Scientists Uncover Hidden Role of Hearing Proteins Linked to Irreversible Deafness
Discovery of a Second Function in TMC Proteins
Proteins long recognized as vital to the sense of hearing have now been found to possess an unexpected second function: they serve as gatekeepers, transferring fatty molecules across cell membranes. When this newly identified role is disrupted—whether by genetic mutations, damage from excessive noise, or the effects of certain medications—it may trigger the death of the ear's fragile sensory cells, leading to irreversible hearing loss.
The findings were unveiled at the 70the Biophysical Society Annual Meeting, held in San Francisco from 21-25 February 2026.
How Hair Cells Convert Sound into Electrical signals
Deep within the inner ear, specialized sensory cells known as hair cells transform sound vibrations into electrical impulses that are transmitted to the brain. Their name derives from the minute, hair-like projections—called stereocilia—arranged in tight bundles resembling a narrow crest.
"When sound waves bend these delicate structures, ion channels open, allowing charged particles to enter the cell and initiate the electrical signal that conveys sound to the brain," explained Hubert Lee, a postdoctoral fellow working in the laboratory of Angela Ballesteros at the National Institute of Deafness and Other Communication Disorders (NIDCD), part of the National Institutes of Health.
He added that when defects arise in these channel proteins, the hair cells perish. As they lack the ability to regenerate, any resulting loss is permanent.
TMC1 and TMC2 - More Than Just Ion Channels
The channel proteins known as TMC1 and TMC2 have long been recognized as the molecular machinery responsible for converting sound vibrations into electrical signals. Mutations in TMC1 are among the principal causes of inherited deafness. However, researchers at the National Institute on Deafness and Other Communication Disorders have now identified an entirely separate function for these proteins.
"We discovered that TMC1 and TMC2 are not solely ion channels essential for hearing—they also play a role in regulating the cell membrane," said Ballesteros. "We believe it is this membrane-regulating function, rather than their channel activity, that triggers hair cell death when disrupted."
The Lipid Scramblase Discovery - A Critical Breakthrough
The channels also function as so-called lipid scramblases—molecular systems responsible for redistributing fatty molecules, known as phospholipids, between the inner and outer layers of a cell membrane. Under normal conditions, specific phospholipids remain confined to particular sides of the membrane. However, when phosphatidylserine shifts to the cell's outer surface, it typically signals that the cell is undergoing death.
"Hair cells in mouse models carrying TMC1 mutations associated with hearing loss display this membrane imbalance phosphatidylserine becomes externalized and the membrane begins to bleb and disintegrate," Ballesteros explained. "This is a recognized hallmark of apoptosis. It is what ultimately destroys the hair cells."
Why Some Antibiotics Can Cause Hearing Loss
The findings also help explain why some medications are associated with hearing loss as a side effect. Aminoglycosides, a widely used of antibiotics, have long been recognized for their ototoxic effects. Researchers discovered that these drugs activate the same membrane-disrupting scramblase activity within living systems.
"Scientists originally believed these drugs caused hearing loss by blocking the channel function of TMC proteins in vivo," Lee explained. "What we are observing instead is that, within the complex environment of a living hair cell, these compounds act as powerful disruptors, causing the collapse of membrane asymmetry. In contrast, within the controlled conditions of our reconstituted system, the protein appears unaffected, indicating that additional elements such as lipid specificity or absent protein partners—may be involved."
Cholesterol's Role in Protecting Hearing
The researchers further found that scramblase activity is influenced by the amount of cholesterol present within the cell membrane. This discovery may open the door to future strategies centred on dietary adjustments or cholesterol regulation, with the aim of safeguarding hearing against ototoxic medications or inherited forms of deafness.
"If we can fully understand how these drugs activate the scramblase, we may be able to develop new treatments that avoid triggering this effect," said Yein Christina Park, a graduate student in the NIH-JHU programme and co-first author of the study. "In time, it may be possible to produce antibiotics that do not carry the risk of permanent hearing loss."
Key Takeaways from the Study
- TMC1 and TMC2 proteins have a newly identified membrane-regulating function.
- Disruption of this function may cause irreversible hair cell death.
- Aminoglycoside antibiotics may trigger hearing loss by activating lipid scramblase activity.
- Cholesterol levels in cell membranes may influence vulnerability to damage.
- Future treatments could focus on preventing membrane imbalance rather than blocking ion channels.
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