1. Cell Biology
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Pregnancy-associated plasma protein-aa supports hair cell survival by regulating mitochondrial function

  1. Mroj Alassaf
  2. Emily C Daykin
  3. Jaffna Mathiaparanam
  4. Marc A Wolman  Is a corresponding author
  1. University of Wisconsin-Madison, United States
Research Article
  • Cited 2
  • Views 917
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Cite this article as: eLife 2019;8:e47061 doi: 10.7554/eLife.47061

Abstract

To support cell survival, mitochondria must balance energy production with oxidative stress. Inner ear hair cells are particularly vulnerable to oxidative stress; thus require tight mitochondrial regulation. We identified a novel molecular regulator of the hair cells' mitochondria and survival: Pregnancy-associated plasma protein-aa (Pappaa). Hair cells in zebrafish pappaa mutants exhibit mitochondrial defects, including elevated mitochondrial calcium, transmembrane potential, and reactive oxygen species (ROS) production and reduced antioxidant expression. In pappaa mutants, hair cell death is enhanced by stimulation of mitochondrial calcium or ROS production and suppressed by a mitochondrial ROS scavenger. As a secreted metalloprotease, Pappaa stimulates extracellular insulin-like growth factor 1 (IGF1) bioavailability. We found that the pappaa mutants' enhanced hair cell loss can be suppressed by stimulation of IGF1 availability and that Pappaa-IGF1 signaling acts post-developmentally to support hair cell survival. These results reveal Pappaa as an extracellular regulator of hair cell survival and essential mitochondrial function.

Article and author information

Author details

  1. Mroj Alassaf

    Department of Integrative Biology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Emily C Daykin

    Department of Integrative Biology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jaffna Mathiaparanam

    Department of Integrative Biology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Marc A Wolman

    Department of Integrative Biology, University of Wisconsin-Madison, Madison, United States
    For correspondence
    mawolman@wisc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8929-779X

Funding

Greater Milwaukee Foundation

  • Marc A Wolman

Saudi Ministry of Education

  • Mroj Alassaf

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (L00457-A1) of the University of Wisconsin.

Reviewing Editor

  1. David W Raible, University of Washington, United States

Publication history

  1. Received: March 22, 2019
  2. Accepted: June 14, 2019
  3. Accepted Manuscript published: June 17, 2019 (version 1)
  4. Version of Record published: June 26, 2019 (version 2)

Copyright

© 2019, Alassaf 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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