AAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivo
Abstract Background Uncoupling protein 2 (UCP2), activated by excessive reactive oxygen species (ROS) in vivo, has the dual effect of reducing ROS to protect against oxidative stress and reducing ATP production to regulate cellular metabolism. Both the UCP2 and ROS are increased in cochleae in age-r...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-10-01
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| Series: | Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s10020-022-00552-y |
| _version_ | 1811336561584766976 |
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| author | Chunli Zhao Zijing Yang Zhongrui Chen Wenqi Liang Shusheng Gong Zhengde Du |
| author_facet | Chunli Zhao Zijing Yang Zhongrui Chen Wenqi Liang Shusheng Gong Zhengde Du |
| author_sort | Chunli Zhao |
| collection | DOAJ |
| description | Abstract Background Uncoupling protein 2 (UCP2), activated by excessive reactive oxygen species (ROS) in vivo, has the dual effect of reducing ROS to protect against oxidative stress and reducing ATP production to regulate cellular metabolism. Both the UCP2 and ROS are increased in cochleae in age-related hearing loss (ARHL). However, the role of UCP2 in sensory hair cells in ARHL remains unclear. Methods Male C57BL/6 J mice were randomly assigned to an 8-week-old group (Group 1), a 16-week-old group (Group 2), a 16-week-old + adeno-associated virus-inner ear (AAV-ie) group (Group 3), and a 16-week-old + AAV-ie-UCP2 group (Group 4). Mice aged 8 weeks were administrated with AAV-ie-GFP or AAV-ie-UCP2 via posterior semicircular canal injection. Eight weeks after this viral intervention, hearing thresholds and wave-I amplitudes were tested by auditory brainstem response (ABR). Subsequently, the cochlear basilar membrane was dissected for investigation. The number of hair cells and inner hair cell (IHC) synapses, the level of ROS, and the expression of AMP-activated protein kinase α (AMPKα), were assessed by immunofluorescence staining. In addition, mitochondrial function was determined, and the expression of AMPKα and UCP2 proteins was further evaluated using western blotting. Results Mice with early-onset ARHL exhibited enhanced oxidative stress and loss of outer hair cells and IHC synapses, while UCP2 overexpression aggravated hearing loss and cochlear pathophysiological changes in mice. UCP2 overexpression resulted in a notable decrease in the number of IHCs and IHC synapses, caused ATP depletion and excessive ROS generation, increased AMPKα protein levels, and promoted IHC apoptosis, especially in the apical and middle turns of the cochlea. Conclusion Collectively, our data suggest that UCP2 overexpression may cause mitochondrial dysfunction via energy metabolism, which activates mitochondrion-dependent cellular apoptosis and leads to IHC loss, ultimately exacerbating ARHL. |
| first_indexed | 2024-04-13T17:41:17Z |
| format | Article |
| id | doaj.art-3a4525452203421891e0f913a6cafac1 |
| institution | Directory Open Access Journal |
| issn | 1076-1551 1528-3658 |
| language | English |
| last_indexed | 2024-04-13T17:41:17Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-3a4525452203421891e0f913a6cafac12022-12-22T02:37:10ZengBMCMolecular Medicine1076-15511528-36582022-10-0128111510.1186/s10020-022-00552-yAAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivoChunli Zhao0Zijing Yang1Zhongrui Chen2Wenqi Liang3Shusheng Gong4Zhengde Du5Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical UniversityDepartment of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical UniversityDepartment of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical UniversityDepartment of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical UniversityDepartment of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical UniversityDepartment of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical UniversityAbstract Background Uncoupling protein 2 (UCP2), activated by excessive reactive oxygen species (ROS) in vivo, has the dual effect of reducing ROS to protect against oxidative stress and reducing ATP production to regulate cellular metabolism. Both the UCP2 and ROS are increased in cochleae in age-related hearing loss (ARHL). However, the role of UCP2 in sensory hair cells in ARHL remains unclear. Methods Male C57BL/6 J mice were randomly assigned to an 8-week-old group (Group 1), a 16-week-old group (Group 2), a 16-week-old + adeno-associated virus-inner ear (AAV-ie) group (Group 3), and a 16-week-old + AAV-ie-UCP2 group (Group 4). Mice aged 8 weeks were administrated with AAV-ie-GFP or AAV-ie-UCP2 via posterior semicircular canal injection. Eight weeks after this viral intervention, hearing thresholds and wave-I amplitudes were tested by auditory brainstem response (ABR). Subsequently, the cochlear basilar membrane was dissected for investigation. The number of hair cells and inner hair cell (IHC) synapses, the level of ROS, and the expression of AMP-activated protein kinase α (AMPKα), were assessed by immunofluorescence staining. In addition, mitochondrial function was determined, and the expression of AMPKα and UCP2 proteins was further evaluated using western blotting. Results Mice with early-onset ARHL exhibited enhanced oxidative stress and loss of outer hair cells and IHC synapses, while UCP2 overexpression aggravated hearing loss and cochlear pathophysiological changes in mice. UCP2 overexpression resulted in a notable decrease in the number of IHCs and IHC synapses, caused ATP depletion and excessive ROS generation, increased AMPKα protein levels, and promoted IHC apoptosis, especially in the apical and middle turns of the cochlea. Conclusion Collectively, our data suggest that UCP2 overexpression may cause mitochondrial dysfunction via energy metabolism, which activates mitochondrion-dependent cellular apoptosis and leads to IHC loss, ultimately exacerbating ARHL.https://doi.org/10.1186/s10020-022-00552-yUCP2ARHLIHCAMPKαMitochondrionApoptosis |
| spellingShingle | Chunli Zhao Zijing Yang Zhongrui Chen Wenqi Liang Shusheng Gong Zhengde Du AAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivo Molecular Medicine UCP2 ARHL IHC AMPKα Mitochondrion Apoptosis |
| title | AAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivo |
| title_full | AAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivo |
| title_fullStr | AAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivo |
| title_full_unstemmed | AAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivo |
| title_short | AAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivo |
| title_sort | aav ie mediated ucp2 overexpression accelerates inner hair cell loss during aging in vivo |
| topic | UCP2 ARHL IHC AMPKα Mitochondrion Apoptosis |
| url | https://doi.org/10.1186/s10020-022-00552-y |
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