Cell membrane tension in disease and emerging strategies for its regulation and measurement

Abstract

Cell membrane tension is a fundamental biophysical parameter that governs a wide range of cellular processes, including migration, division, mechanosensitive signaling, and membrane repair. Rather than serving as a passive structural property, membrane tension functions as a dynamic mechanical regulator that integrates cytoskeletal forces, membrane reservoir dynamics, and extracellular mechanical cues to coordinate cell behavior. In this review, we discuss the molecular mechanisms underlying membrane tension regulation, its pathological significance, and the emerging experimental techniques available for its measurement and manipulation. By integrating mechanobiological and disease-oriented perspectives, this review presents a comprehensive framework for understanding how membrane tension is regulated and perturbed in health and disease, and highlights open questions and future directions for the field.

Keywords

membrane tension plasma membrane membrane-cortex attachment actomyosin contractility mechanotransduction

Introduction

Cells have been considered as active mechanical entities that continuously sense, generate, and respond to physical forces.^1,2 The ability of cells to migrate, divide, and organize into tissues depends on the precise coordination of cytoskeletal dynamics, membrane remodeling, and intracellular signaling, all of which are subject to mechanical regulation.³ In particular, central to this mechanical regulation is the plasma membrane as the physical interface between the cell and its environment and a dynamic platform through which mechanical information is received, integrated, and transduced into cellular responses.^2,4 Among the physical properties of the plasma membrane, membrane tension has emerged as a key mechanical integrator, globally coupling membrane geometry to cytoskeletal organization and intracellular signaling.^5,6 It reflects the mechanical state of the plasma membrane encompassing both the in-plane lipid bilayer tension and the membrane–cytoskeleton adhesion energy, and functions as a global physical constraint that links local membrane deformation to cell-wide mechanical responses.⁷

Therefore, membrane tension is a dynamic variable that actively regulates cells, indicating that its precise control is essential for regulating fundamental cellular processes. During cell migration, spatial gradients of membrane tension restrict excessive protrusion formation and establish front–rear polarity, providing the spatial regulation required for coherent organization of actin polymerization across the cell surface.^7,8 Membrane tension similarly couples the mechanical state of the membrane to vesicular trafficking: transient tension increases during cell spreading trigger exocytosis to supply membrane for surface expansion, enabling membrane area to be dynamically matched to cell shape change.⁹ Beyond membrane remodeling, membrane tension is a critical component of mechanotransduction, where perturbations in tension influence actin assembly, cortical contractility, and membrane–cytoskeleton attachment to shape cell polarity and morphogenesis.¹⁰ Specialized structures such as caveolae further highlight the importance of membrane tension homeostasis, rapidly flattening under mechanical stress, and this reflects the existence of dedicated cellular mechanisms for maintaining tension within a physiologically appropriate range.¹¹ When this homeostasis is lost, membrane tension dysregulation drives pathological outcomes including cancer cell invasion, immune cell activation, and fibrotic tissue remodeling.⁵ According to this, considerable progress has been made in elucidating the biophysical and molecular basis of membrane tension and its contributions to cell biology. These advances have largely proceeded in parallel with key aspects of mechanobiology and strategies for regulation and measurement.

Here, we first address the pathological significance of membrane tension, illustrating how its dysregulation contributes to disease processes. We subsequently examine the molecular and structural determinants of membrane tension and discuss the experimental strategies through which it can be manipulated. We conclude by critically evaluating the methodologies employed to measure membrane tension in living cells, with the aim of providing an integrated framework for understanding membrane tension as a central regulator of cellular mechanics.

What is membrane tension, operationally?

Although membrane tension is widely recognized as a key physical parameter in cell biology, its operational definition in living cells differs from the classical concept of membrane tension in simple lipid bilayers. To interpret this parameter accurately, it is essential to distinguish between intrinsic and effective membrane tension. In synthetic lipid bilayers, membrane tension is defined as in-plane tension of the lipid membrane that resists surface expansion (Figure 1(b)). This tension arises solely from the thermodynamic state of the lipid molecules. In living cells, however, the concept expands into effective membrane tension. Because the plasma membrane is mechanically coupled to the underlying actin cortex through multiple membrane–cytoskeleton linker proteins, such as the ERM (ezrin–radixin–moesin) family (Figure 1(a)), any mechanical deformation of the surface must overcome both the bilayer’s tension and the adhesion to the cytoskeleton.¹² ERM proteins function as molecular crosslinkers that connect transmembrane proteins and phospholipids in the plasma membrane to filamentous actin in the cortical cytoskeleton.¹³ In their inactive conformation, ERM proteins adopt a closed structure in which the actin-binding domain is masked; activation requires both binding to phosphatidylinositol 4,5-bisphosphate (PIP₂) at the plasma membrane and phosphorylation of a conserved threonine residue in the C-terminal domain.¹³ This phosphorylation event is mediated by several kinases, including Rho-associated kinase (ROCK), protein kinase C (PKC), and lymphocyte-oriented kinase (LOK), which promote the open conformation of ERM proteins and stabilize membrane–cortex attachment.^13,14 Through these regulatory mechanisms, ERM proteins dynamically control the mechanical coupling between the plasma membrane and the actin cortex and influence the transmission of cortical contractile forces to the cell surface. Consequently, the “effective” membrane tension measured operationally at the cell surface is a composite property: it integrates the intrinsic tension of the bilayer with the strength of membrane-cortex adhesion (Figure 1(c)).

Figure 1.

Schematic illustration of membrane tension (a) Membrane-cortex coupling in living cells. (b) Intrinsic bilayer tension. In synthetic lipid bilayers, membrane tension corresponds to in-plane tension of the lipid membrane resisting surface expansion. (c) Effective membrane tension. Plasma membrane is mechanically coupled to the underlying actin cortex through membrane-cytoskeleton linker proteins and cortical contractility generated by actomyosin networks. These schemes were created by Biorender.

However, this definition implicitly assumes that membrane tension is spatially uniform and rapidly equilibrated across the cell surface, which may not fully reflect its behavior in living cells. Indeed, experimental evidence has demonstrated that membrane tension is far from uniform, varying significantly across different regions of the cell surface and evolving over time in response to mechanical perturbations. The picket-fence model provides a framework for understanding spatial heterogeneity in membrane tension.¹⁵ In this model, the plasma membrane is partitioned into small compartments by the cortical actin cytoskeleton (“fences”) and anchored transmembrane proteins (“pickets”), which restrict lateral lipid diffusion and impede the rapid equilibration of tension across compartment boundaries. As a result, membrane tension can be locally regulated rather than being globally uniform. In addition, recent studies have highlighted the importance of membrane morphology and intracellular mechanics in governing the kinetics of tension propagation.^16,17 The crumpled membrane model proposes that the contractile cortical cytoskeleton maintains the plasma membrane in a crumpled configuration with excess surface area, such that tension propagation is buffered by the need to mechanically unfold these membrane reservoirs rather than being instantaneously transmitted.¹⁷ Within this framework, the pace of tension propagation is governed by intracellular pressure and the degree of membrane crumpling, explaining the slow propagation speeds observed in certain cell types.

Together, these frameworks indicate that membrane tension cannot be regarded as a uniformly distributed and instantaneously equilibrated physical parameter. Instead, it emerges as a spatially heterogeneous and temporally regulated property of the membrane–cortex system, shaped by structural compartmentalization and dynamic mechanical buffering.

Pathological significance: What does membrane tension change in disease?

Plasma membrane tension functions as an active mechanical regulator rather than a passive biophysical parameter. By coupling membrane mechanics to cytoskeletal organization and mechanosensitive signaling pathways, membrane tension influences how cells interpret mechanical cues and execute behavioral programs.^5,7 In pathological contexts, altered membrane tension can reshape cell migration, adhesion dynamics, and mechanosensitive signaling, thereby contributing to disease processes such as cancer invasion and cellular plasticity.¹⁸

In migrating cancer cells, membrane tension sets the mechanical permissiveness of the cell surface (Figure 2(a)). Reduced membrane tension lowers the energetic barrier for membrane deformation, facilitating protrusive activity and enabling cells to migrate through confined microenvironments.¹⁴ Conversely, elevated tension stabilizes the cell cortex and suppresses lamellipodial extension, thereby mechanically restricting edge advancement and cell spreading.¹⁹ Through its influence on curvature-sensing proteins and leading-edge dynamics, membrane tension regulates the balance between mechanical stability and invasive plasticity that ultimately governs metastatic dissemination.¹⁴ This mechanism, whereby malignant transformation is accompanied by reduced plasma membrane tension, appears to be conserved across multiple cancer types. Metastatic breast cancer cells (MDA-MB-231, Hs578 T) exhibit approximately twofold lower plasma membrane tension than non-invasive epithelial cells (MCF10 A) and low-invasive breast cancer lines (AU565, MCF7).¹⁴ This pattern extends beyond breast cancer, as aggressive prostate cancer (PC-3) and pancreatic cancer (PANC-1) cells similarly display reduced membrane tension.^14,20 The lower tension state in metastatic cells correlates with increased membrane deformation, including prominent ruffles and blebs, consistent with a mechanically permissive surface that facilitates protrusive activity and invasion.^14,21 Conversely, the capacity to maintain elevated membrane tension is a hallmark of normal epithelial identity, preserved across species and tissue types.¹⁴

Figure 2.

Membrane tension as a regulator of pathological cellular behaviors created with BioRender.com. (a) Low membrane tension promotes protrusive activity and invasive migration. High membrane tension stabilizes the cortex and suppresses lamellipodial extension. (b) Membrane tension regulates focal adhesion organization at the leading edge, influencing directional persistence and migration efficiency. (c) Increased membrane tension activates mechanosensitive ion channels, triggering calcium-dependent signaling pathways that regulate gene expression. (d) Membrane tension homeostasis is essential for plasma membrane integrity and repair under mechanical stress.

Membrane tension also regulates adhesion organization during migration (Figure 2(b)). Tension-dependent positioning of focal adhesions at the leading-edge influences directional persistence and migration efficiency.²² Elevated tension can restrict excessive membrane protrusion and limit nascent adhesion formation, whereas reduced tension facilitates more dynamic adhesion turnover and edge advancement.^19,22 Through this mechanical feedback, membrane tension ensures that actin-driven protrusions remain coordinated with substrate attachment during directional migration. When tension-dependent directional migration is disrupted, especially in myoblasts, it can contribute to the progression of muscular dystrophies. Dystrophin mechanically links actin cytoskeleton to extracellular matrix, thereby maintaining focal adhesion tension and directional cell migration.²³ In Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), disease-causing missense mutations such as L54 R and L172H fail to increase focal adhesion tension in myoblasts, unlike wild-type dystrophin, indicating that these mutations compromise the mechanical function of dystrophin as a focal adhesion allosteric regulator.²³ Consequently, myoblasts harboring these mutations exhibit impaired directional migration alongside reduced mechanosignaling, establishing a direct link between focal adhesion tension loss and defective mechanotransduction that contributes to disease progression.

Beyond migration, membrane tension modulates mechanosensitive signaling and membrane integrity (Figure 2(c)). In pathological environments where cells are subjected to sustained mechanical stress, such as elevated interstitial pressure and ECM stiffening characteristic of renal fibrosis, abnormal increases in membrane tension drive persistent activation of Piezo-type mechanosensitive ion channel component 1 (PIEZO1). Physical forces including shear stress, compression, stretch, and osmotic stress induce changes in membrane tension that open PIEZO1 to allow permeation of cations, with a preference for calcium.²⁴ For example, in osteoarthritis, inflammatory signaling via interleukin-1 (IL-1α) upregulates PIEZO1 expression in articular chondrocytes, rendering these cells hypersensitive to mechanical loading, leading to excess calcium influx through PIEZO1, which leads to rarefaction of cortical F-actin, decreased cellular stiffness, and increased susceptibility to mechanical microtrauma.^25,26 Furthermore, membrane tension also regulates transcriptional programs through Hippo-Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ) pathway.²⁷ Plasma membrane tension influences YAP/TAZ mechanotransduction by modulating membrane trafficking and caveolae dynamics, which collectively regulate the nuclear translocation of YAP/TAZ in response to mechanical stimuli.²⁸ Remodeling of extracellular space and impaired responses to mechanical cues through YAP/TAZ contribute to disease states such as fibrosis, muscle diseases, and cancer.^27,29 In glioblastoma, for instance, membrane tension variations directly contribute to YAP/TAZ-mediated regulation of cell adhesion, migration, and ECM remodeling, thereby promoting tumor invasion and disease progression.³⁰

Membrane tension also plays a critical role in plasma membrane repair (Figure 2(d)). Cells exposed to repetitive mechanical stress, such as migrating cancer cells or contracting muscle fibers, depend on tightly regulated tension homeostasis to prevent catastrophic membrane rupture.³¹ When tension buffering or repair capacity is compromised, membrane fragility increases and contributes to tissue degeneration, as observed in muscular dystrophies and related degenerative diseases.

Regulators: Three axes governing membrane tension

Membrane tension in living cells emerges from the dynamic interplay of multiple mechanical processes rather than from membrane stretch alone. In cellular systems, membrane tension is primarily regulated by three principal mechanical axes: membrane–cortex attachment, actomyosin contractility, and membrane surface availability.^5,32 These mechanisms determine how mechanical forces are transmitted to plasma membrane and how cells maintain surface tension homeostasis under changing mechanical conditions (Figure 3).

Figure 3.

Scheme of three axes governing membrane tension created with BioRender.com. (a) Membrane-cortex attachment mediated by ERM proteins control membrane tension by modulating membrane-cytoskeleton coupling. (b) Actomyosin contractility generates cortical tension that is transmitted to the plasma membrane through cytoskeletal linkers. (c) Membrane surface availability regulates tension through caveolar membrane reservoirs and trafficking process such as exocytosis and endocytosis.

Membrane-cortex attachment

The effective mechanical tension at the plasma membrane depends on its mechanical coupling to the underlying actin cortex, as membrane alone cannot sustain stable tension without cytoskeletal support (Figure 3(a)).^14,33 Membrane–cortex attachment is mediated by linker proteins such as the ERM family and spectrin-ankyrin complexes, which physically connect transmembrane proteins and phospholipids to cortical actin filaments, forming a mechanically resilient submembranous scaffold.^14,34 Through this linkage, forces generated within the actin cortex are transmitted directly to the plasma membrane. The degree of membrane–cortex coupling is regulated upstream by the phosphorylation state of ERM proteins and phosphatidylinositol 4,5-bisphosphate (PIP2) levels.³⁵ ERM activation occurs in a two-step process. PIP2 binding to the Four-point-one, Ezrin, Radixin, Moesin domain (FERM) domain induces a conformational change, followed by C-terminal threonine phosphorylation, stabilizing membrane–cortex attachment and increasing effective membrane tension.^35,36 Conversely, PIP2 depletion via phospholipase C (PLC) promotes ERM dephosphorylation and release from the cortex, weakening membrane–cortex coupling, reducing resistance to membrane deformation, and promoting membrane detachment.³⁵ Such reduction in membrane–cortex adhesion facilitates protrusive activity and favors bleb-based migration modes. Thus, membrane tension in cells does not simply reflect membrane stretch but rather arises from the degree of mechanical coupling between the plasma membrane and the cortical cytoskeleton.⁵

Actomyosin contractility

Actomyosin contractility, the force-generating process in which non-muscle myosin II motors slide anti-parallel actin filaments to produce mechanical stress within the cortical network, represents the second major axis regulating membrane tension by generating cortical mechanical stress (Figure 3(b)).³³ The actin cortex, a thin contractile network underlying the plasma membrane, produces tension through non-muscle myosin II–driven contraction.¹² Because the plasma membrane is mechanically coupled to the actin cortex via membrane–cortex linkers such as ERM proteins, contractile forces generated within the actin networks are transmitted to the cell surface.^12,14 Thus, increased actomyosin contractility elevates cortical tension, stiffens the cortex, and raises apparent membrane tension.^12,37

Actomyosin contractility is primarily regulated by the RhoA–Rho-associated coiled-coil containing protein kinase (ROCK)–myosin II signaling pathway.^38,39 Activation of RhoA stimulates ROCK, which phosphorylates myosin light chains (MLC) at Ser19, increasing motor activity and promoting cortical tension.³⁹ Additionally, ROCK simultaneously inhibits myosin light chain phosphatase (MLCP) through phosphorylation of its targeting subunit myosin phosphatase target subunit 1 (MYPT1), thereby sustaining elevated MLC phosphorylation and maintaining contractile force generation.³⁸ Conversely, inactivation of this pathway dephosphorylates MLC, reduces actomyosin contractility, and lowers membrane tension. Together, RhoA-ROCK-myosin II axis dynamically tunes mechanical state of the cell surface by setting the level of force generation within the actin cortex.

Membrane surface

The third regulatory axis involves membrane area regulation through membrane reservoirs and vesicular trafficking (Figure 3(c)). Because membrane tension rises when surface area becomes limited under mechanical load, cells employ buffering mechanisms that rapidly supply additional membrane.⁴⁰

Caveolae are flask-shaped invaginations of the plasma membrane enriched with caveolin and cavin proteins that function as membrane reservoirs.^11,41 Under acute mechanical stress, caveolae flatten and release additional membrane surface, thereby buffering sudden increases in membrane tension.^11,42 When buffering capacity of caveolae is exceeded, cells engage vesicular trafficking pathways as a secondary mechanism to regulate membrane area.^11,40 Elevated membrane tension suppresses endocytosis, as the energetic cost of membrane bending rises under high tension, while simultaneously stimulating exocytosis from recycling membrane pools, which expands plasma membrane surface area and relieves tension buildup.^9,43 This bidirectional regulation including reduced endocytosis and enhanced exocytosis acts as a coordinated feedback system that dynamically adjusts membrane area in response to mechanical demand, thereby maintaining tension within a physiological range.

How to modulate membrane tension: Experimental and engineering approaches

Membrane tension can be experimentally manipulated through diverse strategies that target membrane area, membrane reservoirs, cytoskeletal contractility, or genetic regulators.^40,44 These approaches enable controlled perturbation of the mechanical state of the plasma membrane and provide valuable insight into tension-dependent cellular behaviors.

Physical perturbation

Membrane tension can be directly modulated through controlled physical perturbations that alter membrane area or surface stress. Two widely used approaches are osmotic challenge and mechanical stretching (Figure 4(a)).^44,45 Osmotic challenge exploits the relationship between cell volume and membrane surface strain. In practice, cells are exposed to hypotonic solutions prepared by diluting culture medium or PBS with distilled water, which reduces extracellular osmolarity and drives water influx.⁴⁶ Acute hypotonic swelling increases membrane tension by stretching the plasma membrane as cell volume expands. Whereas hypertonic treatment, achieved by supplementing medium with membrane-impermeant solutes such as sucrose or mannitol, shrinks the cell, introduces membrane slack, and reduces effective membrane tension.^45–48 Membrane tension changes occur within seconds of osmotic shock and closely follow cell volume dynamics.

Figure 4.

Experimental and engineering strategies to modulate membrane tension created with BioRender.com. (a) Acute osmotic swelling under hypotonic conditions increases cell volume and stretches the plasma membrane, thereby elevating membrane tension. Hypertonic shrinkage reduces cell volume and lowers membrane tension. (b) External mechanical strain applied to adherent cells of tissues increases membrane tension by flattening membrane folds and membrane reservoirs such as caveolae (c) Inhibition of non-muscle myosin II (e.g., by blebbistatin). reduces actomyosin-generated cortical contractility, decreases cortical prestress and lowers effective membrane tension. (d) Inhibition of RhoA or ROCK signaling reduces myosin light chain phosphorylation and actomyosin contractility, leading to decreased cortical tension and reduced membrane tension. (e) Optogenetic systems enable light-induced recruitment of RhoA to the plasma membrane using engineered photosensitive dimerization modules (e.g., CRY2-CIBN). (f) Genetic manipulation of ERM proteins alters mechanical coupling between the plasma membrane and the actin cortex.

Mechanical stretching of adherent cells or tissues also provides a strategy to elevate membrane tension at larger scales (Figure 4(b)). Cells cultured on flexible silicone membranes can be subjected to uniaxial or biaxial cyclic strain by applying vacuum-driven deformation to the substrate.¹¹ When external strain is applied, caveolae progressively flatten and disassemble in an actin and ATP-independent manner, reducing membrane slack and shifting the plasma membrane into a mechanically strained state. Once the caveolar reservoir is depleted, additional strain directly elevates effective membrane tension.⁴⁹ Unlike osmotic challenge, mechanical stretching perturbs membrane tension without directly altering intracellular ion concentrations or osmolarity, making it more suitable for isolating membrane tension-specific effects.

Physical perturbations provide high sensitivity for inducing rapid and robust tension shifts, but they often lack molecular and spatial specificity. Osmotic challenge is easily implemented, yet it alters intracellular ionic strength and volume, which can confound downstream signaling analysis.^46,47 In contrast, mechanical stretching offers precise control over substrate strain but is largely restricted to adherent cultures.⁴⁹ The requirement for specialized, substrate-dependent hardware severely limits its use in non-adherent cells or complex in vivo environments. In addition, long-term stretching can induce cellular mechanoadaptation, in which the cytoskeleton reinforces itself over time, potentially confounding the interpretation of steady-state tension responses.⁵⁰

Cytoskeletal manipulation

Membrane tension can be modulated by manipulating cytoskeletal contractility, which directly alters cortical prestress and membrane–cortex mechanical coupling.^33,44 The actin cortex, a thin contractile network underlying the plasma membrane, generates mechanical tension through non-muscle myosin II–driven contraction. Because the plasma membrane is mechanically coupled to this cortex via membrane–cytoskeleton linker proteins, changes in cortical contractility directly influence effective membrane tension.^12,33 A widely used pharmacological approach is inhibition of non-muscle myosin II with blebbistatin, a small-molecule inhibitor that binds the myosin ATPase intermediate state and blocks myosin heads in an actin-detached conformation, thereby preventing cross-bridge cycling and reducing actomyosin-generated cortical prestress (Figure 4(c)).⁵¹ Treatment with blebbistatin decreases cortical tension by more than 50%, promotes bleb-based protrusions, and reduces effective membrane tension in a dose-dependent manner.³⁷ Conversely, enhanced actomyosin contractility, achieved by direct RhoA activation or ROCK-mediated myosin light chain phosphorylation, increases cortical tension and strengthens force transmission to the plasma membrane, and suppresses bleb expansion.^12,33,37 At the molecular level, actomyosin contractility is primarily regulated by the RhoA–ROCK–myosin II signaling pathway (Figure 4(d)). When RhoA is activated, it stimulates ROCK-mediated phosphorylation of myosin light chains, increasing myosin motor activity and promoting cortical tension.^52,53 Together, inhibition of RhoA or ROCK with pharmacological agents such as Y-27632 reduces cortical prestress and decreases membrane tension.⁵⁴ Cytoskeletal manipulation offers advantages of directly targeting the force-generating machinery of the cell, enabling precise modulation of cortical tension without altering cell volume or osmolarity.

Pharmacological modulation of the actomyosin cortex is widely applicable across diverse cell types and exhibits relatively high in vivo compatibility. However, these global perturbations suffer from poor subcellular spatial resolution, making it impossible to investigate localized tension gradients or compartmentalized mechanical responses.⁵⁵ Moreover, because the actomyosin machinery governs a broad spectrum of cellular functions, from cargo transport to gene expression, the pleiotropic effects of inhibitors like blebbistatin or Y-27632 necessitate careful controls.⁵⁶ Such measures are essential to ensure that observed phenotypes are directly attributable to specific changes in membrane tension rather than broader cytoskeletal disruption.⁵⁶

Optogenetic control and genetic engineering of membrane tension

Optogenetics uses genetically encoded light-sensitive proteins to control specific signaling pathways with high spatiotemporal precision, enabling reversible activation or inhibition of target molecules in living cells upon illumination.⁵⁷ This approach overcomes a key limitation of pharmacological perturbations, which act globally and often have off-target effects, by allowing localized and temporally defined manipulation of cytoskeletal contractility and membrane–cortex coupling. In particular, optogenetic activation of RhoA can provide a direct method to elevate actomyosin contractility and increase cortical tension (Figure 4(e)). Light-induced recruitment of RhoA to the plasma membrane is achieved using engineered light-sensitive dimerization systems, such as Cryptochrome 2–CIB1 N-terminal domain (CRY2–CIBN) or light-oxygen-voltage (LOV) domain-based modules, in which RhoA is fused to a photosensitive domain that undergoes rapid heterodimerization upon blue-light illumination.^57,58 In these systems, for instance, CIBN is anchored to the plasma membrane, while RhoA-fused light-sensitive partner remains cytosolic in the dark. Upon illumination, light-triggered protein–protein interaction drives acute membrane recruitment of RhoA, leading to localized activation of the RhoA–ROCK–myosin II pathway. Light-induced recruitment of the optogenetic guanine nucleotide exchange factor-RhoA construct (optoGEF-RhoA) to the plasma membrane causes a rapid and local increase in cellular traction, intercellular tension, and tissue compaction, while sequestration of the same construct to mitochondria produces the opposite effect, demonstrating bidirectional optogenetic control of contractile forces.⁵⁷ Spatially restricted activation further demonstrated that local increases in contractility can generate anisotropic tension patterns and drive directed cell deformation.⁵⁷ These studies demonstrate that optogenetic RhoA systems represent powerful tools for actively manipulating membrane tension in a controlled manner.

Engineering membrane–cortex attachment represents another strategy to modulate effective membrane tension. Membrane tension is genetically modulated by altering the activity of ERM proteins (Figure 4(f)). Morpholino-mediated knockdown of ERM reduced membrane–cortex attachment and lowered effective membrane tension, promoting bleb-based migration.¹⁰ In contrast, overexpression of constitutively active ERM strengthened membrane–cortex coupling, increased apparent membrane tension, and suppressed blebbing. Enhanced attachment also restricts membrane deformation and stabilizes lamellipodial protrusions.¹⁰ These findings demonstrate that membrane tension can be modulated through genetic manipulation of membrane–cortex coupling strength. Together, these approaches illustrate how engineered signaling systems enable direct and quantitative control of membrane tension.

Optogenetic tools represent the current standard for spatiotemporal resolution, allowing researchers to manipulate tension at specific subcellular locations with millisecond-scale reversibility.⁵⁷ Despite these advantages, their sensitivity can be inconsistent due to inherent variations in exogenous protein expression levels across different cells.⁵⁹ The stringent technical requirements, most notably genetic modification and specialized optical setups, further limit their applicability in primary cells or clinical samples. Similarly, while genetic manipulation of ERM proteins directly targets the molecular interface between the membrane and the cortex, it possesses a chronic nature, typically requiring hours to days for phenotypic expression.¹³ This slow onset potentially triggers compensatory mechanical pathways, which may mask the primary effects of tension modulation. As a result, these genetic approaches may not capture the immediate mechanical responses that acute perturbation methods can reveal, necessitating careful experimental design when interpreting long-term tension alterations.⁶⁰

How to measure membrane tension

Accurate quantification of membrane tension is essential for understanding how cells sense and respond to mechanical cues, as it provides a direct readout of the mechanical state of the cell surface and enables mechanistic interpretation of tension-dependent behaviors such as migration, division, and signaling. Membrane tension can be quantified using several complementary approaches, each with distinct advantages and limitations.

Membrane tether pulling with optical tweezers is one of the most widely used force-based methods for measuring membrane tension.⁶¹ In this method, a micron-sized bead attached to the cell surface is trapped by a focused laser beam and pulled away from the membrane to extract a thin membrane tether.^61–63 The steady-state force required to maintain this tether reflects effective membrane tension, which integrates intrinsic bilayer tension and membrane–cortex adhesion strength.^14,19,63 Because tether formation mechanically isolates a narrow membrane tube from the cell body, this approach provides a sensitive readout of changes in surface mechanical state in response to pharmacological or genetic perturbations.⁶⁴

Complementary approaches such as micropipette aspiration provide an alternative force-based measurement by applying a defined negative pressure to a portion of the cell membrane. As the membrane is aspirated into the pipette, the relationship between applied pressure and membrane deformation allows the estimation of apparent cortical tension.⁶⁵ This method was instrumental in establishing cortical tension as a quantifiable mechanical parameter in cell biomechanics, providing the first systematic framework for relating applied force to membrane deformation and laying the conceptual groundwork for subsequent tension measurement approaches.⁶⁶ It remains particularly well suited for suspended or spherical cells.

In addition to mechanical perturbation methods, fluorescence-based approaches enable non-contact measurement of membrane tension. Mechanosensitive probes such as fluorescent lipid tension reporter (Flipper-TR) insert into the lipid bilayer and exhibit changes in fluorescence lifetime depending on membrane packing and lateral tension.⁴⁵ These probes contain a planarizable molecular rotor structure whose conformation depends on the mechanical constraints imposed by surrounding lipids. Under low tension, looser lipid packing allows partial twisting of the probe, shortening its fluorescence lifetime. In contrast, increased membrane tension promotes tighter lipid ordering and restricts probe rotation, stabilizing a more planar conformation and prolonging fluorescence lifetime. Therefore, changes in membrane tension are transduced into measurable shifts in fluorescence decay kinetics, which can be quantified using fluorescence lifetime imaging microscopy (FLIM).⁴⁵ These probes allow real-time monitoring of membrane tension with subcellular spatial resolution and are particularly advantageous for dynamic processes such as migration and division.

While fluorescence-based approaches such as Flipper-TR enable non-contact measurement of membrane tension, they are limited in their ability to directly quantify the specific mechanical forces transmitted via individual receptors. To complement these methods, DNA-based molecular tension probes have emerged as an alternative strategy for mapping mechanical forces at the cell surface.⁶⁷ In this approach, surface-immobilized DNA hairpin or duplex structures are mechanically unfolded by piconewton-scale forces transmitted through receptors such as integrins, generating fluorescence signals that report the magnitude of forces applied by specific molecules. However, conventional DNA probes, which represent the naturally occurring biological stereoisomer of DNA, are susceptible to nuclease degradation, restricting their application to brief imaging windows. This limitation has been addressed by the development of L-DNA–based tension probes, the non-biological stereoisomer of DNA, which are resistant to enzymatic degradation and enable stable force imaging over extended periods.⁶⁸ L-DNA–based probes offer critical advantages even during short-term measurements currently used in mechano-profiling of cells, enabling cleaner imaging without the need for extensive background subtraction. Furthermore, to improve quantitative resolution, tandem tension sensors (TTS)-advanced DNA probes incorporating dual force-responsive elements with distinct thresholds-have been developed. These sensors allow self-calibrated measurements and enable the detection of force heterogeneity that single-threshold sensors cannot resolve. In parallel, polarity-sensitive ratiometric fluorescence probes have been introduced to overcome the requirement for fluorescence lifetime imaging microscopy (FLIM).⁶⁹ These probes detect changes in lipid packing of the plasma membrane and convert tension-dependent changes into intensity-based readouts, thereby enabling real-time imaging of membrane tension using conventional fluorescence microscopy while maintaining subcellular spatial resolution.

Membrane tension can also be inferred from analysis of thermally driven membrane fluctuations. In flicker spectroscopy, high-resolution imaging is used to quantify spontaneous membrane undulations. As membrane tension increases, fluctuation amplitude decreases because the membrane becomes mechanically constrained.⁷⁰ By analyzing such fluctuation spectra, investigators can estimate relative changes in membrane tension without applying external force. Although indirect, this approach provides insight into baseline mechanical states and is useful for measuring membrane tension in suspended cells.

Conclusion

Membrane tension has emerged as a central mechanical regulator of cell behavior, governed by three interconnected axes: membrane–cortex attachment, actomyosin contractility, and membrane area regulation. Disruption of these regulatory mechanisms underlies a broad spectrum of pathological conditions, including cancer invasion, muscular dystrophies, osteoarthritis, and fibrosis, inferring the clinical relevance of tension homeostasis at the molecular level.

Despite significant progress, several important challenges still remain. A major limitation is the difficulty of measuring membrane tension in vivo with sufficient spatiotemporal resolution. Current understanding of membrane tension is largely derived from in vitro systems, and membrane tension remains poorly understood in intact tissues, where cells are embedded in mechanically complex three-dimensional environments. Existing tools such as optical tweezers and micropipette aspiration are invasive and largely restricted to isolated cells, while fluorescent reporters such as Flipper-TR are currently limited in their ability to resolve tension gradients across tissues in vivo. Therefore, development of next-generation tension reporters with improved sensitivity, photostability, and compatibility with in vivo imaging systems will be essential for bridging this gap.

A second challenge concerns the cell-type specificity of tension regulation. The relative contributions of membrane–cortex attachment, actomyosin contractility, and membrane trafficking to overall tension homeostasis are likely to differ substantially across cell types and physiological contexts, yet systematic comparative studies remain scarce. Future studies that combine spatiotemporally precise tension manipulation using optogenetic or chemically inducible tools with transcriptomic or proteomic profiling will be essential for mapping how tension-dependent signaling is organized differently across cell types and disease states.

Looking forward, membrane tension represents a promising but underexplored therapeutic target. Restoring tension homeostasis in cancer cells, for example by reinforcing membrane–cortex attachment or elevating cortical tension to suppress invasive protrusions, may offer new strategies to limit metastatic dissemination. Realizing this therapeutic potential will require not only deeper mechanistic understanding but also the development of tension-modulating tools with sufficient cell type selectivity and in vivo deliverability. Ultimately, membrane tension stands at the intersection of biophysics, cell biology, and medicine, and its continued investigation promises to yield both fundamental insights and translational opportunities.

Footnotes

ORCID iD

Jieung Baek

Author contributions

H.L conducted the literature search, wrote the original draft for the sections on membrane tension regulation, pathological significance, experimental manipulation, and measurement, and created figures. Y.K wrote the introduction and created figure. J.K wrote the section on the definition and biophysical basis of membrane tension. J.B conceived the topic, supervised the manuscript preparation, and revised the manuscript critically for important intellectual content.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Research Foundation of Korea (NRF) Grants funded by the Korea government (MSIT) (Nos. RS-2023-00213047 and RS-2024-00405818).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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