BETHESDA, MD — Proteins long known to be essential for hearing may have an additional, previously unrecognized role: regulating the structure and stability of cell membranes. When this function becomes disrupted—due to genetic mutations, noise exposure, or certain medications—it may trigger the death of delicate inner ear sensory cells, leading to permanent hearing loss.
The findings were presented this week at the 70th Biophysical Society Annual Meeting in San Francisco.
Deep inside the inner ear, specialized sensory cells known as hair cells convert sound vibrations into electrical signals that are transmitted to the brain. These cells are named for the tiny hair-like projections, called stereocilia, that sit atop them in tightly organized bundles.
Sensory hair cells of the mouse inner ear stained with phalloidin to highlight actin-rich structures called stereocilia, which are arranged in bundles forming the mechanosensory organelle of the inner ear sensory cells. Three rows of outer hair cells (top) and a single row of inner hair cells (bottom) are visible, illustrating the precise cellular organization required for sound detection. Image credit: Angela Ballesteros.
“When sound vibrations bend these hair-like structures, it opens channels that let ions flow into the cell, triggering a signal that carry sound to the brain,” explained Hubert Lee, a postdoctoral fellow in the lab of Angela Ballesteros at the National Institute on Deafness and Other Communication Disorders (NIDCD) at the National Institutes of Health. “But when there’s a problem with these channel proteins, the hair cells die. And these cells don’t regenerate—so the hearing loss is permanent.”
For years, scientists have understood that two proteins—TMC1 and TMC2—play a central role in converting sound into electrical signals. Mutations in TMC1 are among the most common causes of inherited deafness. However, researchers now report that these proteins may also serve another critical function unrelated to sound transduction.
“We found that TMC1 and TMC2 are not only ion channels important for hearing—they also regulate the cell membrane. And we think this membrane regulatory function, not the channel function, is what leads to hair cell death when things go wrong.”
The researchers discovered that these proteins act as lipid scramblases, molecular systems that redistribute phospholipids—fatty molecules that form cell membranes—from one side of the membrane to the other. Under normal conditions, phospholipids remain asymmetrically distributed. When the phospholipid phosphatidylserine flips to the outer surface of the membrane, it often signals that a cell is undergoing programmed death.
“Hair cells from mouse models carrying mutations in TMC1 that cause hearing loss exhibit this membrane dysregulation—phosphatidylserine gets externalized, and the membrane starts blebbing and falling apart,” Ballesteros said. “This is an apoptotic hallmark. It’s what’s killing the hair cells.”
Possible Link to Ototoxic Medications
The findings may also help explain why certain medications—particularly aminoglycoside antibiotics—are known to cause hearing loss as a side effect. The researchers observed that these drugs activate the same membrane-disrupting scramblase activity in living hair cells.
“Scientists initially thought these drugs caused hearing loss by blocking the channel function of TMCs in vivo,” Lee said. “But what we’re seeing now is that in the chaotic environment of the living hair cell, these drugs act as potent disruptors, triggering a collapse of membrane asymmetry. Yet, in the serene isolation of our reconstituted system, the protein remains indifferent to them, suggesting that other factors, such as lipid specificity or missing protein partners, are at play.”
Implications for Future Treatments
The team also found that scramblase activity depends on cholesterol levels in the cell membrane—an observation that may open the door to future therapeutic strategies aimed at protecting hearing.
“If we understand the mechanism by which these drugs activate the scramblase, we might be able to design new drugs that lack this effect,” said Yein Christina Park, graduate student at the NIH-JHU program and co-first author of this work. “We could potentially have antibiotics that don’t cause permanent hearing loss.”
About The Biophysical Society
The Biophysical Society, founded in 1958, is a professional, scientific society established to lead an innovative global community working at the interface of the physical and life sciences, across all levels of complexity, and to foster the dissemination of that knowledge. The Society promotes growth in this expanding field through its Annual Meeting, publications, and outreach activities. Its 6,500 members are located throughout the world, where they teach and conduct research in colleges, universities, laboratories, government agencies, and industry.
