Inhibition of DRP-1-Dependent Mitophagy Promotes Cochlea Hair Cell Senescence and Exacerbates Age-Related Hearing Loss

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 (H 2 O 2) 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 H 2 O 2 , 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.

Mitophagy Impairment Aggravates Cisplatin-Induced Ototoxicity

“…Conversely, an activator of mitophagy, the mitochondrial membrane depolarizing agent CCCP [27], actually decreases the cisplatin-induced cytotoxicity which corroborates a previous report suggesting that autophagy suppresses ROS accumulation and oxidative stress in hair cells, thereby preventing cell death [28,29]. Induction of mitophagy mitigates aging-induced cardiovascular damages [30] in addition to promoting hair cell senescence and aggravating agerelated hearing loss [31]. Mitophagy could also lead to the failure of activation of apoptosis and induce resistance of cancer cells to chemotherapeutic treatment [32].…”

Targeting cellular senescence based on interorganelle communication, multilevel proteostasis, and metabolic control

“…For instance, some authors have correlated the accumulation of aberrant mitochondria in senescent cells to insufficient turnover of mitochondrial population due to decreased mitophagic activity and lysosomal dysfunction [ 30 , 40 ]. Likewise, dysfunctional Dnm1l (dynamin 1 like, also known as Drp1)‐dependent mitophagy triggers senescence and contributes to age‐related hearing loss in mice [ 41 ]. Yet, in a model of 3D skin equivalents, pyruvate protected dermal fibroblasts from senescence by improving mitophagic activity and mitochondrial turnover [ 42 ].…”

Age-Related Hearing Loss in C57BL/6J Mice Is Associated with Mitophagy Impairment in the Central Auditory System

“…Moreover, reduced mitophagy was observed in aged cochlea, which increased hearing loss [ 29 ]. This is supported by a study found that the inhibition of dynamin-related protein-1 (DRP-1), which initiates mitophagy, promotes cochlear hair cell senescence and exacerbates age-related hearing loss [ 30 ].…”