Mitochondria contain multiple copies of their own genome (mitochondrial DNA; mtDNA). Once mitochondria are damaged by mutant mtDNA, mitochondrial dysfunction is strongly induced, followed by symptomatic appearance of mitochondrial diseases. Major genetic causes of mitochondrial diseases are defects in mtDNA, and the others are defects of mitochondriaassociating genes that are encoded in nuclear DNA (nDNA). Numerous pathogenic mutations responsible for various types of mitochondrial diseases have been identified in mtDNA; however, it remains uncertain why mitochondrial diseases present a wide variety of clinical spectrum even among patients carrying the same mtDNA mutations (e.g., variations in age of onset, in affected tissues and organs, or in disease progression and phenotypic severity). Diseaserelevant induced pluripotent stem cells (iPSCs) derived from mitochondrial disease patients have therefore opened new avenues for understanding the definitive genotype-phenotype relationship of affected tissues and organs in various types of mitochondrial diseases triggered by mtDNA mutations. In this concise review, we briefly summarize several recent approaches using patient-derived iPSCs and their derivatives carrying various mtDNA mutations for applications in human mitochondrial disease modeling, drug discovery, and future regenerative therapeutics. STEM CELLS 2016;34:801-808
SIGNIFICANCE STATEMENTMitochondria play some crucial roles in maintenance of cellular homeostasis; therefore, mitochondrial dysfunction caused by pathogenic mtDNA mutations induces mitochondrial diseases. Moreover, several recent studies have demonstrated that mitochondrial rejuvenation or maturation must be essential for bona fide cellular reprogramming or differentiation, most likely due to contributions in appropriate intracellular metabolic switching. From the viewpoint of stem cell biology, we also briefly review how induced mitochondrial dysfunction triggered by the molecular pathogenic influence of heteroplasmic mtDNA mutations affects cellular lineagedetermining processes.