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Unanticipated increase in mtDNA deletion heteroplasmy in an in vivo environment

Doll, Thierry, Fruh, Isabelle, Mueller, Matthias, Marcellin, David, Russell, Oliver, Rai, Pavendeep, Taylor, Robert, Lightowlers, Robert, Turnbull, Douglass, Bastien, Julie, Germain, Mitchel, Rygiel, Karolina, Majlinda, Lako and Amy, Reeve (2016) Unanticipated increase in mtDNA deletion heteroplasmy in an in vivo environment. Nature Genetics.


Understanding the mechanism of clonal expansion of mitochondrial DNA (mtDNA) deletions is crucial when exploring the pathogenesis of mitochondrial DNA disease and age-related mitochondrial dysfunction in post-mitotic tissues. Induced pluripotent stem cells (iPSCs) were generated from patient fibroblasts to yield 3 cell lines with varying degrees of heteroplasmy for a ~6kb single, large scale mtDNA deletion. In long term culture the mtDNA deletion levels consistently increased with time and high levels of mtDNA heteroplasmy were associated with respiratory deficiency. Teratomas comprising all three embryonic germ layers were generated from low (20%) and intermediate heteroplasmy (55%) clones. Regardless of whether iPSCs harbouring low or intermediate mtDNA heteroplasmy were used, the final levels of heteroplasmy in all teratoma germ layers increased to a similar high level (>60%). Thus during human stem cell division, cells not only tolerate high mtDNA mutation loads but preferentially replicate deleted mtDNA genomes regardless of their pathogenicity. This has implications for the involvement of mtDNA rearrangements in both disease and ageing.

Item Type: Article
Date Deposited: 15 Apr 2020 00:45
Last Modified: 15 Apr 2020 00:45


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