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This study identifies lysosomes as the primary driver of delayed hair cell death caused by aminoglycoside antibiotics, a major cause of drug-induced hearing loss. Researchers found that aminoglycosides enter hair cells through autophagy rather than endocytosis and accumulate in lysosomes. Activating the lysosomal channel TPC2 protected hair cells by neutralizing lysosomal pH, and while this process affected iron availability, the cell death mechanism was independent of ferroptosis, suggesting a distinct lysosome-based toxicity pathway.
Why it matters
Understanding the mechanism of aminoglycoside-induced hearing loss could lead to protective therapies that prevent this common side effect of important antibiotics. The identification of lysosomal pH regulation as a protective target offers a potential therapeutic strategy to allow continued use of aminoglycosides while minimizing permanent hearing damage.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Aminoglycoside ototoxicity has been widely reported and remains an important public health issue. Unfortunately, the molecular mechanisms of ototoxicity are not well understood. Here, we report the lysosome compartment as the main driver of delayed cell death triggered by aminoglycosides. By labeling early and late endosomes we show that endocytosis is not an significant path of aminoglycoside uptake. Instead, we show that aminoglycosides are delivered to lysosomes primarily through autophagy. Hair cells can be protected from damage by activation of the dual function lysosomal Two-Pore-Channel 2 (TPC2), stimulated by NAADP agonist but not by phosphoinositide PI(3,5,)P2 agonist. These treatments neutralize lysosomal pH. Moreover, luminal pH changes are also accompanied by changes in ferrous iron availability, though classical ferroptosis inhibitors do not prevent a delayed hair cell death. These findings reveal that lysosomal-driven delayed hair cell death is ferroptosis independent, suggesting that toxicity relies on a distinct mechanism that based on the internal conditions of the lysosomal compartment.
Source: Lysosomal ion homeostasis drives delayed hair cell death after aminoglycoside uptake.