Researchers have discovered that biological condensates can influence cellular activities far beyond their immediate environments. Their findings suggest these structures could represent a previously overlooked mechanism through which cells adjust their internal electrochemistry, subsequently impacting the cellular membrane. This means that these seemingly simple blobs can have far-reaching effects on key traits and outcomes, including antibiotic resistance.
Traditionally, research in biological chemistry has centered on the vital components driving life processes, such as protein folding, gene activity, and electrical signaling pathways. These areas provided the most straightforward opportunities for identifying irregularities associated with diseases.
However, recent studies have brought attention to a different type of cellular structure that may be just as crucial. Referred to as biological condensates, these formations arise due to differences in density, akin to oil droplets floating in water, and create compartments within cells without requiring a physical membrane.
Previous investigations have indicated that these blobs can segregate or aggregate certain proteins and molecules, thereby either hindering or enhancing their functions. Additionally, it has been shown that these structures may serve as a different source of energy, potentially fueling various biochemical reactions.
Until now, research had primarily focused on the localized effects generated by these condensates, with little attention paid to how they could influence biochemistry at a distance.
In a new study published on September 10 in the journal Cell, scientists from Duke University and Washington University in St. Louis revealed that biological condensates can impact cellular activity extensively, reaching well beyond their immediate areas. The study indicates that these condensates may represent an overlooked method by which cells fine-tune their internal electrochemistry, which then influences the cellular membrane, allowing these unassuming blobs to modify significant traits such as antibiotic resistance.
“Our research indicates that condensates play a role in cellular functioning that extends beyond mere physical presence, almost as if they have a wireless link to how cells interact with their environment,” said Lingchong You, the James L. Meriam Distinguished Professor of Biomedical Engineering at Duke. “We’ve shown not only the electrical mechanisms underlying this connection, but we’ve also demonstrated that the formation of condensates can enhance cell tolerance to specific antibiotics and increase susceptibility to others.”
“This is probably just the beginning,” added Ashutosh Chilkoti, the Alan L. Kaganov Distinguished Professor of Biomedical Engineering at Duke. “We believe that the influence of these electric potential changes will manifest in numerous ways through cellular behaviors.”
Condensates function similarly to sponges, absorbing various proteins, enzymes, ions, and other biomolecules while excluding others. If they capture enough ions to carry a positive or negative charge, that charge imbalance will inevitably affect the cellular environment surrounding them.
This electrostatic activity provides a pathway for biological condensates to modify the electrical potential of the cellular membrane and the electrochemical environment within the cell. Given that these environmental factors play vital roles in many biological processes, this mechanism allows these simple blobs to significantly influence how cells interact with their surroundings.
“Even a small number of these condensates distributed away from the cell membrane can trigger a cascade of changes that alter this global characteristic,” explained Yifan Dai, an assistant professor of biomedical engineering and a member of the Center for Biomolecular Condensates at Washington University in St. Louis, who conducted this research while a postdoctoral researcher at Duke. “This paper illustrates that the effects of these condensates are unavoidable. As long as these tiny structures exist, they can influence various processes, including gene regulation on a larger scale. When I learned this, it was quite surprising.”
To demonstrate this, the researchers showed that this phenomenon could influence how well bacteria endure certain antibiotics. They induced colonies of E. coli bacteria to produce internal condensates by applying precise stressors or by altering the expression of proteins responsible for forming the condensates. They then measured the resulting electrical charge in the cellular membranes and tested the bacteria with antibiotics.
The findings revealed that the formation of condensates caused certain cellular membranes to become more negatively charged, which directly impacted the cells’ reactions to the antibiotics, as these substances also carry their own charges. However, the researchers emphasized that this is just the tip of the iceberg, as many biochemical processes hinge on the electric potential within the cellular membrane.
“Our work uncovers a role for condensates in regulating overall cellular physiology,” You stated. “Although we still lack a clear mechanistic understanding of how cells utilize this activity to manage their functionality, the discovery that it occurs at all is significant.”
This research was supported by the Air Force Office of Scientific Research (FA9550-20-1-0241) and the National Institutes of Health (R35-GM127042).
