Pregnancy associated plasma protein-aa regulates endoplasmic reticulum-mitochondria associations

  1. Mroj Alassaf
  2. Mary C Halloran  Is a corresponding author
  1. University of Wisconsin, United States

Abstract

Endoplasmic reticulum (ER) and mitochondria form close physical associations to facilitate calcium transfer, thereby regulating mitochondrial function. Neurons with high metabolic demands, such as sensory hair cells, are especially dependent on precisely regulated ER-mitochondria associations. We previously showed that the secreted metalloprotease Pregnancy associated plasma protein-aa (Pappaa) regulates mitochondrial function in zebrafish lateral line hair cells (Alassaf et al., 2019). Here, we show that pappaa mutant hair cells exhibit excessive and abnormally close ER-mitochondria associations, suggesting increased ER-mitochondria calcium transfer. pappaa mutant hair cells are more vulnerable to pharmacological induction of ER-calcium transfer. Additionally, pappaa mutant hair cells display ER stress and dysfunctional downstream processes of the ER-mitochondria axis including altered mitochondrial morphology and reduced autophagy. We further show that Pappaa influences ER-calcium transfer and autophagy via its ability to stimulate insulin-like growth factor-1 bioavailability. Together our results identify Pappaa as a novel regulator of the ER-mitochondria axis.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files are provided for Figures 1-5, and Figure 2-Figure Supplement 1.

Article and author information

Author details

  1. Mroj Alassaf

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

    Integrative Biology Department/Neuroscience Department, University of Wisconsin, Madison, United States
    For correspondence
    mchalloran@wisc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6086-5928

Funding

Ministry of Education Saudi Arabia (Graduate Student Fellowship)

  • Mroj Alassaf

UW-Madison graduate support funds (UW internal funds)

  • Mary C Halloran

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 accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Animals were handled according to approved institutional animal care and use committee (IACUC) protocols (L005704) of the University of Wisconsin.

Reviewing Editor

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

Publication history

  1. Received: June 9, 2020
  2. Accepted: March 23, 2021
  3. Accepted Manuscript published: March 24, 2021 (version 1)
  4. Version of Record published: April 6, 2021 (version 2)

Copyright

© 2021, Alassaf & Halloran

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. Mroj Alassaf
  2. Mary C Halloran
(2021)
Pregnancy associated plasma protein-aa regulates endoplasmic reticulum-mitochondria associations
eLife 10:e59687.
https://doi.org/10.7554/eLife.59687

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