Age-Related Accumulation of Somatic Mitochondrial DNA Mutations in Adult-Derived Human iPSCs

Abstract

The genetic integrity of iPSCs is an important consideration for therapeutic application. In this study, we examine the accumulation of somatic mitochondrial genome (mtDNA) mutations in skin fibroblasts, blood, and iPSCs derived from young and elderly subjects (24-72 years). We found that pooled skin and blood mtDNA contained low heteroplasmic point mutations, but a panel of ten individual iPSC lines from each tissue or clonally expanded fibroblasts carried an elevated load of heteroplasmic or homoplasmic mutations, suggesting that somatic mutations randomly arise within individual cells but arenot detectable in whole tissues. The frequency of mtDNA defects in iPSCs increased with age, andmany mutations were non-synonymous or resided in RNA coding genes and thus can lead torespiratory defects. Our results highlight a need tomonitor mtDNA mutations in iPSCs, especially those generated from older patients, and to examine themetabolic status of iPSCs destined for clinical applications.