohistochemistry and immunofluorescence in conjunction with laser confocal microscopy to study the distribution of PIEZO1 and PIEZO2 in the human carotid sinus and carotid body as well as in the petrosal ganglion of the glossopharyngeal nerve and the superior cervical sympathetic ganglion. PIEZO1 and PIEZO2 were detected in different morphotypes of sensory nerve formations in the walls of the carotid sinus and carotid artery walls. In the carotid body, PIEZO1 was present in a small population of type I glomus cells and absent in nerves, whereas PIEZO2 was present in both clusters of type I glomus cells and nerves. The most prominent expression of PIEZO1 and PIEZO2 in the carotid body was found in type II glomus cells. On the other hand, in the petrosal ganglion, around 25% of neurons were PIEZO1-positive, and around 85% were PIEZO2-positive; regarding the superior cervical sympathetic ganglion, around 71% and 86% displayed PIEZO1 and PIEZO2, respectively. The results of this study suggest that PIEZO1 and PIEZO2 could be involved in the detection and/or mechanotransduction of the human carotid sinus, whereas the role of the carotid body is more doubtful since PIEZO1 and PIEZO2 were only detected in some nerves and PIEZO2 was present in a small population of type I glomus cells, with PIEZO1 being absent in these cells. However, since immunoreactivity for PIEZO2 was detected in type II glomus cells, researchers should investigate whether these cells play a role in the detection of mechanical stimuli and/or participate in mechanotransduction. Full article

Individual cells and cells within the tissues and organs constantly face mechanical challenges, such as tension, compression, strain, shear stress, and the rigidity of cellular and extracellular surroundings. Besides the external mechanical forces, cells and their components are also subjected to intracellular mechanical forces, such as pulling, pushing, and stretching, created by the sophisticated force-generation machinery of the cytoskeleton and molecular motors. All these mechanical stressors switch on the mechanotransduction pathways, allowing cells and their components to respond and adapt. Mechanical force-induced changes at the cell membrane and cytoskeleton are also transmitted to the nucleus and its nucleoskeleton, affecting nucleocytoplasmic transport, chromatin conformation, transcriptional activity, replication, and genome, which, in turn, orchestrate cellular mechanical behavior. The memory of mechanoresponses is stored as epigenetic and chromatin structure modifications. The mechanical state of the cell in response to the acellular and cellular environment also determines cell identity, fate, and immune response to invading pathogens. Here, we give a short overview of the latest developments in understanding these processes, emphasizing their effects on cell nuclei, chromosomes, and chromatin. Full article