Induced pluripotent stem cells (iPSCs) for modeling mitochondrial DNA disorders.

Defects in mitochondrial DNA (mtDNA) are a frequent cause of genetic disease, with a minimum prevalence of 1 in 5,000 individuals. These disorders often present with neurological features, exhibit high clinical variability, and lack effective treatments. Viable disease models would be critical to elucidate the genotype/phenotype relationship and improve disease management. However, the peculiarities of mitochondrial genetics have hampered the generation of animal models, and current cellular models do not carry the nuclear background of the patients and do not exhibit the features of differentiated cells such as postmitotic neurons. Hence, the development of innovative modeling systems is highly needed in order to correctly address the interplay between the nuclear and mitochondrial genome within the appropriate human target cell types. The establishment of induced pluripotent stem cells (iPSCs) from patients affected by mtDNA disorders thus appears as a promising approach. Patient-derived iPSCs would contain both the original nuclear and mitochondrial DNA of the patients and would be capable of differentiating into any cell type of the body, including postmitotic neurons. Here we discuss the potential advantages and critical challenges for the application of the iPSC technology for modeling debilitating mtDNA diseases.