Chunli Zhao1,2, Zijing Yang1,2, Shusheng Gong3,4, Zhengde Du5,6, Zhongrui Chen1,2, Wenqi Liang1,2. 1. Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, No. 95, Yong'an Road, Xicheng, Beijing, 100050, China. 2. Clinical Center for Hearing Loss, Capital Medical University, Beijing, 100050, China. 3. Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, No. 95, Yong'an Road, Xicheng, Beijing, 100050, China. gongss@ccmu.edu.cn. 4. Clinical Center for Hearing Loss, Capital Medical University, Beijing, 100050, China. gongss@ccmu.edu.cn. 5. Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, No. 95, Yong'an Road, Xicheng, Beijing, 100050, China. duzhengde@ccmu.edu.cn. 6. Clinical Center for Hearing Loss, Capital Medical University, Beijing, 100050, China. duzhengde@ccmu.edu.cn.
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.
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.
Authors: Francis Rousset; German Nacher-Soler; Marta Coelho; Sten Ilmjarv; Vivianne Beatrix Christina Kokje; Antoine Marteyn; Yves Cambet; Michael Perny; Marta Roccio; Vincent Jaquet; Pascal Senn; Karl Heinz Krause Journal: Redox Biol Date: 2020-01-20 Impact factor: 11.799
Authors: Dong Jun Park; Sunmok Ha; Jin Sil Choi; Su Hoon Lee; Jeong-Eun Park; Young Joon Seo Journal: Int J Mol Sci Date: 2020-09-25 Impact factor: 5.923