Mitochondrial Dysfunction in Age-Related Hearing Loss
Age-related hearing loss (ARHL), also known as presbycusis, affects 1 in 5 people over age 50 and is irreversible.
This study suggests that age-related mitochondrial dysfunction could cause the neuron loss associated with ARHL.
Mitochondria play a role in neuronal cell death through pathways in sensorineural tissue, leading to impaired hearing.
Aged mice with hearing loss and aged cochleae had damaged mitochondria, reduced cochlear blood flow and increased proinflammatory cytokines.
In today's open access paper, researchers present evidence to suggest that the mitochondrial dysfunction that accompanies aging may be a meaningful cause of the loss of neurons that contributes age-related hearing loss, in the sense that it increases the incidence of necroptosis, a form of programmed cell death. Present thinking on the progressive deafness of old age is that the sensory hair cells of the inner ear largely remain intact, but their connection to the brain atrophies - the nerve cells in question dying in excessive numbers for reasons that continue to be explored.
Mitochondria are the power plants of the cell, producing chemical energy store molecules necessary for cellular processes to run, but they are also deeply involved in the various ways in which cells can undergo programmed cell death. With age, mitochondria become less efficient, they become larger the balance between fission and fusion changes, and the quality control mechanism of mitophagy, responsible for removing damaged mitochondria, falters. This contributes to most of the manifestations of aging in some way, and thus it is important for the research community to push ahead in the development of potential means of restoring mitochondrial function in older people.
Approximately one in five people over the age of 50 have imperfect hearing, and almost half of those aged over 65 years have hearing difficulties. Presbycusis, also termed age-related hearing loss (ARHL), is an irreversible hearing impairment associated with aging due to limited repair capacity of sensorineural tissues in the cochlea. Unfortunately, there is no effective cure for the patients, and future treatment development is still questionable due to lack of mechanistic insight. In order to identify pathologic changes in the aged cochleae, we utilized C57BL/6J mice to investigate the pathophysiology of ARHL, as this strain displays accelerated, high-frequency hearing loss by 3-6 months of age and profound hearing impairment by 15 months of age.
Mitochondria are involved in the metabolic dysregulation associated with ARHL pathology. Morphologically, damage is apparent in the outer hair cells (OHCs) of animal ARHL models. Mitochondria are the principal source of reactive oxygen species (ROS), the production of which is closely associated with ARHL progression. Antioxidants alleviate the deleterious effects of ROS and effectively treat oxidative stress-related diseases in an animal model of ARHL. As mitochondria play key roles in both the respiratory chain and cell death, animal models of ARHL often exhibit defects in mitochondrial enzyme activities and mitochondrial-mediated apoptosis.
Neuronal cell death occurs through various pathways in sensorineural tissue, leading to hearing impairment. Necroptosis is a programmed cell death that exhibits necrosis-like morphological characteristics. The most defined molecular pathway of necroptosis is mediated by TNF-α receptor through receptor-interacting serine/threonine-protein kinase 1 and 3 (RIPK1 and RIPK3) and the pseudokinase mixed-lineage kinase domain-like (MLKL).
We identified increased RIPK3 level in the aging cochlea, especially in the inner and outer hair cells and stria vascularis. Pronounced reduction in cytochrome c oxidase subunits 1 (COX1) and 4 (COX4), indicating that the mitochondria of the aging cochleae were dysfunctional, correlated with the degree of mitochondrial morphological damage. Hearing impairment found in aging animals was associated with a loss of sensory hair cells and neuronal filaments. Our data suggest that mitochondrial degeneration and necroptosis may play a critical role in the pathophysiology of ARHL and provide mechanistic insights for future therapeutic development.