Genetic Therapy in a Mitochondrial Disease Model Suggests a Critical Role for Liver Dysfunction in Mortality

Ankit Sabharwal, Mark D. Wishman, Roberto Lopez Cervera, Makayla R. Serres, Jennifer L. Anderson, Shannon R. Holmberg, Bibekananda Kar, Anthony J. Treichel, Noriko Ichino, Weibin Liu, Jingchun Yang, Yonghe Ding, Yun Deng, Jean M. Lacey, William J. Laxen, Perry R. Loken, Devin Oglesbee, Steven A. Farber, Karl J. Clark, Xiaolei XuStephen C. Ekker

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbere65488
StatePublished - Nov 2022

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology


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