Effects of mitochondrial mutations on hearing and cochlear pathology with age.

Age-related hearing loss is a multi-factorial process involving genetic and environmental factors, including exposure to noise and ototoxic agents, as well as pathological processes. Among these is the accumulation of mitochondrial DNA mutations and deletions. The creation of a transgenic mouse with a loss-of-function deletion of the nuclear gene that encodes the polymerase required to repair damaged mitochondrial DNA (PolgA) enabled evaluation of age-related cochlear pathology associated with random mitochondrial DNA deletions that accrue over the lifespan of the mouse. In comparison with their wild-type or heterozygous counterparts, animals with mutated DNA polymerase gamma developed hearing loss most rapidly. Any loss of mitochondrial DNA polymerase function however, resulted in detrimental effects, as evidenced by hearing tests and histological investigation of transgenic heterozygotes. Cochlear pathology in transgenic animals at 10 months of age included loss of neurons and clumping of surviving neurons in the apical turn of the spiral ganglion. Mitochondrial mutations in young animals, on the other hand, were protective against the development of temporary threshold shift in response to relatively low level noise exposure. This supports the idea that temporary threshold shifts are the result of an active process involving mitochondria and respiratory chain activity. Our results indicate that mitochondrial mutation and deletion can certainly contribute to the development of an aging phenotype, specifically age-related hearing loss.