Abstract
Aging is associated with functional and morphological changes in the sensory organs, including the auditory system. Mitophagy, a process that regulates the turnover of dysfunctional mitochondria, is impaired with aging. This study aimed to investigate the effect of aging on mitophagy in the central auditory system using an age-related hearing loss mouse model. C57BL/6J mice were divided into the following four groups based on age: 1-, 6-, 12-, and 18-month groups. The hearing ability was evaluated by measuring the auditory brainstem response (ABR) thresholds. The mitochondrial DNA damage level and the expression of mitophagy-related genes, and proteins were investigated by real-time polymerase chain reaction and Western blot analyses. The colocalization of mitophagosomes and lysosomes in the mouse auditory cortex and inferior colliculus was analyzed by immunofluorescence analysis. The expression of genes involved in mitophagy, such as PINK1, Parkin, and BNIP3 in the mouse auditory cortex and inferior colliculus, was investigated by immunohistochemical staining. The ABR threshold increased with aging. In addition to the mitochondrial DNA integrity, the mRNA levels of PINK1, Parkin, NIX, and BNIP3, as well as the protein levels of PINK1, Parkin, BNIP3, COX4, LC3B, mitochondrial oxidative phosphorylation (OXPHOS) subunits I–IV in the mouse auditory cortex significantly decreased with aging. The immunofluorescence analysis revealed that the colocalization of mitophagosomes and lysosomes in the mouse auditory cortex and inferior colliculus decreased with aging. The immunohistochemical analysis revealed that the expression of PINK1, Parkin, and BNIP3 decreased in the mouse auditory cortex and inferior colliculus with aging. These findings indicate that aging-associated impaired mitophagy may contribute to the cellular changes observed in an aged central auditory system, which result in age-related hearing loss. Thus, the induction of mitophagy can be a potential therapeutic strategy for age-related hearing loss.
Highlights
Presbycusis or age-related hearing loss is the most common type of sensory disorder among the elderly that results in irreversible sensorineural hearing loss
To investigate the change of hearing loss with aging, hearing thresholds of 8, 16, and 32 kHz in 1, 6, 12, and 18-month groups were evaluated by measuring auditory brainstem response (ABR)
These results indicate that mitochondrial damage in the auditory cortex and hearing thresholds increased with aging
Summary
Presbycusis or age-related hearing loss is the most common type of sensory disorder among the elderly that results in irreversible sensorineural hearing loss. The major site of auditory system that is affected by age-related changes is the cochlea. Age-related pathological changes in the cochlea include the loss of hair cells and spiral ganglion neurons, as well as atrophy of stria vascularis [2,3]. The age-related changes affect the entire auditory system, including the peripheral and central auditory systems [3]. The accumulation of dysfunctional mitochondria results in impaired energy metabolism, which subsequently plays a key role in the development of age-related hearing loss. Aging is associated with increased number of mitochondrial defects [11]. These findings indicate that mitochondrial dysfunction is involved in age-related hearing loss
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