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

Filograna, R.; Koolmeister, C.; Upadhyay, M.; Pajak, A.; Clemente, P.; Wibom, R.; Simard, M. L.; Wredenberg, A.; Freyer, C.; Stewart, J.; Larsson, N.G.

doi:10.1126/sciadv.aav9824

Item

ITEM ACTIONSEXPORT

Add to Basket

Local TagsRelease HistoryDetailsSummary

Released

Journal Article

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

MPS-Authors

/persons/resource/persons281624

Filograna, R.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons281150

Koolmeister, C.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons281626

Upadhyay, M.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons281630

Pajak, A.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons281632

Clemente, P.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons129861

Wredenberg, A.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons129859

Freyer, C.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons129358

Stewart, J.
Stewart – Mitochondrial Mutations and Genome Co-evolution, Research Groups, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons129342

Larsson, N.G.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

External Resource

https://www.ncbi.nlm.nih.gov/pubmed/30949583
(Any fulltext)

Fulltext (restricted access)

There are currently no full texts shared for your IP range.

Fulltext (public)

There are no public fulltexts stored in PuRe

Supplementary Material (public)

There is no public supplementary material available

Citation

Filograna, R., Koolmeister, C., Upadhyay, M., Pajak, A., Clemente, P., Wibom, R., et al. (2019). Modulation of mtDNA copy number ameliorates the pathological consequences of a heteroplasmic mtDNA mutation in the mouse. Sci Adv, 5(4), eaav9824. doi:10.1126/sciadv.aav9824.

Cite as: https://hdl.handle.net/21.11116/0000-000B-4301-8

Abstract

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 tRNA(Ala) 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.