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Cell reprogramming shapes the mitochondrial DNA landscape

Published version
Peer-reviewed

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Authors

Wei, Wei 
Chinnery, Patrick F.  ORCID logo  https://orcid.org/0000-0002-7065-6617

Abstract

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.

Description

Keywords

Article, /631/208, /692/4017, /13, /13/100, article

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723

Volume Title

12

Publisher

Nature Publishing Group UK
Sponsorship
Wellcome Trust (Wellcome) (212219/Z/18/Z)
RCUK | Medical Research Council (MRC) (MC_UU_00015/9)
Leverhulme Trust (RPG-2018-408)