Impacts of impaired mitochondrial dynamics in hearing loss: Potential therapeutic targets

Abstract

Mitochondria are the powerhouse of the cells. Under physiological conditions, mitochondrial fission and fusion maintain a dynamic equilibrium in the cytoplasm, which is referred to as mitochondrial dynamics. As an important approach to regulating mitochondrial function and quantity, the role of mitochondrial dynamics has been demonstrated in the pathogenesis of various disease models, including brain damage, neurodegeneration, and stress. As the vital organ of the peripheral auditory system, the cochlea consumes a significant amount of energy, and the maintenance of mitochondrial homeostasis is essential for the cochlear auditory capacity. OPA1 functions as both a necessary gene regulating mitochondrial fusion and a pathogenic gene responsible for auditory neuropathy, suggesting that an imbalance in mitochondrial dynamics may play a critical role in hearing loss, but relevant studies are few. In this review, we summarize recent evidence regarding the role of mitochondrial dynamics in the pathogenesis of noise-induced hearing loss (NIHL), drug-induced hearing loss, hereditary hearing loss, and age-related hearing loss. The impacts of impaired mitochondrial dynamics on hearing loss are discussed, and the potential of mitochondrial dynamics for the prevention and treatment of hearing loss is considered.

Keywords: OPA1; cochlea; hearing loss; mitochondrial dynamics; mitochondrial quality control.

FIGURE 1

Mitochondrial fission and fusion maintain a dynamic equilibrium via a series of molecules. The GTPase DRP1 located in the cytoplasm plays a dominant role in mitochondrial fission. The DRP1 receptor proteins FIS1, MFF, and MID49/51 are all distributed in the outer mitochondrial membrane. These receptor proteins can recruit DRP1 to the outer membrane to form a helical structure that hydrolyzes GTP, induces mitochondrial constriction and severing, and promotes mitochondrial fission. OPA1, MFN1, and MFN2 are three types of GTPases that govern mitochondrial fusion. MFN1 and MFN2 are localized in the outer mitochondrial membrane and form homologous or heterologous complexes that mediate mitochondrial coupling. OPA1 is involved in inner mitochondrial membrane fusion and the connection of cristae remodeling, and OPA1 mediates inner membrane fusion in turn after outer membrane fusion.

FIGURE 2

The possible role of abnormal mitochondrial dynamics in common forms of hearing loss. Stress conditions including aging, noise, ototoxic drugs, and heredity act on mitochondrial dynamics regulation-related proteins through various mechanisms, mitochondrial dynamics tend to be in the state of fission, excessive fission leads to increased ROS and cytochrome C production, reduced ATP production, mtDNA damage and the inhibition of autophagy, and eventually results in the death of auditory cells.