Therapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiency.

TitleTherapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiency.
Publication TypeJournal Article
Year of Publication2019
AuthorsKim, Y-R, Baek, J-I, Kim, SHwan, Kim, M-A, Lee, B, Ryu, N, Kim, K-H, Choi, D-G, Kim, H-M, Murphy, MP, Macpherson, G, Choo, Y-S, Bok, J, Lee, K-Y, Park, J-W, Kim, U-K
JournalRedox Biol
Volume20
Pagination544-555
Date Published2019 01
ISSN2213-2317
KeywordsAnimals, Apoptosis, Biomarkers, Disease Models, Animal, Fluorescent Antibody Technique, Hair Cells, Auditory, Hearing Loss, Sensorineural, Homozygote, Immunohistochemistry, Isocitrate Dehydrogenase, Mice, Mice, Knockout, Mitochondria, Organophosphorus Compounds, Oxidation-Reduction, Oxidative Stress, Reactive Oxygen Species, Spiral Ganglion, Ubiquinone
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 HO-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 ΔΨ, 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.

DOI10.1016/j.redox.2018.11.013
Alternate JournalRedox Biol
Citation Key10.1016/j.redox.2018.11.013
PubMed ID30508699
PubMed Central IDPMC6279977