14The clinical and largely unpredictable heterogeneity of phenotypes in patients with 15 mitochondrial disorders demonstrates the ongoing challenges in the understanding of this semi-16 autonomous organelle in biology and disease. Here we present a new animal model that 17 recapitulates key components of Leigh Syndrome, French Canadian Type (LSFC), a 18 mitochondrial disorder that includes diagnostic liver dysfunction. LSFC is caused by allelic 19 variations in the Leucine Rich Pentatricopeptide repeat-containing motif (LRPPRC) gene. 20 LRPPRC has native functions related to mitochondrial mRNA polyadenylation and translation as 21 well as a role in gluconeogenesis. We used the Gene-Breaking Transposon (GBT) cassette to 22 create a revertible, insertional mutant zebrafish line in the LRPPRC gene. lrpprc zebrafish 23 homozygous mutants displayed impaired muscle development, liver function and lowered levels 24 of mtDNA transcripts and are lethal by 12dpf, all outcomes similar to clinical phenotypes 25 observed in patients. Investigations using an in vivo lipidomics approach demonstrated 26 accumulation of non-polar lipids in these animals. Transcript profiling of the mutants revealed 27 dysregulation of clinically important nuclearly encoded and mitochondrial transcripts. Using 28 engineered liver-specific rescue as a genetic model therapy, we demonstrate survival past the 29 initial larval lethality, as well as restored normal gut development, mitochondrial morphology 30 2 and triglyceride levels functionally demonstrating a critical role for the liver in the 31 pathophysiology of this model of mitochondrial disease. Understanding the molecular 32mechanism of the liver-mediated genetic rescue underscores the potential to improve the clinical 33 diagnostic and therapeutic developments for patients suffering from these devastating disorders. 35