Abstract
Aminoglycoside antibiotics are widely prescribed to treat a variety of serious bacterial infections. They are extremely useful clinical tools, but have adverse side effects such as oto- and nephrotoxicity. Once inside a cell they are thought to cause mitochondrial dysfunction, subsequently leading to apoptotic cell death due to an increase in reactive oxygen species (ROS) production. Here we present evidence of a direct effect of gentamicin (the most commonly prescribed aminoglycoside) on the respiratory activities of isolated rat liver and kidney mitochondria. We show that gentamicin stimulates state 4 and inhibits state 3u respiratory rates, thereby reducing the respiratory control ratio (RCR) whilst simultaneously causing a collapse of the mitochondrial membrane potential (MtMP). We propose that gentamicin behaves as an uncoupler of the electron transport chain (ETC) – a hypothesis supported by our evidence that it reduces the production of mitochondrial ROS (MtROS). We also show that gentamicin collapses the MtMP in the sensory hair cells (HCs) of organotypic mouse cochlear cultures.
Highlights
Aminoglycosides (AGs) are broad-spectrum antibiotics widely prescribed to treat serious bacterial infections such as those leading to septicaemia and meningitis
Gentamicin for 10 min prior to the addition of 10 mM succinate, in the presence of 2.5 μM rotenone to ensure that nicotinamide adenine dinucleotide (NADH) generated within the tricarboxylic acid (TCA) cycle did not become a factor contributing to oxygen flux
To assess whether the effects observed in isolated mitochondria occur in intact cell systems, and in particular in the cochlea since it is susceptible to AG-induced ototoxicity, we investigated the effect of gentamicin on the mitochondrial membrane potential (MtMP) in the sensory hair cells (HCs) of mouse cochlear cultures
Summary
Aminoglycosides (AGs) are broad-spectrum antibiotics widely prescribed to treat serious bacterial infections such as those leading to septicaemia and meningitis. Permanent hearing loss is found in around 20–30% of patients treated with these antibiotics (Rizzi and Hirose, 2007; Schacht et al, 2012), presenting a much more significant clinical concern. The damage to these organs is assumed to be attributable to the selective retention of AGs within these tissue types, with endocytic and non-selective cation channel-mediated routes in kidneys (Nagai and Takano, 2014) and the mechano-electrical transducer (MET) channels of cochlear sensory hair cells (HCs) (Marcotti et al, 2005; Alharazneh et al, 2011) proposed as the main entry pathways
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