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Membraneless organelles like stress granules are active liquid-liquid phase-separated droplets that are involved in many intracellular processes. Their active and dynamic behavior is often regulated by ATP-dependent reactions. However, how exactly membraneless organelles control their dynamic composition remains poorly understood. Herein, we present a model for membraneless organelles based on RNA-containing active coacervate droplets regulated by a fuel-driven reaction cycle. These droplets emerge when fuel is present, but decay without. Moreover, we find these droplets can transiently up-concentrate functional RNA which remains in its active folded state inside the droplets. Finally, we show that in their pathway towards decay, these droplets break apart in multiple droplet fragments. Emergence, decay, rapid exchange of building blocks, and functionality are all hallmarks of membrane-less organelles, and we believe that our work could be powerful as a model to study such organelles. Membraneless organelles are liquid-liquid phase-separated droplets whose behaviour can be regulated by chemical reactions, but this process is poorly understood. Here, the authors report model membraneless organelles based on coacervate droplets that show fuel-driven dynamic behaviour and concentrate functional RNA.

Liquid-liquid phase separation yields spherical droplets that eventually coarsen to one large, stable droplet governed by the principle of minimal free energy. In chemically fueled phase separation, the formation of phase-separating molecules is coupled to a fuel-driven, non-equilibrium reaction cycle. It thus yields dissipative structures sustained by a continuous fuel conversion. Such dissipative structures are ubiquitous in biology but are poorly understood as they are governed by non-equilibrium thermodynamics. Here, we bridge the gap between passive, close-to-equilibrium, and active, dissipative structures with chemically fueled phase separation. We observe that spherical, active droplets can undergo a morphological transition into a liquid, spherical shell. We demonstrate that the mechanism is related to gradients of short-lived droplet material. We characterize how far out of equilibrium the spherical shell state is and the chemical power necessary to sustain it. Our work suggests alternative avenues for assembling complex stable morphologies, which might already be exploited to form membraneless organelles by cells. Dissipative structures are governed by non-equilibrium thermodynamics. Here, the authors describe a size-dependent transition from active droplets to active spherical shells—a dissipative structure that arises from reaction diffusion gradients.

Liquid-liquid phase separation is the process in which two immiscible liquids demix. This spontaneous phenomenon yields spherical droplets that eventually coarsen to one large, stable droplet governed by the principle of minimal free energy. In chemically fueled phase separation, the formation of phase-separating molecules is coupled to a fuel-driven, non-equilibrium reaction cycle. Chemically fueled phase separation yields dissipative structures sustained by a continuous fuel conversion. Such dissipative structures are ubiquitous in biology but poorly understood as they are governed by non-equilibrium thermodynamics. Here, we bridge the gap between passive, close-to-equilibrium, and active, dissipative structures with chemically fueled phase separation. We observe that spherical, active droplets can transition into a new morphology, i.e., a liquid, spherical shell of droplet material. A spherical shell would be highly unstable at equilibrium. Only by continuously converting chemical energy, this dissipative structure can be sustained. We demonstrate the transition mechanism, which is related to the activation of a product outside of the droplet, and the deactivation within the droplets leading to gradients of droplet material. We characterize how far out of equilibrium the spherical shell state is and the chemical power necessary to sustain it. Our work suggests new avenues for assembling complex stable morphologies, which might already be exploited to form membraneless organelles by cells.Competing Interest StatementThe authors have declared no competing interest.