Biomolecular condensates regulate cellular electrochemical equilibria, 2024, Dai et al.

SNT Gatchaman · Sep 10, 2024

Biomolecular condensates regulate cellular electrochemical equilibria
Yifan Dai; Zhengqing Zhou; Wen Yu; Yuefeng Ma; Kyeri Kim; Nelson Rivera; Javid Mohammed; Erica Lantelme; Heileen Hsu-Kim; Ashutosh Chilkoti; Lingchong You

Control of the electrochemical environment in living cells is typically attributed to ion channels. Here, we show that the formation of biomolecular condensates can modulate the electrochemical environment in bacterial cells, which affects cellular processes globally. Condensate formation generates an electric potential gradient, which directly affects the electrochemical properties of a cell, including cytoplasmic pH and membrane potential. Condensate formation also amplifies cell-cell variability of their electrochemical properties due to passive environmental effect. The modulation of the electrochemical equilibria further controls cell-environment interactions, thus directly influencing bacterial survival under antibiotic stress. The condensate-mediated shift in intracellular electrochemical equilibria drives a change of the global gene expression profile.

Our work reveals the biochemical functions of condensates, which extend beyond the functions of biomolecules driving and participating in condensate formation, and uncovers a role of condensates in regulating global cellular physiology.

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SNT Gatchaman · Sep 10, 2024

Our study provides direct evidence of how the phase separation of associative biomacromolecules can establish an ion gradient within cells. We demonstrate that the ion gradient drastically affects the electrochemical equilibria of a cell by modulating: (1) intracellular ion homeostasis, as seen by the pH/ion concentration difference between the cytoplasm and condensates; and (2) membrane potential, by inducing hyperpolarization of the cell membrane.
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Our results show that condensate formation can regulatespatialdistributionofspeciﬁcionswithinacell,whichprovides a mechanism to regulate cellular electrochemical equilibria that is orthogonal and complementary to ion channels. This effect should go beyond ions to charged small molecules that are involved in the establishment of the electric potential gradient between phases. Since the chemical environment of cells is regulated by both ions and small molecules serving as osmolytes (e.g., glutamate), studying how these molecules collectively deﬁne or are regulated by the electrochemical potential shift induced by condensation can provide new insights into regulation of intracellular physicochemical homeostasis.
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The diffusion length scale of ions is much longer than macromolecules. As such, the chemical effect exerted by condensates can dictate long-range cellular control, as evidenced by the change in the interactions of cells with their environment. Specifically, the intracellular ion gradient established by condensates is rebalanced with the extracellular environment, which leads to a change of the membrane potential. In turn, these changes affect intracellular gene expression on a global scale and the response of cells to environmental perturbations.
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In summary, our ﬁnding uncovers a previously unknown biochemical function of condensates in modulating electrochemical equilibria of cells, which in turn affects global cellular physiology. This function has a distinct effect in generating cellular noise, which further suggests that the cooperativity and signaling between different condensates and cellular components may be a critical—and as yet unstudied—phenomenon by which the interplay of different biomolecular condensates in cells controls cellular homeostasis. This work reveals a new level of the functional complexity of biomolecular condensates and expands our understanding of their cellular functions beyond those encoded in the biomolecules that participate in condensate formation.
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Biomolecular condensates regulate cellular electrochemical equilibria, 2024, Dai et al.

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Biomolecular condensates regulate cellular electrochemical equilibria, 2024, Dai et al.

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