Cell reprogramming shapes the mitochondrial DNA landscape.

dc.contributor.author Wei, Wei dc.contributor.author Gaffney, Daniel J dc.contributor.author Chinnery, Patrick F dc.date.accessioned 2021-10-05T00:26:36Z dc.date.available 2021-10-05T00:26:36Z dc.date.issued 2021-09-02 dc.identifier.issn 2041-1723 dc.identifier.other 34475388 dc.identifier.other PMC8413449 dc.identifier.uri www.repository.cam.ac.uk/handle/1810/328995 dc.description.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<sup>-5</sup>/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. dc.language eng dc.rights Attribution 4.0 International dc.rights.uri creativecommons.org/licenses/by/4.0/ dc.source essn: 2041-1723 dc.source nlmid: 101528555 dc.subject Fibroblasts dc.subject Humans dc.subject DNA, Mitochondrial dc.subject Gene Expression dc.subject Mutation dc.subject Adult dc.subject Aged dc.subject Middle Aged dc.subject Female dc.subject Male dc.subject Genome, Mitochondrial dc.subject Young Adult dc.subject Induced Pluripotent Stem Cells dc.subject Cellular Reprogramming dc.subject Cellular Senescence dc.subject Heteroplasmy dc.title Cell reprogramming shapes the mitochondrial DNA landscape. dc.type Article dc.date.updated 2021-10-05T00:26:36Z prism.issueIdentifier 1 prism.publicationName Nature communications prism.volume 12 rioxxterms.versionofrecord 10.1038/s41467-021-25482-x rioxxterms.version VoR rioxxterms.licenseref.uri creativecommons.org/licenses/by/4.0/ dc.contributor.orcid Gaffney, Daniel J [0000-0002-1529-1862] dc.contributor.orcid Chinnery, Patrick F [0000-0002-7065-6617] pubs.funder-project-id Wellcome Trust (212219/Z/18/Z) pubs.funder-project-id Medical Research Council (MC_UU_00015/9) pubs.funder-project-id Alzheimer’s Society (022) pubs.funder-project-id Leverhulme Trust (RPG-2018-408) pubs.funder-project-id RCUK | Medical Research Council (MC_UU_00015/9)

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