Excessive processing and acetylation of OPA1 aggravate age‐related hearing loss via the dysregulation of mitochondrial dynamics

Author:

Zhang Andi123ORCID,Pan Yi123,Wang Hao123,Ding Rui123,Zou Tianyuan123,Guo Dongye123,Shen Yilin123,Ji Peilin123,Huang Weiyi123,Wen Qing123,Wang Quan123,Hu Haixia123,Wu Jichang123,Xiang Mingliang1234,Ye Bin1234ORCID

Affiliation:

1. Department of Otolaryngology & Head and Neck Surgery, Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai China

2. Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases Shanghai China

3. Ear Institute Shanghai Jiao Tong University School of Medicine Shanghai China

4. Department of Audiology & Speech‐Language Pathology, College of Health Science and Technology Shanghai Jiao Tong University School of Medicine Shanghai China

Abstract

AbstractThe pathogenesis of age‐related hearing loss (ARHL) remains unclear. OPA1 is the sole fusion protein currently known to be situated in the inner mitochondrial membrane, which is pivotal for maintaining normal mitochondrial function. While it has already been demonstrated that mutations in OPA1 may lead to hereditary deafness, its involvement in the occurrence and development of ARHL has not been previously explored. In our study, we constructed D‐gal‐induced senescent HEI‐OC1 cells and the cochlea of C57BL/6J mice with a mutated SUMOylation site of SIRT3 using CRISPR/Cas9 technology. We found enhanced L‐OPA1 processing mediated by activated OMA1, and increased OPA1 acetylation resulting from reductions in SIRT3 levels in senescent HEI‐OC1 cells. Consequently, the fusion function of OPA1 was inhibited, leading to mitochondrial fission and pyroptosis in hair cells, ultimately exacerbating the aging process of hair cells. Our results suggest that the dysregulation of mitochondrial dynamics in cochlear hair cells in aged mice can be ameliorated by activating the SIRT3/OPA1 signaling. This has the potential to alleviate the senescence of cochlear hair cells and reduce hearing loss in mice. Our study highlights the significant roles played by the quantities of long and short chains and the acetylation activity of OPA1 in the occurrence and development of ARHL. This finding offers new perspectives and potential targets for the prevention and treatment of ARHL.

Funder

Science and Technology Commission of Shanghai Municipality

National Natural Science Foundation of China

Publisher

Wiley

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