Molecular and Pathological Analyses of IARS1-Deficient Mice: An IARS Disorder Model

Most mitochondrial diseases are hereditary and highly heterogeneous. Cattle born with the V79L mutation in the isoleucyl-tRNA synthetase 1 (IARS1) protein exhibit weak calf syndrome. Recent human genomic studies about pediatric mitochondrial diseases also identified mutations in the IARS1 gene. Although severe prenatal-onset growth retardation and infantile hepatopathy have been reported in such patients, the relationship between IARS mutations and the symptoms is unknown. In this study, we generated hypomorphic IARS1(V79L) mutant mice to develop an animal model of IARS mutation-related disorders. We found that compared to wild-type mice, IARS(V79L) mutant mice showed a significant increase in hepatic triglyceride and serum ornithine carbamoyltransferase levels, indicating that IARS1(V79L) mice suffer from mitochondrial hepatopathy. In addition, siRNA knockdown of the IARS1 gene decreased mitochondrial membrane potential and increased reactive oxygen species in the hepatocarcinoma-derived cell line HepG2. Furthermore, proteomic analysis revealed decreased levels of the mitochondrial function-associated protein NME4 (mitochondrial nucleoside diphosphate kinase). Concisely, our mutant mice model can be used to study IARS mutation-related disorders.

Automated summary

Most mitochondrial diseases are hereditary and highly heterogeneous. Cattle with the V79L mutation in the IARS1 protein exhibit weak calf syndrome, and recent studies have also found mutations in the IARS1 gene in pediatric mitochondrial diseases. This study generated hypomorphic IARS1(V79L) mutant mice to develop an animal model for IARS mutation-related disorders. The mutant mice showed mitochondrial hepatopathy and changes in mitochondrial function-associated protein levels.