| RRC ID |
49683
|
| 著者 |
Esterberg R, Linbo T, Pickett SB, Wu P, Ou HC, Rubel EW, Raible DW.
|
| タイトル |
Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death.
|
| ジャーナル |
J Clin Invest
|
| 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.
|
| 巻・号 |
126(9)
|
| ページ |
3556-66
|
| 公開日 |
2016-9-1
|
| DOI |
10.1172/JCI84939
|
| PII |
84939
|
| PMID |
27500493
|
| PMC |
PMC5004972
|
| MeSH |
Aminoglycosides / adverse effects*
Aminoglycosides / pharmacology
Animals
Calcium / metabolism*
Cell Death / drug effects*
Cytoplasm / metabolism
Disease Models, Animal
Hair Cells, Auditory / drug effects*
Lateral Line System
Mitochondria / metabolism*
Oxidation-Reduction
Oxygen / chemistry
Reactive Oxygen Species / metabolism*
Transgenes
Zebrafish
|
| IF |
11.864
|
| 引用数 |
42
|
| リソース情報 |
| ゼブラフィッシュ |
Tg(atoh1a:dTomato) |
