PROJECT SUMMARY
Metabolic presbyacusis is a major type of age-related hearing loss (ARHL) associated with decreased
endocochlear potential and elevated auditory thresholds due to degeneration of the stria vascularis (SV). The
SV, located in the lateral wall of the cochlea, is a highly active, bioenergetic, vascularized epithelium that
conducts essential functions necessary for driving hair cell transduction. Recent studies have identified strial
atrophy and pathological alterations of the strial microvasculature, marked by immune cell activation as important
factors contributing to age-related cochlear degeneration. Our recent study suggest that age-related aberrant
macrophage activity is an initial contributor to strial dysfunction, cochlear pathology, and hearing loss. Using an
established ARHL mouse model, we showed increased macrophage activation and inflammation in the SV
beginning at middle age, an age at which there is minimal loss of sensory hair cells and cochlear neurons.
Related to these findings, recent evidence signifies mitochondrial dysfunction to be strongly associated with
immune cell dysregulation. Specifically, the release of mitochondrial damage associated molecular patterns
(mtDAMPs) via impaired mitochondrial quality control (ex. fission & mitophagy) can initiate an inflammatory
response. Our preliminary data using quantitative ultrastructural and immunohistochemical approaches reveal
significant age-related reductions in mitochondrial size and metabolic activity within marginal cells of the SV. In
addition, significant alterations in mitochondrial quality control, which is aimed at preserving mitochondrial
integrity and metabolic activity, was observed beginning at middle age in an ARHL mouse model. Based on these
observations, our central hypothesis is that strial degeneration results from impaired mitochondrial quality
control in marginal cells of the aged cochlea, contributing to increased oxidative stress, macrophage activation,
and inflammation. In Aim 1, we will test the hypothesis that strial dysfunction/degeneration results from
exacerbated mitochondrial fission and subsequent impaired mitophagy in marginal cells of the aged cochlea,
leading to increased oxidative stress and reduced mitochondrial metabolic activity. A well-characterized ARHL
mouse model and a newly developed SV ex vivo system will be employed where the assessment of mitochondrial
quality control, mitochondrial ROS levels, and respiratory capacity within strial marginal cells will be elucidated
over the course of aging. In Aim 2, we will test the hypothesis that impaired mitochondrial quality control
propagates the activation of strial macrophages leading to inflammation via the release of mtDAMPs in marginal
cells of the aged cochlea. A cochlea specific genetic mouse model will be used to determine the extent to which
deletion of Oma1, master regulator of stress induced mitochondrial fission, impacts strial macrophage activation
and inflammation. Ultimately, understanding age-related mitochondrial alterations in the cochlea will aid in the
development of therapeutic agents designed to combat inflammation within the aging inner ear.
