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Clonal expansion of mtDNA deletions: different disease models assessed by digital droplet PCR in single muscle cells

Lookup NU author(s): Selena Trifunov, Dr Angela Pyle, Dr Patrick Yu Wai Man, Dr Florence Burte, Dr Jennifer Duff, Professor Rita HorvathORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2018, The Author(s). Deletions in mitochondrial DNA (mtDNA) are an important cause of human disease and their accumulation has been implicated in the ageing process. As mtDNA is a high copy number genome, the coexistence of deleted and wild-type mtDNA molecules within a single cell defines heteroplasmy. When deleted mtDNA molecules, driven by intracellular clonal expansion, reach a sufficiently high level, a biochemical defect emerges, contributing to the appearance and progression of clinical pathology. Consequently, it is relevant to determine the heteroplasmy levels within individual cells to understand the mechanism of clonal expansion. Heteroplasmy is reflected in a mosaic distribution of cytochrome c oxidase (COX)-deficient muscle fibers. We applied droplet digital PCR (ddPCR) to single muscle fibers collected by laser-capture microdissection (LCM) from muscle biopsies of patients with different paradigms of mitochondrial disease, characterized by the accumulation of single or multiple mtDNA deletions. By combining these two sensitive approaches, ddPCR and LCM, we document different models of clonal expansion in patients with single and multiple mtDNA deletions, implicating different mechanisms and time points for the development of COX deficiency in these molecularly distinct mitochondrial cytopathies.

Publication metadata

Author(s): Trifunov S, Pyle A, Valentino ML, Liguori R, Yu-Wai-Man P, Burté F, Duff J, Kleinle S, Diebold I, Rugolo M, Horvath R, Carelli V

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2018

Volume: 8

Online publication date: 03/08/2018

Acceptance date: 18/07/2018

Date deposited: 20/08/2018

ISSN (electronic): 2045-2322

Publisher: Nature Publishing Group


DOI: 10.1038/s41598-018-30143-z


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Funder referenceFunder name
109915/Z/15/ZWellcome Trust
201064/Z/16/ZWellcome Trust
203105/Z/16/ZWellcome Trust
MR/N027302/1Medical Research Council (MRC)
MR/N025431/1Medical Research Council (MRC)