The Mitochondrial m.3243A>G Mutation on the Dish, Lessons from In Vitro Models

Abstract

The m.3243A>G mutation in the tRNA Leu(UUR) gene (MT-TL1) is one of the most common pathogenic point mutations in human mtDNA. Patient symptoms vary widely and the severity of the disease ranges from asymptomatic to lethal. The reason for the high heterogeneity of m.3243A>G-associated disease is still unknown, and the treatment options are limited, with only supportive interventions available. Furthermore, the heteroplasmic nature of the m.3243A>G mutation and lack of specific animal models of mtDNA mutations have challenged the study of m.3243A>G, and, besides patient data, only cell models have been available for studies. The most commonly used cell models are patient derived, such as fibroblasts and induced pluripotent stem cell (iPSC)-derived models, and cybrid models where the mutant DNA is transferred to an acceptor cell. Studies on cell models have revealed cell-type-specific effects of the m.3243A>G mutation and that the tolerance for this mutation varies between cell types and between patients. In this review, we summarize the literature on the effects of m.3243A>G in cell models.