Role of mitochondrial dysfunction and mitochondrial DNA mutations in age-related hearing loss.

Mitochondrial DNA (mtDNA) mutations/deletions are considered to be associated with the development of age-related hearing loss (AHL). We assessed the role of accumulation of mtDNA mutations in the development of AHL using Polg(D257A) knock-in mouse, which exhibited increased spontaneous mtDNA mutation rates during aging and showed accelerated aging primarily due to increased apoptosis. They exhibited moderate hearing loss and degeneration of the hair cells, spiral ganglion cells and stria vascularis by 9 month of age, while wild-type animals did not. We next examined if mitochondrial damage induced by systemic application of germanium dioxide caused progressive hearing loss and cochlear damage. Guinea pigs and mice given germanium dioxide exhibited degeneration of the muscles and kidney and developed hearing loss due to degeneration of cochlear tissues, including the stria vascularis. Calorie restriction, which causes a metabolic shift toward increased energy metabolism in some organs, has been shown to attenuate AHL and age-related cochlear degeneration and to lower quantity of mtDNA deletions in the cochlea of mammals. Together these findings indicate that decreased energy metabolism due to accumulation of mtDNA mutations/deletions and decline of respiratory chain function play an important role in the manifestation of AHL.