Hair cell apoptosis and deafness in Tmc1 mutations

Area of Science:

• Otolaryngology
• Genetics
• Cell Biology

Background:

• Transmembrane channel-like protein 1 (TMC1) is crucial for the mechano-electrical transducer (MET) channel in cochlear outer hair cells.
• Mutations in TMC1 are a significant cause of inherited deafness and hair cell degeneration.

Purpose of the Study:

• To investigate the molecular mechanisms underlying hearing loss and hair cell death in mice with specific TMC1 mutations (p.T416K, p.M412K, p.D569N).
• To explore the role of mitochondrial dysfunction and calcium regulation in TMC1-associated deafness.

Main Methods:

• Utilized Calcein-AM, MitoTracker, and Annexin V to assess hair cell apoptosis and mitochondrial health in neonatal Tmc1 mutant mice.
• Measured acoustic brainstem responses to determine hearing thresholds.
• Investigated the activity of the stereociliary PMCA2 Ca2+ pump and its relation to calcium levels and apoptosis.
• Employed Cre-Lox excision to correct the Tmc1 mutation and assess functional recovery.

Main Results:

• Tmc1 mutant mice exhibited mitochondrial dysfunction and initiated apoptosis by postnatal day 6, despite functional MET channels.
• Deafness was observed by postnatal day 15-21, correlating with reduced PMCA2 density and decreased MET channel Ca2+ permeability.
• Blocking the PMCA2 pump induced apoptosis, suggesting elevated hair bundle Ca2+ promotes cell death.
• Early genetic correction of the Tmc1 mutation preserved hearing and restored PMCA2 density.

Conclusions:

• TMC1 mutations trigger hair cell apoptosis via mitochondrial dysfunction and dysregulated calcium homeostasis, involving reduced PMCA2 pump function.
• Stereociliary PMCA2 density is critical for maintaining hair cell health and preventing apoptosis.
• Targeting PMCA2 function or restoring TMC1 may offer therapeutic strategies for deafness.