Abstract

The clinical and largely unpredictable heterogeneity of phenotypes in patients with mitochondrial disorders demonstrates the ongoing challenges in the understanding of this semi-autonomous organelle in biology and disease. Previously, we used the gene-breaking transposon to create 1200 transgenic zebrafish strains tagging protein-coding genes (1), including the lrpprc locus. Here we present and characterize a new genetic revertible animal model that recapitulates components of Leigh Syndrome French Canadian Type (LSFC), a mitochondrial disorder that includes diagnostic liver dysfunction. LSFC is caused by allelic variations in the LRPPRC gene, involved in mitochondrial mRNA polyadenylation and translation. lrpprc zebrafish homozygous mutants displayed biochemical and mitochondrial phenotypes similar to clinical manifestations observed in patients, including dysfunction in lipid homeostasis. We were able to rescue these phenotypes in the disease model using a liver-specific genetic model therapy, functionally demonstrating a previously under-recognized critical role for the liver in the pathophysiology of this disease.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data is provided along with the manuscript. Raw sequencing data has been uploaded on NCBI SRA. ID: PRJNA683704

The following data sets were generated

Article and author information

Author details

  1. Ankit Sabharwal

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4355-0355
  2. Mark D Wishman

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Roberto Lopez Cervera

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. MaKayla R Serres

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jennifer L Anderson

    Department of Embryology, Carnegie Institution for Science, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Shannon R Holmberg

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Bibekananda Kar

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Anthony J Treichel

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4393-7034
  9. Noriko Ichino

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7009-8299
  10. Weibin Liu

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Jingchun Yang

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Yonghe Ding

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Yun Deng

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Jean M Lacey

    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. William J Laxen

    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Perry R Loken

    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Devin Oglesbee

    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Steven Arthur Farber

    Department of Embryology, Carnegie Institution for Science, Baltimore, Maryland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8037-7312
  19. Karl J Clark

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9637-0967
  20. Xiaolei Xu

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4928-3422
  21. Stephen C Ekker

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    For correspondence
    ekker.stephen@mayo.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0726-4212

Funding

National Institutes of Health (GM63904)

  • Stephen C Ekker

National Institutes of Health (DA14546)

  • Stephen C Ekker

Marriott Foundation

  • Stephen C Ekker

Mayo Foundation for Medical Education and Research

  • Stephen C Ekker

National Institutes of Health (DK093399)

  • Steven Arthur Farber

Carnegie Institution for Science

  • Steven Arthur Farber

G. Harold and Leila Y. Mathers Charitable Foundation

  • Steven Arthur Farber

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

Reviewing Editor

  1. Wenbiao Chen, Vanderbilt University, United States

Ethics

Animal experimentation: All adult zebrafish and embryos were maintained according to the guidelines established by Mayo Clinic Institutional Animal Care and Use Committee (IACUC number: A34513-13-R16).

Version history

  1. Preprint posted: May 9, 2020 (view preprint)
  2. Received: December 15, 2020
  3. Accepted: November 16, 2022
  4. Accepted Manuscript published: November 21, 2022 (version 1)
  5. Accepted Manuscript updated: November 22, 2022 (version 2)
  6. Version of Record published: January 20, 2023 (version 3)

Copyright

© 2022, Sabharwal 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. Ankit Sabharwal
  2. Mark D Wishman
  3. Roberto Lopez Cervera
  4. MaKayla R Serres
  5. Jennifer L Anderson
  6. Shannon R Holmberg
  7. Bibekananda Kar
  8. Anthony J Treichel
  9. Noriko Ichino
  10. Weibin Liu
  11. Jingchun Yang
  12. Yonghe Ding
  13. Yun Deng
  14. Jean M Lacey
  15. William J Laxen
  16. Perry R Loken
  17. Devin Oglesbee
  18. Steven Arthur Farber
  19. Karl J Clark
  20. Xiaolei Xu
  21. Stephen C Ekker
(2022)
Genetic therapy in a mitochondrial disease model suggests a critical role for liver dysfunction in mortality
eLife 11:e65488.
https://doi.org/10.7554/eLife.65488

Share this article

https://doi.org/10.7554/eLife.65488

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