Therapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiency
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 investi...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-01-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231718307298 |
| _version_ | 1831689943895769088 |
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| author | Ye-Ri Kim Jeong-In Baek Sung Hwan Kim Min-A Kim Byeonghyeon Lee Nari Ryu Kyung-Hee Kim Deok-Gyun Choi Hye-Min Kim Michael P. Murphy Greg Macpherson Yeon-Sik Choo Jinwoong Bok Kyu-Yup Lee Jeen-Woo Park Un-Kyung Kim |
| author_facet | Ye-Ri Kim Jeong-In Baek Sung Hwan Kim Min-A Kim Byeonghyeon Lee Nari Ryu Kyung-Hee Kim Deok-Gyun Choi Hye-Min Kim Michael P. Murphy Greg Macpherson Yeon-Sik Choo Jinwoong Bok Kyu-Yup Lee Jeen-Woo Park Un-Kyung Kim |
| author_sort | Ye-Ri Kim |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-20T10:58:37Z |
| format | Article |
| id | doaj.art-d71b374266564676820b6c5f775c1afa |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-20T10:58:37Z |
| publishDate | 2019-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-d71b374266564676820b6c5f775c1afa2022-12-21T19:43:04ZengElsevierRedox Biology2213-23172019-01-0120544555Therapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiencyYe-Ri Kim0Jeong-In Baek1Sung Hwan Kim2Min-A Kim3Byeonghyeon Lee4Nari Ryu5Kyung-Hee Kim6Deok-Gyun Choi7Hye-Min Kim8Michael P. Murphy9Greg Macpherson10Yeon-Sik Choo11Jinwoong Bok12Kyu-Yup Lee13Jeen-Woo Park14Un-Kyung Kim15Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, KNU Creative BioResearch Group (BK21 Plus Project), Kyungpook National University, Daegu, Republic of KoreaDepartment of Aroma-Applied Industry, College of Herbal Bio-industry, Daegu Haany University, Gyeongsan, Republic of KoreaDepartment of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, KNU Creative BioResearch Group (BK21 Plus Project), Kyungpook National University, Daegu, Republic of KoreaDepartment of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, KNU Creative BioResearch Group (BK21 Plus Project), Kyungpook National University, Daegu, Republic of KoreaDepartment of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, KNU Creative BioResearch Group (BK21 Plus Project), Kyungpook National University, Daegu, Republic of KoreaDepartment of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, KNU Creative BioResearch Group (BK21 Plus Project), Kyungpook National University, Daegu, Republic of KoreaDepartment of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, KNU Creative BioResearch Group (BK21 Plus Project), Kyungpook National University, Daegu, Republic of KoreaDepartment of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of KoreaDepartment of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, KNU Creative BioResearch Group (BK21 Plus Project), Kyungpook National University, Daegu, Republic of KoreaMedical Research Council (MRC)-Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, United KingdomAntipodean Pharmaceuticals Inc, L2 14 Viaduct Harbour Rd, Auckland, New ZealandDepartment of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of KoreaDepartment of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea; BK21PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of KoreaDepartment of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Corresponding author.School of Life Sciences, KNU Creative BioResearch Group (BK21 Plus Project), Kyungpook National University, Daegu, Republic of Korea; Department of Biochemistry, School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea; Corresponding author at: School of Life Sciences, KNU Creative BioResearch Group (BK21 Plus Project), Kyungpook National University, Daegu, Republic of Korea.Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, KNU Creative BioResearch Group (BK21 Plus Project), Kyungpook National University, Daegu, Republic of Korea; Corresponding author at: School of Life Sciences, KNU Creative BioResearch Group (BK21 Plus Project), Kyungpook National University, Daegu, Republic of Korea.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, MitoQhttp://www.sciencedirect.com/science/article/pii/S2213231718307298 |
| spellingShingle | Ye-Ri Kim Jeong-In Baek Sung Hwan Kim Min-A Kim Byeonghyeon Lee Nari Ryu Kyung-Hee Kim Deok-Gyun Choi Hye-Min Kim Michael P. Murphy Greg Macpherson Yeon-Sik Choo Jinwoong Bok Kyu-Yup Lee Jeen-Woo Park Un-Kyung Kim Therapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiency Redox Biology |
| title | Therapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiency |
| title_full | Therapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiency |
| title_fullStr | Therapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiency |
| title_full_unstemmed | Therapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiency |
| title_short | Therapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiency |
| title_sort | therapeutic potential of the mitochondria targeted antioxidant mitoq in mitochondrial ros induced sensorineural hearing loss caused by idh2 deficiency |
| url | http://www.sciencedirect.com/science/article/pii/S2213231718307298 |
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