Cellular mechanisms of noise-induced hearing loss

Abstract

Exposure to intense sound or noise can result in purely temporary threshold shift (TTS), or leave a residual permanent threshold shift (PTS) along with alterations in growth functions of auditory nerve output. Recent research has revealed a number of mechanisms that contribute to noise-induced hearing loss (NIHL). The principle cause of NIHL is damage to cochlear hair cells and associated synaptopathy. Contributions to TTS include reversible damage to hair cell (HC) stereocilia or synapses, while moderate TTS reflects protective purinergic hearing adaptation. PTS represents permanent damage to or loss of HCs and synapses. While the substrates of HC damage are complex, they include the accumulation of reactive oxygen species and the active stimulation of intracellular stress pathways, leading to programmed and/or necrotic cell death. Permanent damage to cochlear neurons can also contribute to the effects of NIHL, in addition to HC damage. These mechanisms have translational potential for pharmacological intervention and provide multiple opportunities to prevent HC damage or to rescue HCs and spiral ganglion neurons that have suffered injury. This paper reviews advances in our understanding of cellular mechanisms that contribute to NIHL and their potential for therapeutic manipulation.

Keywords: Apoptosis; Damage signaling; Hair cell; Noise-induced hearing loss; Pharmacotherapy; Survival signaling.

Fig. 1.. Diagram illustrating damage processes and pathways thought to contribute to HC loss due to acoustic overexposure.

Noise initiates the production of ROS via release of Ca²⁺ from the endoplasmic reticulum and/or entry from extracellular fluid, which induces release of ROS from mitochondria, and by activation of NADPH oxidases. ROS can activate NF-κB, leading to the production of pro-inflammatory cytokines, and also κRas/cdc42/JNK pathway leading to the expression of stress and apoptosis genes. Pro-apoptotic factors further increase mitochondrial membrane permeability, leading to the release of additional ROS. The JNK pathway can be inhibited by the ERK MAPK or AKT, signaling molecules that can be activated by growth factors.

Fig. 2.. Diagram of the intrinsic pathway of apoptosis.

Apoptosis can be initiated when pro-apoptotic proteins such as BAX or BAD which overwhelm anti-apoptotic proteins of the BCL family. This destabilizes mitochondrial membranes, releasing Cytochrome c into the cytoplasm. Interaction of Cytochrome c with APAF forms an apoptosome, which enzymatically cleaves pro-caspase 1 into its active form. This initiator caspase in turn cleaves executor caspases (3, 6 and 7), which mediate programmed death and orderly fragmentation of the cell.