Genetic therapy in a mitochondrial disease model suggests a critical role for liver dysfunction in mortality

• Published in: eLife Vol. 11
• Main Authors: Sabharwal, Ankit, Wishman, Mark D, Cervera, Roberto Lopez, Serres, MaKayla R, Anderson, Jennifer L, Holmberg, Shannon R, Kar, Bibekananda, Treichel, Anthony J, Ichino, Noriko, Liu, Weibin, Yang, Jingchun, Ding, Yonghe, Deng, Yun, Lacey, Jean M, Laxen, William J, Loken, Perry R, Oglesbee, Devin, Farber, Steven A, Clark, Karl J, Xu, Xiaolei, Ekker, Stephen C
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 21.11.2022; eLife Sciences Publications, Ltd
• Subjects: Amino acids; Animal models; Animals; Canada; Cytochrome; Danio rerio; Developmental Biology; Disease; Disease Models, Animal; Fibroblasts; gene-breaking transposon; Genetic Therapy; Genetics and Genomics; Homeostasis; Leigh Syndrome French Canadian Type; Liver; Liver diseases; Liver Diseases - genetics; Liver Diseases - therapy; LRPPRC; Metabolism; Mitochondria; Mitochondrial Diseases - genetics; Mitochondrial Diseases - therapy; mRNA; Mutation; Neoplasm Proteins - genetics; Patients; Phenotypes; Physiology; Polyadenylation; Proteins; Research Advance; zebrafish; Zebrafish - genetics; Canada; Leigh Syndrome French Canadian Type; gene-breaking transposon; genetics; developmental biology; mitochondria; genomics; zebrafish; LRPPRC
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.65488

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 (Ichino et al., 2020), including the 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 gene, involved in mitochondrial mRNA polyadenylation and translation. 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.