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.

日本語要旨:

ミトコンドリアDNAの代表的な病的変異であるm.3243A>G変異を持つ患者由来の線維芽細胞からiPS細胞を作製し、神経細胞と心筋細胞への分化誘導を行い、変異率と誘導効率とを検討した。変異率の高い(90％以上の)iPS細胞は分化が阻害されるとともに、細胞死が誘導されることを示した。