부산대학교 도서관

Summary: Genetic instability of the mitochondrial genome (mtDNA) plays an important role in human aging and disease. Thus far, it has proven difficult to develop successful treatment strategies for diseases that are caused by mtDNA instability. To address this issue, we developed a model of mtDNA disease in the nematode C. elegans, an animal model that can rapidly be screened for genes and biological pathways that reduce mitochondrial pathology. These worms recapitulate all the major hallmarks of mtDNA disease in humans, including increased mtDNA instability, loss of respiration, reduced neuromuscular function, and a shortened lifespan. We found that these phenotypes could be rescued by intervening in numerous biological pathways, including IGF-1/insulin signaling, mitophagy, and the mitochondrial unfolded protein response, suggesting that it may be possible to ameliorate mtDNA disease through multiple molecular mechanisms. : Haroon et al. describe a genetically engineered C. elegans that carries an error-prone copy of DNA polymerase γ, the enzyme that replicates the mitochondrial genome. This worm recapitulates the major hallmarks of mitochondrial disease in humans. The authors identify multiple biological pathways that could potentially delay disease progression. Keywords: mitochondrial genome, mitophagy, mitochondrial unfolded protein response, IGF-1/insulin signaling, polymerase gamma, mutation, mitochondrial disease, mitochondrial DNA depletion, RNAi, neuromuscular dysfunction