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Understanding mitochondrial DNA maintenance disorders at the single muscle fibre level

Lookup NU author(s): Dr Diana Lehmann, Dr Helen Tuppen, Georgia Campbell, Charlotte Alston, Dr Conor LawlessORCiD, Hannah Rosa, Dr Mariana Rocha, Dr Amy Reeve, Dr Thomas NichollsORCiD, Professor Robert Taylor, Emeritus Professor Doug Turnbull, Dr Amy VincentORCiD



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


Clonal expansion of mitochondrial DNA (mtDNA) deletions is an important pathological mechanism in adults with mtDNA maintenance disorders, leading to a mosaic mitochondrial respiratory chain deficiency in skeletal muscle. This study had two aims: (i) to determine if different Mendelian mtDNA maintenance disorders showed similar pattern of mtDNA deletions and respiratory chain deficiency and (ii) to investigate the correlation between the mitochondrial genetic defect and corresponding respiratory chain deficiency. We performed a quantitative analysis of respiratory chain deficiency, at a single cell level, in a cohort of patients with mutations in mtDNA maintenance genes. Using the same tissue section, we performed laser microdissection and single cell genetic analysis to investigate the relationship between mtDNA deletion characteristics and the respiratory chain deficiency. The pattern of respiratory chain deficiency is similar with different genetic defects. We demonstrate a clear correlation between the level of mtDNA deletion and extent of respiratory chain deficiency within a single cell. Long-range and single molecule PCR shows the presence of multiple mtDNA deletions in approximately one-third of all muscle fibres. We did not detect evidence of a replicative advantage for smaller mtDNA molecules in the majority of fibres, but further analysis is needed to provide conclusive evidence.

Publication metadata

Author(s): Lehmann D, Tuppen HAL, Campbell G, Alston CL, Lawless C, Rosa HS, Rocha MC, Reeve AK, Nicholls TJ, Deschauer M, Zierz S, Taylor RW, Turnbull DM, Vincent AE

Publication type: Article

Publication status: Published

Journal: Nucleic Acids Research

Year: 2019

Volume: 47

Issue: 14

Pages: 7430–7443

Print publication date: 01/08/2019

Online publication date: 31/05/2019

Acceptance date: 16/05/2019

Date deposited: 31/05/2019

ISSN (print): 0305-1048

ISSN (electronic): 1362-4962

Publisher: Oxford University Press


DOI: 10.1093/nar/gkz472


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust
213464/Z/18/ZWellcome Trust
MR/L016354/1Medical Research Council (MRC)