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

Eunju Kang, Xinjian Wang, Rebecca Tippner-Hedges, Hong Ma, Clifford D L Folmes, Nuria Marti Gutierrez, Yeonmi Lee, Crystal Van Dyken, Riffat Ahmed, Ying Li, Amy Koski, Tomonari Hayama, Shiyu Luo, Cary Harding, Paula Amato, Jeffrey Jensen, David Battaglia, David Lee, Diana Wu, Andre TerzicDon P. Wolf, Taosheng Huang, Shoukhrat Mitalipov

Research output: Contribution to journalArticle

88 Citations (Scopus)

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 are not detectable in whole tissues. The frequency of mtDNA defects in iPSCs increased with age, and many mutations were non-synonymous or resided in RNA coding genes and thus can lead to respiratory defects. Our results highlight a need to monitor mtDNA mutations in iPSCs, especially those generated from older patients, and to examine the metabolic status of iPSCs destined for clinical applications. Mitalipov, Huang, and colleagues show that human iPSCs derived from older adults carry more mitochondrial DNA mutations than those derived from younger individuals. Defects in metabolic function caused by mtDNA mutations suggest careful screening of hiPSC clones for mutational load before clinical application.

Original languageEnglish (US)
JournalCell Stem Cell
DOIs
StateAccepted/In press - Sep 1 2015

Fingerprint

Mitochondrial DNA
Mutation
Fibroblasts
Induced Pluripotent Stem Cells
Skin
Mitochondrial Genome
Point Mutation
Clone Cells
RNA
Genes

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

Cite this

Age-Related Accumulation of Somatic Mitochondrial DNA Mutations in Adult-Derived Human iPSCs. / Kang, Eunju; Wang, Xinjian; Tippner-Hedges, Rebecca; Ma, Hong; Folmes, Clifford D L; Gutierrez, Nuria Marti; Lee, Yeonmi; Van Dyken, Crystal; Ahmed, Riffat; Li, Ying; Koski, Amy; Hayama, Tomonari; Luo, Shiyu; Harding, Cary; Amato, Paula; Jensen, Jeffrey; Battaglia, David; Lee, David; Wu, Diana; Terzic, Andre; Wolf, Don P.; Huang, Taosheng; Mitalipov, Shoukhrat.

In: Cell Stem Cell, 01.09.2015.

Research output: Contribution to journalArticle

Kang, E, Wang, X, Tippner-Hedges, R, Ma, H, Folmes, CDL, Gutierrez, NM, Lee, Y, Van Dyken, C, Ahmed, R, Li, Y, Koski, A, Hayama, T, Luo, S, Harding, C, Amato, P, Jensen, J, Battaglia, D, Lee, D, Wu, D, Terzic, A, Wolf, DP, Huang, T & Mitalipov, S 2015, 'Age-Related Accumulation of Somatic Mitochondrial DNA Mutations in Adult-Derived Human iPSCs', Cell Stem Cell. https://doi.org/10.1016/j.stem.2016.02.005
Kang, Eunju ; Wang, Xinjian ; Tippner-Hedges, Rebecca ; Ma, Hong ; Folmes, Clifford D L ; Gutierrez, Nuria Marti ; Lee, Yeonmi ; Van Dyken, Crystal ; Ahmed, Riffat ; Li, Ying ; Koski, Amy ; Hayama, Tomonari ; Luo, Shiyu ; Harding, Cary ; Amato, Paula ; Jensen, Jeffrey ; Battaglia, David ; Lee, David ; Wu, Diana ; Terzic, Andre ; Wolf, Don P. ; Huang, Taosheng ; Mitalipov, Shoukhrat. / Age-Related Accumulation of Somatic Mitochondrial DNA Mutations in Adult-Derived Human iPSCs. In: Cell Stem Cell. 2015.
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