Structural Abnormalities in Inner Hair Cells Following Kanamycin-Induced Outer Hair Cell Loss

Mutations in a number of genes encoding mitochondrial aminoacyl-tRNA synthetases lead to non-syndromic and/or syndromic sensorineural hearing loss in humans, while their cellular and physiological pathology in cochlea has rarely been investigated in vivo. In this study, we showed that histidyl-tRNA synthetase HARS2, whose deficiency is associated with Perrault syndrome 2 (PRLTS2), is robustly expressed in postnatal mouse cochlea including the outer and inner hair cells. Targeted knockout of Hars2 in mouse hair cells resulted in delayed onset (P30), rapidly progressive hearing loss similar to the PRLTS2 hearing phenotype. Significant hair cell loss was observed starting from P45 following elevated reactive oxygen species (ROS) level and activated mitochondrial apoptotic pathway. Despite of normal ribbon synapse formation, whole-cell patch clamp of the inner hair cells revealed reduced calcium influx and compromised sustained synaptic exocytosis prior to the hair cell loss at P30, consistent with the decreased supra-threshold wave I amplitudes of the auditory brainstem response. Starting from P14, increasing proportion of morphologically abnormal mitochondria was observed by transmission electron microscope, exhibiting swelling, deformation, loss of cristae and emergence of large intrinsic vacuoles that are associated with mitochondrial dysfunction. Though the mitochondrial abnormalities are more prominent in inner hair cells, it is the outer hair cells suffering more severe cell loss. Taken together, our results suggest that conditional knockout of Hars2 in mouse cochlear hair cells leads to accumulating mitochondrial dysfunction and ROS stress, triggers progressive hearing loss highlighted by hair cell synaptopathy and apoptosis, and is differentially perceived by inner and outer hair cells.

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Selective Inner Hair Cell Loss in a Neonate Harbor Seal (Phoca vitulina)

Animals ◽

10.3390/ani12020180 ◽

2022 ◽

Vol 12 (2) ◽

pp. 180

Author(s):

Maria Morell ◽

Laura Rojas ◽

Martin Haulena ◽

Björn Busse ◽

Ursula Siebert ◽

...

Keyword(s):

Hair Cell ◽

Hair Cells ◽

Marine Mammal ◽

Cell Loss ◽

Harbor Seal ◽

Phoca Vitulina ◽

Outer Hair Cells ◽

Hair Cell Loss ◽

Inner Hair Cell ◽

Inner Hair Cells

Congenital hearing loss is recognized in humans and other terrestrial species. However, there is a lack of information on its prevalence or pathophysiology in pinnipeds. It is important to have baseline knowledge on marine mammal malformations in the inner ear, to differentiate between congenital and acquired abnormalities, which may be caused by infectious pathogens, age, or anthropogenic interactions, such as noise exposure. Ultrastructural evaluation of the cochlea of a neonate harbor seal (Phoca vitulina) by scanning electron microscopy revealed bilateral loss of inner hair cells with intact outer hair cells. The selective inner hair cell loss was more severe in the basal turn, where high-frequency sounds are encoded. The loss of inner hair cells started around 40% away from the apex or tip of the spiral, reaching a maximum loss of 84.6% of hair cells at 80–85% of the length from the apex. Potential etiologies and consequences are discussed. This is believed to be the first case report of selective inner hair cell loss in a marine mammal neonate, likely congenital.

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Oral Ethanol Potentiates the Loss of Outer Hair Cells in Cisplatin-Exposed Rats

Otolaryngology ◽

10.1016/j.otohns.2007.03.006 ◽

2007 ◽

Vol 137 (2) ◽

pp. 327-331 ◽

Cited By ~ 1

Author(s):

Dilip Madnani ◽

Geming Li ◽

Christopher M. Frenz ◽

Dorothy A. Frenz

Keyword(s):

Hair Cell ◽

Hair Cells ◽

Outer Hair Cell ◽

Fold Increase ◽

Cell Loss ◽

Saline Group ◽

Outer Hair Cells ◽

Hair Cell Loss ◽

Auditory Hair Cells ◽

Ethanol Group

OBJECTIVE: The aim of this study was to examine the effect of oral ethanol on cisplatin ototoxicity. STUDY DESIGN AND SETTING: Twenty-seven-week-old, female Fisher 344 rats were divided into 4 experimental groups. The animals were administered per os (PO) saline (group 1), PO ethanol (group 2), PO saline with intraperitoneal (IP) cisplatin (group 3), or PO ethanol with IP cisplatin (group 4). After 3 days, scanning electron microscopy and counts of outer auditory hair cells were performed. RESULTS: A 2-fold increase in outer hair cell loss was obtained in the basal cochlear turn of rats receiving concomitant cisplatin and ethanol compared with animals receiving cisplatin and saline. No hair cell loss was observed in the middle cochlear turn of any experimental group. CONCLUSION: Our findings support potentiation of ototoxicity when cisplatin is combined with oral ethanol. SIGNIFICANCE: Contraindications for alcohol use in cancer patients receiving cisplatin are implicated.

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Prestin-Dependence of Outer Hair Cell Survival and Partial Rescue of Outer Hair Cell Loss in PrestinV499G/Y501H Knockin Mice

PLoS ONE ◽

10.1371/journal.pone.0145428 ◽

2015 ◽

Vol 10 (12) ◽

pp. e0145428 ◽

Cited By ~ 8

Author(s):

Mary Ann Cheatham ◽

Roxanne M. Edge ◽

Kazuaki Homma ◽

Emily L. Leserman ◽

Peter Dallos ◽

...

Keyword(s):

Hair Cell ◽

Cell Survival ◽

Outer Hair Cell ◽

Cell Loss ◽

Hair Cell Loss

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Noise-induced and age-related hearing loss: new perspectives and potential therapies

F1000Research ◽

10.12688/f1000research.11310.1 ◽

2017 ◽

Vol 6 ◽

pp. 927 ◽

Cited By ~ 78

Author(s):

M Charles Liberman

Keyword(s):

Hearing Loss ◽

Hair Cell ◽

Sensorineural Hearing Loss ◽

Hair Cells ◽

Auditory Nerve ◽

Cell Loss ◽

Sensorineural Hearing ◽

Hair Cell Loss ◽

Age Related ◽

Age Related Hearing Loss

The classic view of sensorineural hearing loss has been that the primary damage targets are hair cells and that auditory nerve loss is typically secondary to hair cell degeneration. Recent work has challenged that view. In noise-induced hearing loss, exposures causing only reversible threshold shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of the synaptic connections between hair cells and the auditory nerve. Similarly, in age-related hearing loss, degeneration of cochlear synapses precedes both hair cell loss and threshold elevation. This primary neural degeneration has remained a “hidden hearing loss” for two reasons: 1) the neuronal cell bodies survive for years despite loss of synaptic connection with hair cells, and 2) the degeneration is selective for auditory nerve fibers with high thresholds. Although not required for threshold detection when quiet, these high-threshold fibers are critical for hearing in noisy environments. Research suggests that primary neural degeneration is an important contributor to the perceptual handicap in sensorineural hearing loss, and it may be key to the generation of tinnitus and other associated perceptual anomalies. In cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from surviving auditory neurons and re-establishment of their peripheral synapses; thus, treatments may be on the horizon.

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Neurotrophin gene therapy may be able to treat individuals with noise-induced hearing loss or neural presbyacusis

10.31219/osf.io/spkxh ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Gene Therapy ◽

Hearing Loss ◽

Hair Cell ◽

Hair Cells ◽

Cell Loss ◽

Cell Populations ◽

Noise Induced Hearing Loss ◽

Hair Cell Loss ◽

Functional Impairments ◽

Peripheral Axon

Neurotrophin (NT) cochlear gene therapy might perhaps give a single treatment that might greatly enhance neuronal survival, resulting in CI patients, provided the many challenges described above can be adequately addressed and safety concerns allayed by more animal model investigations. This is particularly crucial for juvenile CI patients, who have to rely on electrical hearing for the remainder of their lives, and whose outcomes are quite different. In addition, NT gene therapy may have the potential to treat patients with noise-induced hearing loss or neural presbyacusis (e.g., age-related cochlear synaptopathy), where primary neuronal loss is a key cause of hearing loss. Animal research into noise-induced hearing loss has shown that even exposures that generate only reversible threshold alterations and no hair cell loss can lead to permanent loss of SGN synapses on hair cells, resulting in functional impairments and ultimately SGN degeneration. Cochlear synapses frequently precede both hair cell loss and threshold increases in human ears, according to current studies. Cochlear synaptopathy is characterized by ears with intact hair cell populations and normal audiograms as "hidden" hearing loss. Many frequent perceptual abnormalities, including speech-in-noise difficulties, tinnitus, and hyperacusis, are likely produced by suppressing affected neurons, which radically alters information processing. Thus, in the future, NT gene therapy may be successful in inducing SGN peripheral axon resprouting and synaptic regeneration into residual (or even regenerated) hair cell populations. We have demonstrated compelling evidence that, in this investigation, BDNF gene therapy can boost SGN survival and enhance peripheral axon maintenance or rerouting. NT-3 has been found in adult animals exposed to acoustic damage to induce synaptic regeneration of these fibers, reconnecting them to hair cells and their ribbon synapses, and restoring hearing function. Combining BDNF and NT-3 gene therapy may be the most effective way to maintain/restore a more normal cochlear neuronal substrate.

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Disruption of Atg7-dependent autophagy causes electromotility disturbances, outer hair cell loss, and deafness in mice

Cell Death and Disease ◽

10.1038/s41419-020-03110-8 ◽

2020 ◽

Vol 11 (10) ◽

Author(s):

Han Zhou ◽

Xiaoyun Qian ◽

Nana Xu ◽

Shasha Zhang ◽

Guangjie Zhu ◽

...

Keyword(s):

Hair Cells ◽

Outer Hair Cell ◽

Cell Loss ◽

Outer Hair Cells ◽

Hair Cell Loss ◽

Timely Manner ◽

Profound Hearing Loss ◽

Genetic Ablation ◽

Hearing Function ◽

Over Time

Abstract Atg7 is an indispensable factor that plays a role in canonical nonselective autophagy. Here we show that genetic ablation of Atg7 in outer hair cells (OHCs) in mice caused stereocilium damage, somatic electromotility disturbances, and presynaptic ribbon degeneration over time, which led to the gradual wholesale loss of OHCs and subsequent early-onset profound hearing loss. Impaired autophagy disrupted OHC mitochondrial function and triggered the accumulation of dysfunctional mitochondria that would otherwise be eliminated in a timely manner. Atg7-independent autophagy/mitophagy processes could not compensate for Atg7 deficiency and failed to rescue the terminally differentiated, non-proliferating OHCs. Our results show that OHCs orchestrate intricate nonselective and selective autophagic/mitophagy pathways working in concert to maintain cellular homeostasis. Overall, our results demonstrate that Atg7-dependent autophagy plays a pivotal cytoprotective role in preserving OHCs and maintaining hearing function.

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