Abstract
Mitochondrial diseases are genetically heterogeneous and present a broad clinical spectrum among patients; in most cases, genetic determinants of mitochondrial diseases are heteroplasmic mitochondrial DNA (mtDNA) mutations. However, it is uncertain whether and how heteroplasmic mtDNA mutations affect particular cellular fate-determination processes, which are closely associated with the cell-type-specific pathophysiology of mitochondrial diseases. In this study, we established two isogenic induced pluripotent stem cell (iPSC) lines each carrying different proportions of a heteroplasmic m.3243A>G mutation from the same patient; one exhibited apparently normal and the other showed most likely impaired mitochondrial respiratory function. Low proportions of m.3243A>G exhibited no apparent molecular pathogenic influence on directed differentiation into neurons and cardiomyocytes, whereas high proportions of m.3243A>G showed both induced neuronal cell death and inhibited cardiac lineage commitment. Such neuronal and cardiac maturation defects were also confirmed using another patient-derived iPSC line carrying quite high proportion of m.3243A>G. In conclusion, mitochondrial respiratory dysfunction strongly inhibits maturation and survival of iPSC-derived neurons and cardiomyocytes; our presenting data also suggest that appropriate mitochondrial maturation actually contributes to cellular fate-determination processes during development.
Highlights
IntroductionMitochondria possess multiple copies of their own genome (mitochondrial DNA; mtDNA) and play some crucial roles in cellular energy metabolism
Mitochondria possess multiple copies of their own genome and play some crucial roles in cellular energy metabolism
MtDNA haplogroups, which are known to be associated with various phenotypes, affect their intrinsic gene expression signatures involved in pluripotency, differentiation, DNA methylation and mitochondrial energy metabolism
Summary
Mitochondria possess multiple copies of their own genome (mitochondrial DNA; mtDNA) and play some crucial roles in cellular energy metabolism. Disease-relevant iPSCs carrying heteroplasmic mtDNA mutations will greatly help us to open new avenues for studying the patient-specific definitive genotype–phenotype relationship of affected tissues and organs in mitochondrial diseases.. Several groups and we have reported the generation and the application of patient-derived iPSCs carrying various heteroplasmic mtDNA mutations toward in vitro human mitochondrial disease modeling; it remains uncertain whether and how such heteroplasmic mtDNA mutations affect particular cellular fate-determination processes during development. Received 02.9.16; revised 14.11.16; accepted 16.12.16; Edited by M Agostini most likely impaired mitochondrial respiratory function Using these isogenic iPSC lines, we demonstrated that induced mitochondrial respiratory dysfunction triggered by high proportions of m.3243. A4G strongly inhibits maturation and survival of iPSC-derived neurons and cardiomyocytes Such in vitro neuronal and cardiac maturation defects were confirmed by using another patient-derived iPSC line carrying quite high proportion of m.3243. Our presenting data demonstrate that isogenic iPSC lines with different proportions of m.3243 A4G would make enormous contributions as in vitro human cellular disease models to greatly facilitate iPSC-based drug discovery and regenerative therapeutics in mitochondrial diseases
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