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Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death
Robert Esterberg, … , Edwin W. Rubel, David W. Raible
Robert Esterberg, … , Edwin W. Rubel, David W. Raible
Published August 8, 2016
Citation Information: J Clin Invest. 2016;126(9):3556-3566. https://doi.org/10.1172/JCI84939.
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Research Article Otology

Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death

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Abstract

Exposure to aminoglycoside antibiotics can lead to the generation of toxic levels of reactive oxygen species (ROS) within mechanosensory hair cells of the inner ear that have been implicated in hearing and balance disorders. Better understanding of the origin of aminoglycoside-induced ROS could focus the development of therapies aimed at preventing this event. In this work, we used the zebrafish lateral line system to monitor the dynamic behavior of mitochondrial and cytoplasmic oxidation occurring within the same dying hair cell following exposure to aminoglycosides. The increased oxidation observed in both mitochondria and cytoplasm of dying hair cells was highly correlated with mitochondrial calcium uptake. Application of the mitochondrial uniporter inhibitor Ru360 reduced mitochondrial and cytoplasmic oxidation, suggesting that mitochondrial calcium drives ROS generation during aminoglycoside-induced hair cell death. Furthermore, targeting mitochondria with free radical scavengers conferred superior protection against aminoglycoside exposure compared with identical, untargeted scavengers. Our findings suggest that targeted therapies aimed at preventing mitochondrial oxidation have therapeutic potential to ameliorate the toxic effects of aminoglycoside exposure.

Authors

Robert Esterberg, Tor Linbo, Sarah B. Pickett, Patricia Wu, Henry C. Ou, Edwin W. Rubel, David W. Raible

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Figure 4

Timing of mitochondrial oxidation relative to mitochondrial membrane potential in dying hair cells exposed to aminoglycosides.

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Timing of mitochondrial oxidation relative to mitochondrial membrane pot...
(A) Mean mitoSOX fluorescence in dying lateral line hair cells colabeled with TMRE and exposed to 400 μM neomycin. Data are aligned to TMREhalf-min, corresponding to dye redistribution from mitochondria into cytoplasm. (B) Relationship between maximal mitoSOX and TMRE fluorescence. Points represent paired maximal fluorescence data from individual cells. (C) Relationship between rise in fluorescence signal of mitoSOX and TMRE relative to cell clearance. Points represent paired data from the time that either indicator reached its half-maximal value relative to the time of cell clearance. Error bars = SEM; n = 39 cells from 1 to 3 neuromasts per animal and 6 animals.
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