Mitochondrial Calcium Transporters Mediate Sensitivity to Noise-Induced Losses of Hair Cells and Cochlear Synapses

Abstract

Mitochondria modulate cellular calcium homeostasis by the combined action of the mitochondrial calcium uniporter (MCU), a selective calcium entry channel, and the sodium calcium exchanger (NCLX), which extrudes calcium from mitochondria. In this study, we investigated MCU and NCLX in noise-induced hearing loss (NIHL) using adult CBA/J mice and noise-induced alterations of inner hair cell (IHC) synapses in MCU knockout mice. Following noise exposure, immunoreactivity of MCU increased in cochlear sensory hair cells of the basal turn, while immunoreactivity of NCLX decreased in a time- and exposure-dependent manner. Inhibition of MCU activity via MCU siRNA pretreatment or the specific pharmacological inhibitor Ru360 attenuated noise-induced loss of sensory hair cells and synaptic ribbons, wave I amplitudes, and NIHL in CBA/J mice. This protection was afforded, at least in part, through reduced cleavage of caspase 9 (CC9). Furthermore, MCU knockout mice on a hybrid genetic CD1 and C57/B6 background showed resistance to noise-induced seizures compared to wild-type littermates. Owing to the CD1 background, MCU knockouts and littermates suffer genetic high frequency hearing loss, but their IHCs remain intact. Noise-induced loss of IHC synaptic connections and reduction of auditory brainstem response (ABR) wave I amplitude were recovered in MCU knockout mice. These results suggest that cellular calcium influx during noise exposure leads to mitochondrial calcium overload via MCU and NCLX. Mitochondrial calcium overload, in turn, initiates cell death pathways and subsequent loss of hair cells and synaptic connections, resulting in NIHL.

Outcomes of Peptide Vaccine GV1001 Treatment in a Murine Model of Acute Noise-Induced Hearing Loss

“…In detail, the ROS and RNS generation have been associated with dysregulation of Ca 2+ homeostasis and NADPH oxidase expression, even though the precise origin and mechanism of generation of free radical species resulting from noise exposure remain elusive. Previous literature indicates that acoustic overstimulation increases the Ca 2+ trafficking into the hair cells via intracellular and extracellular routes, subsequently changing mitochondrial membrane permeability to allow ROS release by the mitochondria [36,37]. In other words, Ca 2+ and ROS can crosstalk between intracellular organs [38].…”

Synaptic mitochondria regulate hair-cell synapse size and function

“…In auditory hair cells, excitotoxic noise damage can also alter ribbon size and lead to hearing deficits (Jensen et al, 2015; Liberman et al, 2015). Excitotoxic damage is thought to be initiated by mito-Ca 2+ overload and subsequent ROS production (Böttger and Schacht, 2013; Wang et al, 2018). Mechanistically, precisely how ribbon size is established during development or altered under pathological conditions is not fully understood.…”

Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: A Systematic Review

“…The mitochondrial calcium uniporter (MCU) is a major specific calcium channel for calcium uptake from the cytosol into mitochondria [51] and the overexpression of MCU renders cells susceptible to apoptotic cell death [52]. Noise exposure caused an overexpression of MCU in HCs of the cochlear basal turn [53]. Inhibiting MCU resulted in the attenuation of NIHL with prevention of noise-induced OHC loss and noise-induced loss of IHC synaptic ribbons [53].…”

“…Noise exposure caused an overexpression of MCU in HCs of the cochlear basal turn [53]. Inhibiting MCU resulted in the attenuation of NIHL with prevention of noise-induced OHC loss and noise-induced loss of IHC synaptic ribbons [53].…”