Increased burden of mitochondrial DNA deletions and point mutations in early-onset age-related hearing loss in mitochondrial mutator mice

Mitochondrial DNA (mtDNA) mutations are thought to have a causal role in a variety of age-related neurode-generative diseases, including age-related hearing loss (AHL). In the current study, we investigated the roles of mtDNA deletions and point mutations in AHL in mitochondrial mutator mice (Polg(mut/mut)) that were backcrossed onto CBA/CaJ mice, a well-established model of late-onset AHL. mtDNA deletions accumulated significantly with age in the inner ears of Polg(mut/mut) mice, while there were no differences in mtDNA deletion frequencies in the inner ears between 5 and 17 months old Polg(+/+)( )mice or 5 months old Polg(+/+) and Polg(mut/mut) mice. mtDNA deletions also accumulated significantly in the inner ears of CBA/CaJ mice during normal aging. In contrast, 5 months old Polg(mut/mut) mice displayed a 238-fold increase in mtDNA point mutation frequencies in the inner ears compared to age-matched Pole(+/+) mice, but there were no differences in mtDNA point mutation frequencies in the inner ears between 5 and 17 months old Polg(mut/mut )mice. Seventeen-month-old Polg(mut/mut) mice also displayed early-onset severe hearing loss associated with a significant reduction in neural output of the cochlea, while age-matched Polg(+/+) mice displayed little or no hearing impairment. Consistent with the physiological and mtDNA deletion test result, 17-month-old Polg(mut/mut) mice displayed a profound loss of spiral ganglion neurons in the cochlea. Thus, our data suggest that a higher burden of mtDNA point mutations from a young age and age-related accumulation of mtDNA deletions likely contribute to early-onset AHL in mitochondrial mutator mice.