RRC ID 49683
Author Esterberg R, Linbo T, Pickett SB, Wu P, Ou HC, Rubel EW, Raible DW.
Title Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death.
Journal 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.
Volume 126(9)
Pages 3556-66
Published 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 12.282
Times Cited 42
Zebrafish Tg(atoh1a:dTomato)