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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 7

Mitochondrial-targeted electron sinks reduce mitochondrial and cytoplasmic oxidation following aminoglycoside exposure, and mitigate aminoglycoside toxicity.

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Mitochondrial-targeted electron sinks reduce mitochondrial and cytoplasm...
(A) Concentrations of TEMPOL and mitoTEMPO were determined by administration of either drug alone (solid lines) or with 200 μM neomycin (dashed lines). For subsequent experiments, cells were preincubated with 50 μM TEMPOL or mitoTEMPO for 30 minutes before neomycin exposure. n = 5 neuromasts from 5 animals per group. (B) Fluorescence intensity of cellROX or mitoSOX following pretreatment with TEMPOL or mitoTEMPO and coexposure to CsA. Hair cells were first loaded with indicator dye, then pretreated 30 minutes with TEMPOL or mitoTEMPO, followed by coexposure to CsA. One-way ANOVA, Tukey post-test. n = 15 (control), 19 (CsA), 21 (CsA + TEMPOL), and 20 (CsA + mitoTEMPO) neuromasts from 3 to 5 animals per group. (C) Effects of TEMPOL or mitoTEMPO pretreatment on hair cell number following neomycin exposure. n = 5 neuromasts from 5 animals per group from 2 experiments. (D) Maximal cellROX fluorescence change in dying cells after 50 μM neomycin exposure. n = 10 (neomycin), 7 (neomycin + TEMPOL), and 7 (neomycin + mitoTEMPO), from 3 animals per group. (E) Effects of mitoTEMPO cotreatment with CsA on hair cell number following neomycin exposure. n = 5 neuromasts from 5 animals per group. (F) Mean transformed (F/F0) HyPer intensity data in dying hair cells first exposed to mitoTEMPO, or CsA and mitoTEMPO, and then exposed to 50 μM neomycin. Fluorescence data were aligned to the point of cell clearance from the neuromast. The dashed bar represents (F/F0) of 1, corresponding to preneomycin baseline levels. n = 39 (50 μM neomycin, dying), 20 (CsA), and 11 (CsA + mitoTEMPO) cells from 1 to 3 neuromasts per animal. Two-way ANOVA in C and E, Tukey post-test. In D, 1-way ANOVA, Holm- Šidák post-test. In all instances, error bars = SEM; *P < 0.05, **P < 0.01, ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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