Genetic therapy in a mitochondrial disease model suggests a critical role for liver dysfunction in mortality
- Mayo Clinic, United States
- Carnegie Institution for Science, United States
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
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Zebrafish Model for LSFCNCBI Sequence Read Archive, PRJNA683704.
Article and author information
Author details
Anthony J Treichel
Steven Arthur Farber
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.
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).
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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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
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