Therapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiency
| Autor: | Sung Hwan Kim, Kyung-Hee Kim, Ye-Ri Kim, Greg Macpherson, Hye-Min Kim, Min-A Kim, Kyu-Yup Lee, Nari Ryu, Jeong-In Baek, Un-Kyung Kim, Byeonghyeon Lee, Deok-Gyun Choi, Michael P. Murphy, Yeon-Sik Choo, Jeen-Woo Park, Jinwoong Bok |
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| Přispěvatelé: | Murphy, Mike [0000-0003-1115-9618], Apollo - University of Cambridge Repository |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Mitochondrial ROS Ubiquinone Clinical Biochemistry Fluorescent Antibody Technique Apoptosis Mitochondrion medicine.disease_cause Biochemistry MitoQ chemistry.chemical_compound Mice 0302 clinical medicine lcsh:QH301-705.5 Mice Knockout lcsh:R5-920 Homozygote ROS Immunohistochemistry Isocitrate Dehydrogenase Cell biology Mitochondria medicine.anatomical_structure Hair cell Idh2 Antioxidant lcsh:Medicine (General) Spiral Ganglion Oxidation-Reduction Research Paper Hearing Loss Sensorineural 03 medical and health sciences Organophosphorus Compounds Ototoxicity Hair Cells Auditory medicine otorhinolaryngologic diseases Animals Cochlea Spiral ganglion Organic Chemistry Hearing loss medicine.disease Disease Models Animal Oxidative Stress 030104 developmental biology chemistry lcsh:Biology (General) NADP+ NADP(+) sense organs Reactive Oxygen Species 030217 neurology & neurosurgery Oxidative stress Biomarkers |
| Zdroj: | Redox Biology Redox Biology, Vol 20, Iss, Pp 544-555 (2019) |
| ISSN: | 2213-2317 |
| Popis: | 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: Idh2, NADP+, ROS, Hearing loss, Antioxidant, MitoQ |
| Databáze: | OpenAIRE |
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