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Cell reprogramming shapes the mitochondrial DNA landscape

Wei, Wei, Gaffney, Daniel J., Chinnery, Patrick F.·2021·Nature Communications
DOI 10.1038/s41467-021-25482-xPMC PMC8413449
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Abstract

Individual induced pluripotent stem cells (iPSCs) show considerable phenotypic heterogeneity, but the reasons for this are not fully understood. Comprehensively analysing the mitochondrial genome (mtDNA) in 146 iPSC and fibroblast lines from 151 donors, we show that most age-related fibroblast mtDNA mutations are lost during reprogramming. However, iPSC-specific mutations are seen in 76.6% (108/141) of iPSC lines at a mutation rate of 8.62 × 10−5/base pair. The mutations observed in iPSC lines affect a higher proportion of mtDNA molecules, favouring non-synonymous protein-coding and tRNA variants, including known disease-causing mutations. Analysing 11,538 single cells shows stable heteroplasmy in sub-clones derived from the original donor during differentiation, with mtDNA variants influencing the expression of key genes involved in mitochondrial metabolism and epidermal cell differentiation. Thus, the dynamic mtDNA landscape contributes to the heterogeneity of human iPSCs and should be considered when using reprogrammed cells experimentally or as a therapy.

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Metadata

Authors
Wei, W., Gaffney, D. J., & Chinnery, P. F.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-09-02
Volume
12
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-021-25482-x
PMC
PMC8413449
Cited by
47
References
5
Language
en
Licence
Funders
  • Wellcome Trust (212219/Z/18/Z)
  • RCUK | Medical Research Council (MC_UU_00015/9)
  • Leverhulme Trust (RPG-2018-408)

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