Molecular regulation of auditory hair cell death and approaches to protect sensory receptor cells and/or stimulate repair following acoustic trauma.

Christine T Dinh,Esperanza Bas,Stefania Goncalves,Azel Zine,Thomas R Van De Water

doi:10.3389/fncel.2015.00096

Abstract

Loss of auditory sensory hair cells (HCs) is the most common cause of hearing loss. This review addresses the signaling pathways that are involved in the programmed and necrotic cell death of auditory HCs that occur in response to ototoxic and traumatic stressor events. The roles of inflammatory processes, oxidative stress, mitochondrial damage, cell death receptors, members of the mitogen-activated protein kinase (MAPK) signal pathway and pro- and anti-cell death members of the Bcl-2 family are explored. The molecular interaction of these signal pathways that initiates the loss of auditory HCs following acoustic trauma is covered and possible therapeutic interventions that may protect these sensory HCs from loss via apoptotic or non-apoptotic cell death are explored.

Highlights

Auditory hair cells (HCs) are important for the conversion of acoustic sound energy into electrical impulses that travel to the auditory centers of the brain for hearing
There are several signaling pathways that are involved in apoptosis and necrosis of auditory HCs, including (1) expression of extracellular pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα) and recruited of neutrophils and macrophages to the cochlea; and (2) generation of oxidative stress in the form of ROS and reactive nitrogen species (RNS) such as superoxide (O.2−), peroxynitrite (ONOO−), and hydroxyl (OH·) radicals (Figure 2)
It is hypothesized that FOXO3 can regulate the expression and activation of various pro-apoptotic and pro-survival proteins of the Bcl-2 family that can lead to mitochondrial stress, transient opening of the MPT pore, collapse of the mitochondrial membrane potential, release of mitochondrial pro-death proteins into the cytoplasm, and transient increases in ROS from the electron transport chain (ETC)

Summary

Introduction

Auditory hair cells (HCs) are important for the conversion of acoustic sound energy into electrical impulses that travel to the auditory centers of the brain for hearing. Genetic mutations can cause structural or physiologic abnormalities within the cochlea and impair cochlear homeostasis. These insults to the inner ear can promote cell death of auditory HCs and hearing loss. Several signaling cascades are activated following an insult to the cochlea; these pathways can be pro-inflammatory, pro-death, and even pro-survival. The signaling cascades that occur on a cellular and a molecular level are highly complex and in many ways entwine; there is significant cross communication between pathways and it is the culmination of all of these activities that tilt the pendulum of cell survival and cell death in one direction or the other. Several drug therapies take advantage of key events that occur following acoustic injury by targeting, promoting, or inhibiting different pathways that favor cell survival

Cell Death

Auditory Hair Cell Death

Stress Signaling in Auditory Hair Cell Death

Acoustic Trauma and Auditory HC Death

Conclusion