AUTHOR=Lin Hanqing , Xiong Hao , Su Zhongwu , Pang Jiaqi , Lai Lan , Zhang Huasong , Jian Bingquan , Zhang Weijian , Zheng Yiqing
TITLE=Inhibition of DRP-1-Dependent Mitophagy Promotes Cochlea Hair Cell Senescence and Exacerbates Age-Related Hearing Loss
JOURNAL=Frontiers in Cellular Neuroscience
VOLUME=13
YEAR=2019
URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2019.00550
DOI=10.3389/fncel.2019.00550
ISSN=1662-5102
ABSTRACT=Background: Mitochondrial dysfunction is considered to contribute to the development of age-related hearing loss (AHL). The regulation of mitochondrial function requires mitochondrial quality control, which includes mitophagy and dynamics. Dynamin-related Protein 1 (DRP-1) is believed to play a central role in this regulation. However, the underlying mechanism of DRP-1 in AHL remains unclear. Here, we examined whether the decline of DRP-1-dependent mitophagy contributes to the development of AHL.
Methods: We induced cellular and cochlear senescence using hydrogen peroxide (H2O2) and evaluated the level of senescence through senescence-associated β-galactosidase staining. We evaluated mitophagy levels via fluorescence imaging and Western Blotting of LC3II and P62. Mitochondrial function was assessed by ATP assay, mtDNA assay, and JC-1.
Results: We found that both the expression of DRP-1 and the mitophagy level decreased in senescent cells and aged mice. DRP-1 overexpression in HEI-OC1 cells initiated mitophagy and preserved mitochondrial function when exposed to H2O2, while cells with DRP-1 silencing displayed otherwise. Moreover, inhibition of DRP-1 by Mdivi-1 blocked mitophagy and exacerbated hearing loss in aged C57BL/6 mice.
Conclusion: These results indicated that DRP-1 initiated mitophagy, eliminated mitochondrial dysfunction, and may protect against oxidative stress-induced senescence. These results provide a potential therapeutic target for AHL.