Abstract
Aminoglycoside antibiotics are implicated as culprits of hearing loss in more than 120,000 individuals annually. Research has shown that the sensory cells, but not supporting cells, of the cochlea are readily damaged and/or lost after use of such antibiotics. High-frequency outer hair cells (OHCs) show a greater sensitivity to antibiotics than high- and low-frequency inner hair cells (IHCs). We hypothesize that variations in mitochondrial metabolism account for differences in susceptibility. Fluorescence lifetime microscopy was used to quantify changes in NAD(P)H in sensory and supporting cells from explanted murine cochleae exposed to mitochondrial uncouplers, inhibitors, and an ototoxic antibiotic, gentamicin (GM). Changes in metabolic state resulted in a redistribution of NAD(P)H between subcellular fluorescence lifetime pools. Supporting cells had a significantly longer lifetime than sensory cells. Pretreatment with GM increased NAD(P)H intensity in high-frequency sensory cells, as well as the NAD(P)H lifetime within IHCs. GM specifically increased NAD(P)H concentration in high-frequency OHCs, but not in IHCs or pillar cells. Variations in NAD(P)H intensity in response to mitochondrial toxins and GM were greatest in high-frequency OHCs. These results demonstrate that GM rapidly alters mitochondrial metabolism, differentially modulates cell metabolism, and provides evidence that GM-induced changes in metabolism are significant and greatest in high-frequency OHCs.
Highlights
Used for the treatment of life-threatening gram-negative bacterial infections, aminoglycoside (AG) antibiotics are one of the most commonly prescribed antibiotics in both developing and industrialized countries
To verify the entry of GM into cochlear cells, confocal microscopy images were acquired from GM conjugated to Texas Red (GTTR) at 10-min intervals over a 30-min standard incubation time
No labeling of the supporting cells was observed under our incubation conditions. While this does not rule out the possibility of low-level uptake, we estimate that the concentration of GM in the pillar cells is at least 100-fold lower than in the sensory cells
Summary
Used for the treatment of life-threatening gram-negative bacterial infections, aminoglycoside (AG) antibiotics are one of the most commonly prescribed antibiotics in both developing and industrialized countries. As powerful and cost-effective broadspectrum antibiotics, AGs are attractive treatment options, in economically disadvantaged populations around the world.[1,2] They are used in industrialized countries to treat numerous infections.[3] Despite their high efficacy and potential to save numerous lives annually, AGs frequently cause nephrotoxicity and/or ototoxicity in patients undergoing treatment. This HL is triggered by damage and eventual loss of high- and low-frequency cochlear sensory cells (inner and outer hair cells)
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