In living cells, regulation of the electrochemical environment is supposed to be managed by ion channels—protein complexes that reside in cell membranes and assume definite shapes. So, it’s surprising to learn that the electrochemical environment is also managed by bodies that are nothing like ion channels—bodies that float through the cell’s cytoplasm untethered, as though inside a miniature lava lamp. And, like the contents of a lava lamp, these bodies are shape-shifting blobs.
The blobs, which are more properly known as biomolecular condensates, are liquid-like, self-assembling, non-membrane-bounded, phase-separated compartments. They are already known to have local effects. For example, biomolecular condensates can separate or agglomerate certain molecules, either hindering or promoting the activity of said molecules, typically proteins and nucleic acids. Also, biomolecular condensates can provide an alternative energy source that might power some aspects of biological chemistry.
And now, thanks to the work of researchers from Duke University and Washington University in St. Louis (WashU), we know that biomolecular condensates can also have nonlocal effects. Specifically, when biomolecular condensates form, they can generate electric potential gradients, directly affecting the cytoplasmic pH and membrane potential, properties that in turn affect cells’ global traits and outcomes. In the bacterial cells studied by the Duke/WashU team, these global traits included resistance to antibiotics.
Detailed findings appeared in Cell, in an article titled, “Biomolecular condensates regulate cellular electrochemical equilibria.”
“Condensate formation … amplifies cell-cell variability of their electrochemical properties due to passive environmental effect,” the article’s authors reported. “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 research shows that condensates influence cells well beyond direct physical contact, almost like they have a wireless connection to how cells interact with the environment,” said Duke’s Lingchong You, PhD, the James L. Meriam Distinguished Professor of Biomedical Engineering and one of the study’s two senior authors. “Beyond demonstrating the electrical mechanisms behind this connection, we’ve proven that condensate formation can make cells more tolerant to certain types of antibiotics and more susceptible to others.”
“This is likely just the tip of the iceberg,” added the study’s other senior author, Duke’s Ashutosh Chilkoti, PhD, the acting chair of biomedical engineering and the Alan L. Kaganov Distinguished Professor of biomedical engineering. “We expect that these electric potential effects express themselves in a wide variety of ways through cellular behaviors.”
This electrostatic activity provides a handle for the formation of biological condensates to affect the electrical potential of the cellular membrane and the electrochemical environment within the cell. And because these environmental factors are crucial to many biological processes, it provides a mechanism for these unassuming blobs to directly affect how cells interact with the world around them.
“Even a tiny number of these condensates centrally distributed well away from the cell membrane can create a chain reaction that can change this global property,” explained the study’s lead author, Yifan Dai, PhD, an assistant professor of biomedical engineering at WashU, who conducted the research as a postdoctoral researcher at Duke. “This paper shows there is no escape from these effects. As long as these tiny blobs form, many things are influenced, even gene regulation on a global scale. When I saw that, it was quite shocking to me.”
To prove this point, the researchers worked to show that this phenomenon can affect how well bacteria survive interactions with certain antibiotics. The researchers caused colonies of Escherichia coli bacteria to form internal condensates either by stressing them in just the right way or by manipulating the gene expression of the condensate-forming proteins. They then tested the resulting electrical charge in their cellular membranes and exposed them to antibiotics.
The results showed that condensate formation caused some cellular membranes to become more negatively charged, which directly affected whether or not the cells reacted to the antibiotics, since they are also charged particles. But this is just the beginning of this line of research, the researchers say, as many biochemical processes depend on the electric potential held within the cellular membrane.
“Our work uncovers a role of condensates in regulating global cellular physiology,” You said. “While we don’t yet have a concrete mechanistic understanding of how cells are deploying this activity to regulate their functionality, it’s a major discovery that it’s happening at all.”
