Multiple mechanisms of aminoglycoside ototoxicity are distinguished by subcellular localization of action

Area of Science:

• Ototoxicity and cellular toxicology
• Mechanosensory cell biology
• Vertebrate sensory systems

Background:

• Mechanosensory hair cells in vertebrates are vulnerable to environmental toxins, leading to hearing and balance disorders.
• Aminoglycoside antibiotics (e.g., neomycin, gentamicin) and antineoplastic agents are common causes of hair cell loss.
• Understanding the mechanisms of hair cell death is crucial for developing therapeutic interventions.

Purpose of the Study:

• To elucidate the distinct cellular pathways of aminoglycoside-induced hair cell death in zebrafish.
• To differentiate the timing and molecular mechanisms of acute versus delayed hair cell death.
• To inform potential therapeutic strategies for preventing ototoxicity.

Main Methods:

• Exposure of zebrafish lateral line hair cells to neomycin and gentamicin.
• Time-course analysis of cell death following drug exposure.
• Washout experiments to assess the requirement for continuous exposure.
• Mitochondrial and lysosomal function assays.
• Assessment of antioxidant and endolysosomal modulation effects.

Main Results:

• Neomycin induced acute hair cell death within 1 hour, linked to mitochondrial calcium fluxes and mitigated by mitoTEMPO.
• Gentamicin induced delayed hair cell death up to 24 hours, associated with lysosomal accumulation and responsive to endolysosomal manipulation.
• Delayed death did not require continuous drug exposure, indicating distinct downstream signaling pathways.

Conclusions:

• Aminoglycoside ototoxicity involves at least two distinct cellular death pathways with different kinetics and molecular underpinnings.
• Acute toxicity is linked to mitochondrial dysfunction, while delayed toxicity involves lysosomal pathways.
• Targeting early cellular events rather than specific death pathways may offer a more effective therapeutic approach for aminoglycoside-induced hair cell loss.