Weak Ergodicity Breaking of Receptor Motion in Living Cells Stemming from Random Diffusivity

Abstract

Molecular transport in living systems regulates numerous processes underlying biological function.\ud Although many cellular components exhibit anomalous diffusion, only recently has the subdiffusive\ud motion been associated with nonergodic behavior. These findings have stimulated new questions for their\ud implications in statistical mechanics and cell biology. Is nonergodicity a common strategy shared by living\ud systems? Which physical mechanisms generate it? What are its implications for biological function? Here,\ud we use single-particle tracking to demonstrate that the motion of dendritic cell-specific intercellular\ud adhesion molecule 3-grabbing nonintegrin (DC-SIGN), a receptor with unique pathogen-recognition\ud capabilities, reveals nonergodic subdiffusion on living-cell membranes In contrast to previous studies, this\ud behavior is incompatible with transient immobilization, and, therefore, it cannot be interpreted according to\ud continuous-time random-walk theory. We show that the receptor undergoes changes of diffusivity,\ud consistent with the current view of the cell membrane as a highly dynamic and diverse environment.\ud Simulations based on a model of an ordinary random walk in complex media quantitatively reproduce all\ud our observations, pointing toward diffusion heterogeneity as the cause of DC-SIGN behavior. By studying\ud different receptor mutants, we further correlate receptor motion to its molecular structure, thus establishing\ud a strong link between nonergodicity and biological function. These results underscore the role of disorder\ud in cell membranes and its connection with function regulation. Because of its generality, our approach\ud offers a framework to interpret anomalous transport in other complex media where dynamic heterogeneity\ud might play a major role, such as those found, e.g., in soft condensed matter, geology, and ecology.Peer ReviewedPostprint (published version

Characterizing anomalous diffusion in crowded polymer solutions and gels over five decades in time with variable-lengthscale fluorescence correlation spectroscopy

“…50 and 51, where it was argued that the anomalous diffusion detected in dextran solutions was arising from the presence of different micro-environments. Similar interpretations have also been invoked in the case of intracellular diffusion: Recently, a spatially varying, random diffusivity 101 has been shown to be consistent with receptor motion in dendritic cells 102 .…”

Nonergodic subdiffusion from transient interactions with heterogeneous partners

“…The model discussed in this paper proposes a mechanistic explanation for the nonergodic subdiffusion observed in several biological systems [3][4][5][6][7], based on the occurrence of specific, transient interactions with a heterogeneous population of interacting partners. The model displays many similarities with the long-time behavior of the heavy-tail CTRW [9] and the patch model [19].…”

“…Such anomalous diffusion can have different physical origins and a large amount of models have been proposed for its interpretation, some of the most relevant ones being recently discussed by Metzler and co-workers [2]. The detailed analysis of the particle trajectories has shown that some processes characterized by anomalous diffusion also exhibit differences between ensemble and time averaged observables, such as the mean squared displacement itself [3][4][5][6][7]. This feature, known as weakergodicity breaking [8], reflects the physical nature of specific stochastic mechanisms, for which time averages are random and thus irreproducible in spite of the large statistics.…”

Distributional behaviors of time-averaged observables in the Langevin equation with fluctuating diffusivity: Normal diffusion but anomalous fluctuations

“…Other distributional behaviors have been found in other diffusion processes such as a quenched trap model [15,16] and stored-energy-driven Levy flight (SEDLF) [14,17], where the PDF of the normalized TMSDs (timeaveraged diffusion coefficients) follows other distributions depending on the power-law exponent in the waiting time distribution, the spatial dimension as well as parameters controlling jumps of a random walker. It is important to clarify whether fluctuations of time-averaged observables are intrinsic or not, because diffusion coefficients obtained by single-particle-tracking experiments in living cells exhibit large fluctuations [10,[18][19][20][21]. Such large fluctuations will have relevance to distributional behaviors in stochastic models of anomalous diffusion.…”