The mitochondrion: a perpetrator of acquired hearing loss

Abstract

Age, drugs, and noise are major causes of acquired hearing loss. The involvement of reactive oxygen species (ROS) in hair cell death has long been discussed, but there is considerably less information available as to the mechanisms underlying ROS formation. Most cellular ROS arise in mitochondria and this review will evaluate evidence for mitochondrial pathology in general and dysfunction of the mitochondrial respiratory chain in particular in acquired hearing loss. We will discuss evidence that different pathways can lead to the generation of ROS and that oxidative stress might not necessarily be causal to all three pathologies. Finally, we will detail recent advances in exploiting knowledge of aminoglycoside-mitochondria interactions for the development of non-ototoxic antibacterials. This article is part of a Special Issue entitled "Annual Reviews 2013".

Keywords: ROS; SOD; mitochondrial DNA; mtDNA; rRNA; reactive oxygen species; ribosomal RNA; superoxide dismutase.

Figure 1. Structures of drugs and complexes with ribosomal RNA

Left: The three-dimensional structure of the ribosomal A site in complex with 4,5- and 4,6-disubstituted 2-deoxystreptamines. The common neamine core is denoted in yellow; ring III of the 4,6-aminoglycosides (tobramycin) in red; rings III and IV of the 4,5-aminoglycosides (paromomycin) in blue. Right: Neomycin is a 4,5-disubstituted 2-deoxystreptamine, tobramycin and kanamycin are 4,6-disubstituted 2-deoxystreptamines, and apramycin is a 4-monosubstituted 2-deoxystreptamine.

Figure 2. Drug effects on protein synthesis and recombinant microorganisms

A. Susceptibility to aminoglycosides of the mitochondrial and the cytosolic decoding site as assessed by MIC assays (minimal inhibitory concentrations) on recombinant microorganisms with hybrid ribosomes. B. Relationship between inhibition of protein synthesis in mitochondrial hybrid ribosomes and relative cochleotoxicity of aminoglycoside antibiotics. The potencies of a series of cochleotoxic aminoglycosides (Ak, amikacin; Gm, gentamicin; Ne, neamine; Nm, neomycin) in inhibiting protein synthesis in hybrid mitochondrial ribosomes (see Table 1) correlates with their previously reported relative cochleotoxicity (Kotecha and Richardson, 1994). C. Susceptibility to aminoglycosides of mutant and wild-type mitochondrial hybrid ribosomes. Dose-response curves with wild-type mitochondrial (red squares), mutant A1555G (green triangles), and mutant C1494T (blue inverted triangles) hybrid ribosomes; bacterial ribosomes (black circles) are included for comparison. Left: Gentamicin-induced increase in mis-incorporation of the near-cognate [³H]-leucine using polyU as template relative to the drug-free control (mean ± SD; n ≥ 3). Right: Gentamicin-induced inhibition of luciferase synthesis relative to the drug-free control (mean ± SD; n ≥ 3). Modified from Proc. Natl. Acad. Sci. USA 2008, 105: 20888–20893 with permission from the publisher.