RIPOR2-mediated autophagy dysfunction is critical for aminoglycoside-induced hearing loss

Abstract

Aminoglycosides (AGs) are potent antibiotics capable of treating a wide variety of life-threatening infections, however, they are ototoxic and cause irreversible damage to cochlear hair cells. Despite substantial progress, little is known about the molecular pathways critical for hair cell function and survival that are affected by AG exposure. We demonstrate here that gentamicin, a representative AG antibiotic, binds to and triggers within minutes translocation of RIPOR2 in murine hair cells from stereocilia to the pericuticular area. Then, by interacting with a central autophagy component GABARAP, RIPOR2 affects autophagy activation. Reducing the expression of RIPOR2 or GABARAP completely prevents AG-induced hair cell death and subsequent hearing loss in mice. Additionally, abolishing the expression of PINK1 or Parkin, two key mitochondrial autophagy proteins, prevents hair cell death and subsequent hearing loss caused by AG. In summary, our study demonstrates that RIPOR2-mediated autophagic dysfunction is essential for AG-induced hearing loss.