iPSCs for modeling mtDNA diseases

Abstract Mitochondrial disease due to mutations in the mitochondrial genome (mtDNA) is a common cause of human inherited disorders. mtDNA disorders manifest various clinical phenotypes, with severe neurological, muscular, cardiac and metabolic defects and present vast clinical variability between patients. Current transgenic technologies are not efficient in targeted modification of mitochondrial genome and thus the pathogenetic mechanisms underlying these disorders are largely unknown, as lack of model systems has hampered mechanistic studies. As transgenic animal models do not exist, patient cells are the best research material; however, many of these disorders present very tissue-specific manifestations in cell types that are not easily available from patients. The generation of induced pluripotent stem cells (iPSCs) from patient cells has opened up novel ways to use patient-derived material in disease modeling. Heteroplasmic mtDNA mutations can be carried from somatic patient cells to iPSCs and further to the differentiated cells, making iPSC-derived models applicable for mtDNA disease studies and providing a valuable research tool for this group of hereditary disorders where traditional model systems have been scarce.