Hearing Impairment in a Mouse Model of Diabetes Is Associated with Mitochondrial Dysfunction, Synaptopathy, and Activation of the Intrinsic Apoptosis Pathway
Although previous studies continuously report an increased risk of hearing loss in diabetes patients, the impact of the disease on the inner ear remains unexplored. Herein, we examine the pathophysiology of diabetes-associated hearing impairment and cochlear synaptopathy in a mouse model of diabetes...
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MDPI AG
2021-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/16/8807 |
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| author | Ah-Ra Lyu Tae-Hwan Kim Sun-Ae Shin Eung-Hyub Kim Yang Yu Akanksha Gajbhiye Hyuk-Chan Kwon A Reum Je Yang Hoon Huh Min Jung Park Yong-Ho Park |
| author_facet | Ah-Ra Lyu Tae-Hwan Kim Sun-Ae Shin Eung-Hyub Kim Yang Yu Akanksha Gajbhiye Hyuk-Chan Kwon A Reum Je Yang Hoon Huh Min Jung Park Yong-Ho Park |
| author_sort | Ah-Ra Lyu |
| collection | DOAJ |
| description | Although previous studies continuously report an increased risk of hearing loss in diabetes patients, the impact of the disease on the inner ear remains unexplored. Herein, we examine the pathophysiology of diabetes-associated hearing impairment and cochlear synaptopathy in a mouse model of diabetes. Male B6.BKS(D)-<i>Lepr</i><sup>db</sup>/J (db/db, diabetes) and heterozygote (db/+, control) mice were assigned into each experimental group (control vs. diabetes) based on the genotype and tested for hearing sensitivity every week from 6 weeks of age. Each cochlea was collected for histological and biological assays at 14 weeks of age. The diabetic mice exerted impaired hearing and a reduction in cochlear blood flow and C-terminal-binding protein 2 (CtBP2, a presynaptic ribbon marker) expression. Ultrastructural images revealed severely damaged mitochondria from diabetic cochlea accompanied by a reduction in Cytochrome c oxidase subunit 4 (COX4) and CR6-interacting factor 1 (CRIF1). The diabetic mice presented significantly decreased levels of platelet endothelial cell adhesion molecule (PECAM-1), B-cell lymphoma 2 (BCL-2), and procaspase-9, but not procaspase-8. Importantly, significant changes were not found in necroptotic programmed cell death markers (receptor-interacting serine/threonine-protein kinase 1, RIPK1; RIPK3; and mixed lineage kinase domain-like pseudokinase, MLKL) between the groups. Taken together, diabetic hearing loss is accompanied by synaptopathy, microangiopathy, damage to the mitochondrial structure/function, and activation of the intrinsic apoptosis pathway. Our results imply that mitochondrial dysfunction is deeply involved in diabetic hearing loss, and further suggests the potential benefits of therapeutic strategies targeting mitochondria. |
| first_indexed | 2024-03-10T08:45:22Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T08:45:22Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f9e45ee6a22c4ad98d3f10e38b8e88152023-11-22T08:00:44ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-012216880710.3390/ijms22168807Hearing Impairment in a Mouse Model of Diabetes Is Associated with Mitochondrial Dysfunction, Synaptopathy, and Activation of the Intrinsic Apoptosis PathwayAh-Ra Lyu0Tae-Hwan Kim1Sun-Ae Shin2Eung-Hyub Kim3Yang Yu4Akanksha Gajbhiye5Hyuk-Chan Kwon6A Reum Je7Yang Hoon Huh8Min Jung Park9Yong-Ho Park10Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, KoreaBiomedical Convergence Research Center, Chungnam National University Hospital, Daejeon 35015, KoreaBrain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, KoreaDepartment of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, KoreaDepartment of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, KoreaDepartment of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, KoreaDepartment of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, KoreaElectron Microscopy Research Center, Korea Basic Science Institute, Cheongju 28119, KoreaElectron Microscopy Research Center, Korea Basic Science Institute, Cheongju 28119, KoreaDepartment of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, KoreaDepartment of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, KoreaAlthough previous studies continuously report an increased risk of hearing loss in diabetes patients, the impact of the disease on the inner ear remains unexplored. Herein, we examine the pathophysiology of diabetes-associated hearing impairment and cochlear synaptopathy in a mouse model of diabetes. Male B6.BKS(D)-<i>Lepr</i><sup>db</sup>/J (db/db, diabetes) and heterozygote (db/+, control) mice were assigned into each experimental group (control vs. diabetes) based on the genotype and tested for hearing sensitivity every week from 6 weeks of age. Each cochlea was collected for histological and biological assays at 14 weeks of age. The diabetic mice exerted impaired hearing and a reduction in cochlear blood flow and C-terminal-binding protein 2 (CtBP2, a presynaptic ribbon marker) expression. Ultrastructural images revealed severely damaged mitochondria from diabetic cochlea accompanied by a reduction in Cytochrome c oxidase subunit 4 (COX4) and CR6-interacting factor 1 (CRIF1). The diabetic mice presented significantly decreased levels of platelet endothelial cell adhesion molecule (PECAM-1), B-cell lymphoma 2 (BCL-2), and procaspase-9, but not procaspase-8. Importantly, significant changes were not found in necroptotic programmed cell death markers (receptor-interacting serine/threonine-protein kinase 1, RIPK1; RIPK3; and mixed lineage kinase domain-like pseudokinase, MLKL) between the groups. Taken together, diabetic hearing loss is accompanied by synaptopathy, microangiopathy, damage to the mitochondrial structure/function, and activation of the intrinsic apoptosis pathway. Our results imply that mitochondrial dysfunction is deeply involved in diabetic hearing loss, and further suggests the potential benefits of therapeutic strategies targeting mitochondria.https://www.mdpi.com/1422-0067/22/16/8807cochlear mitochondriamicroangiopathysynaptopathysensory lossapoptosisnecroptosis |
| spellingShingle | Ah-Ra Lyu Tae-Hwan Kim Sun-Ae Shin Eung-Hyub Kim Yang Yu Akanksha Gajbhiye Hyuk-Chan Kwon A Reum Je Yang Hoon Huh Min Jung Park Yong-Ho Park Hearing Impairment in a Mouse Model of Diabetes Is Associated with Mitochondrial Dysfunction, Synaptopathy, and Activation of the Intrinsic Apoptosis Pathway International Journal of Molecular Sciences cochlear mitochondria microangiopathy synaptopathy sensory loss apoptosis necroptosis |
| title | Hearing Impairment in a Mouse Model of Diabetes Is Associated with Mitochondrial Dysfunction, Synaptopathy, and Activation of the Intrinsic Apoptosis Pathway |
| title_full | Hearing Impairment in a Mouse Model of Diabetes Is Associated with Mitochondrial Dysfunction, Synaptopathy, and Activation of the Intrinsic Apoptosis Pathway |
| title_fullStr | Hearing Impairment in a Mouse Model of Diabetes Is Associated with Mitochondrial Dysfunction, Synaptopathy, and Activation of the Intrinsic Apoptosis Pathway |
| title_full_unstemmed | Hearing Impairment in a Mouse Model of Diabetes Is Associated with Mitochondrial Dysfunction, Synaptopathy, and Activation of the Intrinsic Apoptosis Pathway |
| title_short | Hearing Impairment in a Mouse Model of Diabetes Is Associated with Mitochondrial Dysfunction, Synaptopathy, and Activation of the Intrinsic Apoptosis Pathway |
| title_sort | hearing impairment in a mouse model of diabetes is associated with mitochondrial dysfunction synaptopathy and activation of the intrinsic apoptosis pathway |
| topic | cochlear mitochondria microangiopathy synaptopathy sensory loss apoptosis necroptosis |
| url | https://www.mdpi.com/1422-0067/22/16/8807 |
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