title: Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death.
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
authors: R
authors: Esterberg
authors: Tor
authors: T
authors: Linbo
authors: Sarah B
authors: SB
authors: Pickett
authors: Patricia
authors: P
authors: Wu
authors: Henry C
authors: HC
authors: Ou
authors: Edwin W
authors: EW
authors: Rubel
authors: David W
authors: DW
authors: Raible
mesh_terms: D000617:Aminoglycosides / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D006198:Hair Cells, Auditory / Q000187:drug effects*; D053403:Lateral Line System; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019076:Transgenes; D015027:Zebrafish
chemical_list: D000617:Aminoglycosides; D017382:Reactive Oxygen Species; D010100:Oxygen; D002118:Calcium