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Modulation of mtDNA copy number ameliorates the pathological consequences of a heteroplasmic mtDNA mutation in the mouse

Lookup NU author(s): Dr Jim StewartORCiD



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


Heteroplasmic mtDNA mutations typically act in a recessive way and cause mitochondrial disease only if present above a certain threshold level. We have experimentally investigated to what extent the absolute levels of wild-type (WT) mtDNA influence disease manifestations by manipulating TFAM levels in mice with a heteroplasmic mtDNA mutation in the tRNAAla gene. Increase of total mtDNA levels ameliorated pathology in multiple tissues, although the levels of heteroplasmy remained the same. A reduction in mtDNA levels worsened the phenotype in postmitotic tissues, such as heart, whereas there was an unexpected beneficial effect in rapidly proliferating tissues, such as colon, because of enhanced clonal expansion and selective elimination of mutated mtDNA. The absolute levels of WT mtDNA are thus an important determinant of the pathological manifestations, suggesting that pharmacological or gene therapy approaches to selectively increase mtDNA copy number provide a potential treatment strategy for human mtDNA mutation disease.

Publication metadata

Author(s): Filograna R, Koolmeister C, Upadhyay M, Pajak A, Clemente P, Wibom R, Simard ML, Wredenberg A, Freyer C, Stewart JB, Larsson NG

Publication type: Article

Publication status: Published

Journal: Science Advances

Year: 2019

Volume: 5

Issue: 4

Online publication date: 03/04/2019

Acceptance date: 11/02/2019

Date deposited: 30/10/2020

ISSN (electronic): 2375-2548

Publisher: American Association for the Advancement of Science (AAAS)


DOI: 10.1126/sciadv.aav9824

PubMed id: 30949583


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