Friday, April 26, 2024
4/26/2024
Project Summary Mutations in human mitochondrial DNA (mtDNA) cause maternally inherited diseases that affect multiple parts of the body including the muscles and nervous system. More than 250 pathogenic mutations have been identified in human mtDNA, causing a spectrum of pathologies in at least 1 in every 5000 subjects. However, it remains unclear how mtDNA mutations lead to disparate clinical phenotypes. As there are currently no cures for mitochondrial diseases, in vivo mouse models harboring pathogenic mtDNA mutations are of critical importance both to understand disease mechanisms and to develop therapeutic approaches. The lack of such models has become a major hurdle to research on mitochondrial medicine. The primary challenge to generate these models originates from the inability to manipulate the mitochondrial genome. Therefore, this project proposes to build a pipeline to identify specific mouse mtDNA mutations homologous to disease-causing human mtDNA mutations, select and characterize mouse cells harboring these mutations, and generate and validate corresponding mutant mouse models. The key components of our pipeline include a large library of mtDNA mutant mouse cells containing theoretically all possible mtDNA mutations, a high-throughput high-sensitivity mtDNA mutation detection assay that can screen tens of thousands of samples per day, and a mouse embryonic stem cell line that allows quick generation of transmitochondrial mouse lines. Using this pipeline, the project will generate: 1) mtDNA mutant mouse fibroblast and embryonic stem cell lines containing mutations homologous to human pathogenic mutations, and 2) mtDNA mutant mouse models containing such mutations. These in vitro and in vivo tools would be highly useful in studying the molecular mechanisms of mitochondrial diseases and the roles of mtDNA mutations in other diseases that are linked with somatic mtDNA mutation accumulation. The production of these novel tools will also be crucial for therapeutic development of mitochondrial diseases.
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