Abstract
Aging has been associated with mitochondrial DNA damage. P66Shc is an age-related adaptor protein that has a substantial impact on mitochondrial metabolism through regulation of the cellular response to oxidative stress. Our study aimed to establish a D-galactose (D-gal)-induced inner ear aging mouse model and to investigate the potential role of p66Shc and its serine 36-phosphorylated form in the inner ear during aging by using this model. Real-time PCR was performed to detect the mtDNA 3873-bp deletion and the level of p66Shc mRNA in the cochlear lateral wall. Western blot analysis was performed to analyze the total and mitochondrial protein levels of p66Shc and the level of Ser36-P-p66Shc in the cochlear lateral wall. Immunofluoresence was performed to detect the location of the Ser36-P-p66Shc expression in the cochlear lateral wall. The results showed that the accumulation of the mtDNA 3873-bp deletion, total and mitochondrial protein levels of p66Shc and level of Ser36-P-p66Shc were significantly increased in the cochlear lateral wall of the D-gal-treated group when compared to the control group and that Ser36-P-p66Shc was mainly localized in the cytoplasm of the cells in the stria vascularis. During aging, the oxidative stress-related increase of p66Shc and Ser36-P-p66Shc might be associated with the accumulation of the mtDNA 3873-bp deletion in the inner ear.
Highlights
Age-related hearing loss (ARHL) or presbycusis is the most common sensory deficit in the elderly, and it has become a severe social and health problem
D-gal did not Induce Hearing Loss To determine the effect of the mitochondrial DNA (mtDNA) 3873-bp deletion on hearing, the auditory status was evaluated with auditory brainstem responses (ABR) after the last D-gal administration
According to the oxidative stress theory by Denham Harman, the age-related loss of physiological function is due to the progressive accumulation of oxidative damage, which determines the lifespan of an organism [39]
Summary
Age-related hearing loss (ARHL) or presbycusis is the most common sensory deficit in the elderly, and it has become a severe social and health problem. Many theories underlying presbycusis have been proposed, the overall mechanisms remain speculative Among these theories, many studies support the idea that a mitochondrial malfunction plays an important role in presbycusis [1,2,3]. The 3867-bp deletion in mice that corresponds to the mtDNA 4977-bp deletion in humans and the mtDNA 4834-bp deletion in rats, which are called common deletions (CD), is the most common mtDNA damage associated with aging [7,8,9]. According to the NCBI reference sequence for mtDNA (NC_005089.1), there are 6 bp added to the mtDNA 3867-bp deletion. Previous studies have suggested that the mtDNA deletion is associated with pathological disorders of presbycusis in human beings, rats and mice [10,11,12,13]. We have previously utilized overdoses of D-galactose (D-gal) to induce an aging model of rats, which harbor increased amounts of the mtDNA 4834-bp deletion in the central and peripheral
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