Mitochondrial Damage and Necroptosis in Aging Cochlea.

Ah-Ra Lyu,Tae Hwan Kim,Sung Jae Park,Yong-Ho Park,Yang Hoon Huh,A Reum Je,Sun-Ae Shin,Yang Yu,Seong-Hun Jeong,Min Jung Park

doi:10.3390/ijms21072505

Abstract

Age-related hearing loss (ARHL) is an irreversible, progressive neurodegenerative disorder and is presently untreatable. Previous studies using animal models have suggested mitochondrial damage and programmed cell death to be involved with ARHL. Thus, we further investigated the pathophysiologic role of mitochondria and necroptosis in aged C57BL/6J male mice. Aged mice (20 months old) exhibited a significant loss of hearing, number of hair cells, neuronal fibers, and synaptic ribbons compared to young mice. Ultrastructural analysis of aged cochleae revealed damaged mitochondria with absent or disorganized cristae. Aged mice also showed significant decrease in cochlear blood flow, and exhibited increase in gene expression of proinflammatory cytokines (IL-1β, IL-6, and TNF-α), receptor-interacting serine/threonine-protein kinase 1 and 3 (RIPK1 and RIPK3) and the pseudokinase mixed-lineage kinase domain-like (MLKL). Immunofluorescence (IF) assays of cytochrome C oxidase I (COX1) confirmed mitochondrial dysfunction in aged cochleae, which correlated with the degree of mitochondrial morphological damage. IF assays also revealed localization and increased expression of RIPK3 in sensorineural tissues that underwent significant necroptosis (inner and outer hair cells and stria vascularis). Together, our data shows that the aging cochlea exhibits damaged mitochondria, enhanced synthesis of proinflammatory cytokines, and provides new evidence of necroptosis in the aging cochlea in in vivo.

Highlights

One in five people over the age of 50 has imperfect hearing, and almost half of those aged over 65 years have hearing difficulties [1,2,3,4]
Our results suggest that the aging cochleae exhibit significant proinflammatory and necroptotic responses when compared to the young cochleae, providing novel evidence that necroptosis is involved in cochlear aging in vivo
We identified increased RIPK3 level in the aging cochlea, especially in the inner and outer hair cells and stria vascularis

Summary

Introduction

One in five people over the age of 50 has imperfect hearing, and almost half of those aged over 65 years have hearing difficulties [1,2,3,4]. Presbycusis, termed age-related hearing loss (ARHL), is an irreversible hearing impairment associated with aging due to limited repair capacity of sensorineural tissues in the cochlea. In order to identify pathologic changes in the aged cochleae, we utilized C57BL/6J mice to investigate the pathophysiology of ARHL, as this strain displays accelerated, high-frequency hearing loss by 3–6 months of age and profound hearing impairment by 15 months of age [6,7,8,9,10,11]. As mitochondria play key roles in both the respiratory chain and cell death, animal models of ARHL often exhibit defects in mitochondrial enzyme activities and mitochondrial-mediated apoptosis. Idh2-knockout mice exhibit accelerated ARHL progression, accompanied by a profound loss of hair cells and spiral ganglion neurons (SGNs), an increase in oxidative damage, and increased apoptotic cell death [15]. The mitochondrial proapoptotic BCL2-antagonist/killer 1 (Bak) gene mediates ARHL in C57BL/6J mice by enhancing mitochondrial fission and cellular apoptosis, both of which are systematic responses to oxidative stress [10]

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