Codeficiency of lysosomal mucolipins 3 and 1 in cochlear hair cells diminishes outer hair cell longevity and accelerates age-related hearing loss

Teerawat Wiwatpanit, Natalie N. Remis, Aisha Ahmad, Yingjie Zhou, John C. Clancy, Mary Ann Cheatham, Jaime Garcia-Anoveros

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Acquired hearing loss is the predominant neurodegenerative condition associated with aging in humans. Although mutations on several genes are known to cause congenital deafness in newborns, few genes have been implicated in age-related hearing loss (ARHL), perhaps because its cause is likely polygenic. Here, we generated mice lacking lysosomal calcium channel mucolipins 3 and 1 and discovered that both male and female mice suffered a polygenic form of hearing loss. Whereas mucolipin 1 is ubiquitously expressed in all cells, mucolipin 3 is expressed in a small subset of cochlear cells, hair cells (HCs) and marginal cells of the stria vascularis, and very few other cell types. Mice lacking both mucolipins 3 and 1, but not either one alone, experienced hearing loss as early as at 1 month of age. The severity of hearing impairment progressed from high to low frequencies and increased with age. Early onset of ARHL in these mice was accompanied by outer HC (OHC) loss. Adult mice conditionally lacking mucolipins in HCs exhibited comparable auditory phenotypes, thereby revealing that the reason for OHC loss is mucolipin codeficiency in the HCs and not in the stria vascularis. Furthermore, we observed that OHCs lacking mucolipins contained abnormally enlarged lysosomes aggregated at the apical region of the cell, whereas other organelles appeared normal. We also demonstrated that these aberrant lysosomes in OHCs lost their membrane integrity through lysosomal membrane permeabilization, a known cause of cellular toxicity that explains why and how OHCs die, leading to premature ARHL.

Original languageEnglish (US)
Pages (from-to)3177-3189
Number of pages13
JournalJournal of Neuroscience
Volume38
Issue number13
DOIs
StatePublished - Mar 28 2018

Fingerprint

Outer Auditory Hair Cells
Auditory Hair Cells
Hearing Loss
Stria Vascularis
Lysosomes
Hair
Membranes
Alopecia
Deafness
Calcium Channels
Age of Onset
Organelles
Genes

Keywords

  • ARHL
  • Hearing
  • Lysosome
  • Mucolipin
  • Presbycusis
  • TRPML

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Wiwatpanit, Teerawat ; Remis, Natalie N. ; Ahmad, Aisha ; Zhou, Yingjie ; Clancy, John C. ; Cheatham, Mary Ann ; Garcia-Anoveros, Jaime. / Codeficiency of lysosomal mucolipins 3 and 1 in cochlear hair cells diminishes outer hair cell longevity and accelerates age-related hearing loss. In: Journal of Neuroscience. 2018 ; Vol. 38, No. 13. pp. 3177-3189.
@article{5b97504b29d6460eafbd0827edf330eb,
title = "Codeficiency of lysosomal mucolipins 3 and 1 in cochlear hair cells diminishes outer hair cell longevity and accelerates age-related hearing loss",
abstract = "Acquired hearing loss is the predominant neurodegenerative condition associated with aging in humans. Although mutations on several genes are known to cause congenital deafness in newborns, few genes have been implicated in age-related hearing loss (ARHL), perhaps because its cause is likely polygenic. Here, we generated mice lacking lysosomal calcium channel mucolipins 3 and 1 and discovered that both male and female mice suffered a polygenic form of hearing loss. Whereas mucolipin 1 is ubiquitously expressed in all cells, mucolipin 3 is expressed in a small subset of cochlear cells, hair cells (HCs) and marginal cells of the stria vascularis, and very few other cell types. Mice lacking both mucolipins 3 and 1, but not either one alone, experienced hearing loss as early as at 1 month of age. The severity of hearing impairment progressed from high to low frequencies and increased with age. Early onset of ARHL in these mice was accompanied by outer HC (OHC) loss. Adult mice conditionally lacking mucolipins in HCs exhibited comparable auditory phenotypes, thereby revealing that the reason for OHC loss is mucolipin codeficiency in the HCs and not in the stria vascularis. Furthermore, we observed that OHCs lacking mucolipins contained abnormally enlarged lysosomes aggregated at the apical region of the cell, whereas other organelles appeared normal. We also demonstrated that these aberrant lysosomes in OHCs lost their membrane integrity through lysosomal membrane permeabilization, a known cause of cellular toxicity that explains why and how OHCs die, leading to premature ARHL.",
keywords = "ARHL, Hearing, Lysosome, Mucolipin, Presbycusis, TRPML",
author = "Teerawat Wiwatpanit and Remis, {Natalie N.} and Aisha Ahmad and Yingjie Zhou and Clancy, {John C.} and Cheatham, {Mary Ann} and Jaime Garcia-Anoveros",
year = "2018",
month = "3",
day = "28",
doi = "10.1523/JNEUROSCI.3368-17.2018",
language = "English (US)",
volume = "38",
pages = "3177--3189",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "13",

}

Codeficiency of lysosomal mucolipins 3 and 1 in cochlear hair cells diminishes outer hair cell longevity and accelerates age-related hearing loss. / Wiwatpanit, Teerawat; Remis, Natalie N.; Ahmad, Aisha; Zhou, Yingjie; Clancy, John C.; Cheatham, Mary Ann; Garcia-Anoveros, Jaime.

In: Journal of Neuroscience, Vol. 38, No. 13, 28.03.2018, p. 3177-3189.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Codeficiency of lysosomal mucolipins 3 and 1 in cochlear hair cells diminishes outer hair cell longevity and accelerates age-related hearing loss

AU - Wiwatpanit, Teerawat

AU - Remis, Natalie N.

AU - Ahmad, Aisha

AU - Zhou, Yingjie

AU - Clancy, John C.

AU - Cheatham, Mary Ann

AU - Garcia-Anoveros, Jaime

PY - 2018/3/28

Y1 - 2018/3/28

N2 - Acquired hearing loss is the predominant neurodegenerative condition associated with aging in humans. Although mutations on several genes are known to cause congenital deafness in newborns, few genes have been implicated in age-related hearing loss (ARHL), perhaps because its cause is likely polygenic. Here, we generated mice lacking lysosomal calcium channel mucolipins 3 and 1 and discovered that both male and female mice suffered a polygenic form of hearing loss. Whereas mucolipin 1 is ubiquitously expressed in all cells, mucolipin 3 is expressed in a small subset of cochlear cells, hair cells (HCs) and marginal cells of the stria vascularis, and very few other cell types. Mice lacking both mucolipins 3 and 1, but not either one alone, experienced hearing loss as early as at 1 month of age. The severity of hearing impairment progressed from high to low frequencies and increased with age. Early onset of ARHL in these mice was accompanied by outer HC (OHC) loss. Adult mice conditionally lacking mucolipins in HCs exhibited comparable auditory phenotypes, thereby revealing that the reason for OHC loss is mucolipin codeficiency in the HCs and not in the stria vascularis. Furthermore, we observed that OHCs lacking mucolipins contained abnormally enlarged lysosomes aggregated at the apical region of the cell, whereas other organelles appeared normal. We also demonstrated that these aberrant lysosomes in OHCs lost their membrane integrity through lysosomal membrane permeabilization, a known cause of cellular toxicity that explains why and how OHCs die, leading to premature ARHL.

AB - Acquired hearing loss is the predominant neurodegenerative condition associated with aging in humans. Although mutations on several genes are known to cause congenital deafness in newborns, few genes have been implicated in age-related hearing loss (ARHL), perhaps because its cause is likely polygenic. Here, we generated mice lacking lysosomal calcium channel mucolipins 3 and 1 and discovered that both male and female mice suffered a polygenic form of hearing loss. Whereas mucolipin 1 is ubiquitously expressed in all cells, mucolipin 3 is expressed in a small subset of cochlear cells, hair cells (HCs) and marginal cells of the stria vascularis, and very few other cell types. Mice lacking both mucolipins 3 and 1, but not either one alone, experienced hearing loss as early as at 1 month of age. The severity of hearing impairment progressed from high to low frequencies and increased with age. Early onset of ARHL in these mice was accompanied by outer HC (OHC) loss. Adult mice conditionally lacking mucolipins in HCs exhibited comparable auditory phenotypes, thereby revealing that the reason for OHC loss is mucolipin codeficiency in the HCs and not in the stria vascularis. Furthermore, we observed that OHCs lacking mucolipins contained abnormally enlarged lysosomes aggregated at the apical region of the cell, whereas other organelles appeared normal. We also demonstrated that these aberrant lysosomes in OHCs lost their membrane integrity through lysosomal membrane permeabilization, a known cause of cellular toxicity that explains why and how OHCs die, leading to premature ARHL.

KW - ARHL

KW - Hearing

KW - Lysosome

KW - Mucolipin

KW - Presbycusis

KW - TRPML

UR - http://www.scopus.com/inward/record.url?scp=85044776991&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85044776991&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.3368-17.2018

DO - 10.1523/JNEUROSCI.3368-17.2018

M3 - Article

VL - 38

SP - 3177

EP - 3189

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 13

ER -