Therapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiency.
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Authors
Kim, Ye-Ri
Baek, Jeong-In
Kim, Sung Hwan
Kim, Min-A
Lee, Byeonghyeon
Ryu, Nari
Kim, Kyung-Hee
Choi, Deok-Gyun
Kim, Hye-Min
Macpherson, Greg
Choo, Yeon-Sik
Bok, Jinwoong
Lee, Kyu-Yup
Park, Jeen-Woo
Kim, Un-Kyung
Publication Date
2019-01Journal Title
Redox Biol
ISSN
2213-2317
Publisher
Elsevier BV
Volume
20
Pages
544-555
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Kim, Y., Baek, J., Kim, S. H., Kim, M., Lee, B., Ryu, N., Kim, K., et al. (2019). Therapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiency.. Redox Biol, 20 544-555. https://doi.org/10.1016/j.redox.2018.11.013
Abstract
Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) is a major NADPH-producing enzyme which is essential for maintaining the mitochondrial redox balance in cells. We sought to determine whether IDH2 deficiency induces mitochondrial dysfunction and modulates auditory function, and investigated the protective potential of an antioxidant agent against reactive oxygen species (ROS)-induced cochlear damage in Idh2 knockout (Idh2-/-) mice. Idh2 deficiency leads to damages to hair cells and spiral ganglion neurons (SGNs) in the cochlea and ultimately to apoptotic cell death and progressive sensorineural hearing loss in Idh2-/- mice. Loss of IDH2 activity led to decreased levels of NADPH and glutathione causing abnormal ROS accumulation and oxidative damage, which might trigger apoptosis signal in hair cells and SGNs in Idh2-/- mice. We performed ex vivo experiments to determine whether administration of mitochondria-targeted antioxidants might protect or induce recovery of cells from ROS-induced apoptosis in Idh2-deficient mouse cochlea. MitoQ almost completely neutralized the H2O2-induced ototoxicity, as the survival rate of Idh2-/- hair cells were restored to normal levels. In addition, the lack of IDH2 led to the accumulation of mitochondrial ROS and the depolarization of ΔΨm, resulting in hair cell loss. In the present study, we identified that IDH2 is indispensable for the functional maintenance and survival of hair cells and SGNs. Moreover, the hair cell degeneration caused by IDH2 deficiency can be prevented by MitoQ, which suggests that Idh2-/- mice could be a valuable animal model for evaluating the therapeutic effects of various antioxidant candidates to overcome ROS-induced hearing loss.
Keywords
Spiral Ganglion, Mitochondria, Animals, Mice, Knockout, Mice, Hearing Loss, Sensorineural, Disease Models, Animal, Reactive Oxygen Species, Organophosphorus Compounds, Ubiquinone, Isocitrate Dehydrogenase, Fluorescent Antibody Technique, Immunohistochemistry, Apoptosis, Oxidation-Reduction, Oxidative Stress, Homozygote, Hair Cells, Auditory, Biomarkers
Sponsorship
Medical Research Council (MC_UU_00015/3)
Identifiers
External DOI: https://doi.org/10.1016/j.redox.2018.11.013
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287484
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