Repository logo

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

Published version



Change log


Trifunov, Selena 
Pyle, Angela 
Valentino, Maria Lucia 
Liguori, Rocco 
Yu-Wai-Man, Patrick 


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.



Adolescent, Adult, Aged, Biopsy, DNA, Mitochondrial, Electron Transport Complex IV, Female, GTP Phosphohydrolases, Gene Dosage, Genes, Recessive, Humans, Male, Middle Aged, Muscle Cells, Muscle Fibers, Skeletal, Mutation, Oxidative Phosphorylation, Polymerase Chain Reaction, Reproducibility of Results, Sequence Deletion, Succinate Dehydrogenase, Young Adult

Journal Title

Sci Rep

Conference Name

Journal ISSN


Volume Title



Springer Science and Business Media LLC
Wellcome Trust (109915_A_15_Z)
Medical Research Council (MR/N025431/2)