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

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cam.issuedOnline2018-11-20
dc.contributor.authorKim, Ye-Ri
dc.contributor.authorBaek, Jeong-In
dc.contributor.authorKim, Sung Hwan
dc.contributor.authorKim, Min-A
dc.contributor.authorLee, Byeonghyeon
dc.contributor.authorRyu, Nari
dc.contributor.authorKim, Kyung-Hee
dc.contributor.authorChoi, Deok-Gyun
dc.contributor.authorKim, Hye-Min
dc.contributor.authorMurphy, Michael P
dc.contributor.authorMacpherson, Greg
dc.contributor.authorChoo, Yeon-Sik
dc.contributor.authorBok, Jinwoong
dc.contributor.authorLee, Kyu-Yup
dc.contributor.authorPark, Jeen-Woo
dc.contributor.authorKim, Un-Kyung
dc.contributor.orcidMurphy, Mike [0000-0003-1115-9618]
dc.date.accessioned2019-01-03T00:30:16Z
dc.date.available2019-01-03T00:30:16Z
dc.date.issued2019-01
dc.description.abstractMitochondrial 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.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.34789
dc.identifier.eissn2213-2317
dc.identifier.issn2213-2317
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/287484
dc.languageeng
dc.language.isoeng
dc.publisherElsevier BV
dc.publisher.urlhttp://dx.doi.org/10.1016/j.redox.2018.11.013
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAntioxidant
dc.subjectHearing loss
dc.subjectIdh2
dc.subjectMitoQ
dc.subjectNADP(+)
dc.subjectROS
dc.subjectAnimals
dc.subjectApoptosis
dc.subjectBiomarkers
dc.subjectDisease Models, Animal
dc.subjectFluorescent Antibody Technique
dc.subjectHair Cells, Auditory
dc.subjectHearing Loss, Sensorineural
dc.subjectHomozygote
dc.subjectImmunohistochemistry
dc.subjectIsocitrate Dehydrogenase
dc.subjectMice
dc.subjectMice, Knockout
dc.subjectMitochondria
dc.subjectOrganophosphorus Compounds
dc.subjectOxidation-Reduction
dc.subjectOxidative Stress
dc.subjectReactive Oxygen Species
dc.subjectSpiral Ganglion
dc.subjectUbiquinone
dc.titleTherapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiency.
dc.typeArticle
dcterms.dateAccepted2018-11-18
prism.endingPage555
prism.publicationDate2019
prism.publicationNameRedox Biol
prism.startingPage544
prism.volume20
pubs.funder-project-idMedical Research Council (MC_UU_00015/3)
rioxxterms.licenseref.startdate2019-01
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1016/j.redox.2018.11.013

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