Mitochondria are highly dynamic multifaceted organelles with various functions including cellular energy metabolism, reactive oxygen species (ROS) generation, calcium homeostasis, and apoptosis. Because of these diverse functions, mitochondria are key regulators of cell survival and death, and their dysfunction is implicated in numerous diseases, particularly neurodegenerative disorders such as Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease. One of the most common neurodegenerative disorders is sensorineural hearing loss (SNHL). SNHL primarily originates from the degenerative changes in the cochlea, which is the auditory portion of the inner ear. Many cochlear cells contain an abundance of mitochondria and are metabolically highly active, rendering them susceptible to mitochondrial dysfunction. Indeed, the causal role of mitochondrial dysfunction in SNHL progression is well established, and therefore, targeted for treatment. In this review, we aim to compile the emerging findings in the literature indicating the role of mitochondrial dysfunction in the progression of sensorineural hearing loss and highlight potential therapeutics targeting mitochondrial dysfunction for hearing loss treatment.

There is considerable interest in whether sensory deficiency is associated with the development of Alzheimers disease (AD). Notably, the relationship between hearing impairment and AD is of high relevance but still poorly understood. In this study, we found early-onset hearing loss in two AD mouse models, 3xTgAD and 3xTgAD/Polβ+/-. The 3xTgAD/Polβ+/- mouse is DNA repair deficient and has more humanized AD features than the 3xTgAD. Both AD mouse models showed increased auditory brainstem response (ABR) thresholds between 16 and 32 kHz at 4 weeks of age, much earlier than any AD cognitive and behavioral changes. The ABR thresholds were significantly higher in 3xTgAD/Polβ+/- mice than in 3xTgAD mice at 16 kHz, and distortion product otoacoustic emission signals were reduced, indicating that DNA damage may be a factor underlying early hearing impairment in AD. Poly ADP-ribosylation and protein expression levels of DNA damage markers increased significantly in the cochlea of the AD mice but not in the adjacent auditory cortex. Phosphoglycerate mutase 2 levels and the number of synaptic ribbons in the presynaptic zones of inner hair cells were decreased in the cochlea of the AD mice. Furthermore, the activity of sirtuin 3 was downregulated in the cochlea of these mice, indicative of impaired mitochondrial function. Taken together, these findings provide new insights into potential mechanisms for hearing dysfunction in AD and suggest that DNA damage in the cochlea might contribute to the development of early hearing loss in AD.

Age-related hearing loss (ARHL) is the most common sensory disability associated with human aging. Yet, there are no approved measures for preventing or treating this debilitating condition. With its slow progression, continuous and safe approaches are critical for ARHL treatment. Nicotinamide Riboside (NR), a NAD+ precursor, is well tolerated even for long-term use and is already shown effective in various disease models including Alzheimer's and Parkinson's disease. It has also been beneficial against noise-induced hearing loss and in hearing loss associated with premature aging. However, its beneficial impact on ARHL is not known. Using two different wild-type mouse strains, we show that long-term NR administration prevents the progression of ARHL. Through transcriptomic and biochemical analysis, we find that NR administration restores age-associated reduction in cochlear NAD+ levels, upregulates biological pathways associated with synaptic transmission and PPAR signaling, and reduces the number of orphan ribbon synapses between afferent auditory neurons and inner hair cells. We also find that NR targets a novel pathway of lipid droplets in the cochlea by inducing the expression of CIDEC and PLIN1 proteins that are downstream of PPAR signaling and are key for lipid droplet growth. Taken together, our results demonstrate the therapeutic potential of NR treatment for ARHL and provide novel insights into its mechanism of action.