SIRT3 promotes auditory function in young adult FVB/nJ mice but is dispensable for hearing recovery after noise exposure

Abstract

Noise-induced hearing loss (NIHL) affects millions of people worldwide and presents a large social and personal burden. Pharmacological activation of SIRT3, a regulator of the mitochondrial oxidative stress response, has a protective effect on hearing thresholds after traumatic noise damage in mice. In contrast, the role of endogenously activated SIRT3 in hearing recovery has not been established. Here we tested the hypothesis that SIRT3 is required in mice for recovery of auditory thresholds after a noise exposure that confers a temporary threshold shift (TTS). SIRT3-specific immunoreactivity is present in outer hair cells, around the post-synaptic regions of inner hair cells, and faintly within inner hair cells. Prior to noise exposure, homozygous Sirt3-KO mice have slightly but significantly higher thresholds than their wild-type littermates measured by the auditory brainstem response (ABR), but not by distortion product otoacoustic emissions (DPOAE). Moreover, homozygous Sirt3-KO mice display a significant reduction in the progression of their peak 1 amplitude at higher frequencies prior to noise exposure. After exposure to a single sub-traumatic noise dose that does not permanently reduce cochlear function, compromise cell survival, or damage synaptic structures in wild-type mice, there was no difference in hearing function between the two genotypes, measured by ABR and DPOAE. The numbers of hair cells and auditory synapses were similar in both genotypes before and after noise exposure. These loss-of-function studies complement previously published gain-of-function studies and help refine our understanding of SIRT3's role in cochlear homeostasis under different damage paradigms. They suggest that SIRT3 may promote spiral ganglion neuron function. They imply that cellular mechanisms of homeostasis, in addition to the mitochondrial oxidative stress response, act to restore hearing after TTS. Finally, we present a novel application of a biomedical statistical analysis for identifying changes between peak 1 amplitude progressions in ABR waveforms after damage.

Activity regulates a cell type-specific mitochondrial phenotype in zebrafish lateral line hair cells

“…Promoting mitochondrial fusion is protective against starvation-mediated apoptosis ( Gomes et al, 2011 ) and SIRTs also regulate mitochondrial fusion ( Uddin et al, 2021 ). SIRT3, located to mitochondria, has been implicated in counteracting age-related hearing loss and noise-induced damage ( Someya and Prolla, 2010 ; Brown et al, 2014 ; Patel et al, 2020 ).…”

Early-Onset Hearing Loss in Mouse Models of Alzheimer’s Disease and Increased DNA Damage in the Cochlea

“…Mitochondrial SIRT3, the NAD + -dependent deacetylase, plays an important role in hair cell survival by regulating mitochondrial function 31,55 , modulating reactive oxygen species, and limiting oxidative damage to cellular components [56][57][58] . We hypothesized that SIRT3 alteration in the cochlea may be involved in the hearing loss in AD.…”