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Genetic analysis of interactions with eukaryotic rRNA identify the mitoribosome as target in aminoglycoside

Sven N Hobbie1, Subramanian Akshay, Sarath K Kalapala

  • 1Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 32, CH-8006 Zurich, Switzerland.

Proceedings of the National Academy of Sciences of the United States of America
|December 24, 2008
PubMed

Insights

Aminoglycoside antibiotics can cause hearing loss by interfering with mitochondrial protein synthesis. Specific mutations increase susceptibility, highlighting the mitochondrial ribosome

Area of Science:

  • Molecular Biology
  • Genetics
  • Ototoxicology

Background:

  • Aminoglycoside ototoxicity is linked to cellular structures and metabolic pathways.
  • Mutations in mitochondrial ribosomal RNA (rRNA) increase susceptibility to aminoglycoside-induced hearing loss, suggesting a role for mitochondrial protein synthesis.

Purpose of the Study:

  • To investigate the molecular interaction of aminoglycosides with eukaryotic ribosomes.
  • To understand the role of the mitochondrial ribosome in aminoglycoside-induced hearing loss.

Main Methods:

  • Constructed bacterial hybrid ribosomes with eukaryotic decoding sites, including mitochondrial and cytosolic variants.
  • Assessed the susceptibility of these hybrid ribosomes to various aminoglycosides.
  • Analyzed sequence alterations corresponding to known mitochondrial deafness mutations (A1555G, C1494T).

Main Results:

  • Mitochondrial hybrid ribosomes showed susceptibility correlating with drug cochleotoxicity.
  • Mutations A1555G and C1494T increased aminoglycoside binding and hypersusceptibility.
  • These mutations led to aminoglycoside-induced mistranslation and inhibited protein synthesis in the mitochondrial ribosome.

Conclusions:

  • Aminoglycosides can directly cause dysfunction of the mitochondrial ribosome.
  • Interference with mitochondrial protein synthesis exacerbates cochlear toxicity, contributing to aminoglycoside-induced deafness.
  • This mechanism is relevant for both sporadic and inherited forms of hearing loss.

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