Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles

Abstract

Unbiased genetic screens implicated a number of uncharacterized genes in hearing loss, suggesting some biological processes required for auditory function remain unexplored. Loss of Kiaa1024L/Minar2, a previously understudied gene, caused deafness in mice, but how it functioned in the hearing was unclear. Here we show that disruption of kiaa1024L/minar2 causes hearing loss in the zebrafish. Defects in mechanotransduction, longer and thinner hair bundles, and enlarged apical lysosomes in hair cells are observed in kiaa1024L/minar2 mutant. In cultured cells, Kiaa1024L/Minar2 is mainly localized to lysosomes and its overexpression recruits cholesterol and increases cholesterol labeling. Strikingly, cholesterol is highly enriched in the hair bundle membrane, and loss of kiaa1024L/minar2 reduces cholesterol localization to the hair bundles. Lowering cholesterol levels aggravates, while increasing cholesterol levels rescues hair cell defects in kiaa1024L/minar2 mutant. Therefore cholesterol plays an essential role in hair bundles, and Kiaa1024L/Minar2 regulates cholesterol distribution and homeostasis to ensure normal hearing.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source Data files have been provided.

Article and author information

Author details

  1. Ge Gao

    Institutes of Brain Science, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Shuyu Guo

    Institutes of Brain Science, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Quan Zhang

    Institutes of Brain Science, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Hefei Zhang

    Institutes of Brain Science, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Cuizhen Zhang

    Institutes of Brain Science, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Gang Peng

    Institute of Brain Science, Fudan University, Shanghai, China
    For correspondence
    gangpeng@fudan.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6625-5426

Funding

National Key Research and Development Program of China (2018YFA0801000)

  • Gang Peng

National Natural Science Foundation of China (31571067)

  • Gang Peng

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Doris K Wu, National Institutes of Health, United States

Ethics

Animal experimentation: The animal use protocols were approved by the Fudan University Shanghai Medical College Institution Animal Care and Use Committee (130227-092, 150119-088 and 190221-147). All animals were handled in accordance with the Fudan University Regulations on Animal Experiments.

Version history

  1. Received: June 7, 2022
  2. Preprint posted: June 26, 2022 (view preprint)
  3. Accepted: October 31, 2022
  4. Accepted Manuscript published: November 1, 2022 (version 1)
  5. Version of Record published: December 1, 2022 (version 2)

Copyright

© 2022, Gao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ge Gao
  2. Shuyu Guo
  3. Quan Zhang
  4. Hefei Zhang
  5. Cuizhen Zhang
  6. Gang Peng
(2022)
Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles
eLife 11:e80865.
https://doi.org/10.7554/eLife.80865

Share this article

https://doi.org/10.7554/eLife.80865

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