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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.
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
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)
PubMed id: 30949583
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