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  Mitochondrial fusion is required for regulation of mitochondrial DNA replication

Ramos, E., Motori, E., Bruser, C., Kuhl, I., Yeroslaviz, A., Ruzzenente, B., et al. (2019). Mitochondrial fusion is required for regulation of mitochondrial DNA replication. PLoS Genet, 15(6), e1008085. doi:10.1371/journal.pgen.1008085.

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Ramos, E.S.1, Author           
Motori, E.1, Author           
Bruser, C., Author
Kuhl, I., Author
Yeroslaviz, A., Author
Ruzzenente, B., Author
Kauppila, J. H. K.1, Author           
Busch, J.1, Author           
Hultenby, K., Author
Habermann, B. H., Author
Jakobs, S., Author
Larsson, N.G.1, Author           
Mourier, A., Author
Affiliations:
1Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society, ou_1942286              

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Free keywords: Animals DNA Copy Number Variations/genetics DNA Replication/genetics DNA, Mitochondrial/*genetics Fibroblasts Humans In Situ Hybridization, Fluorescence Membrane Fusion/genetics Mice Mitochondria, Heart/*genetics/metabolism Mitochondrial Dynamics/*genetics Mitochondrial Membranes/metabolism Mitochondrial Proteins/*genetics Mutagenesis Myocytes, Cardiac/metabolism Transcription, Genetic
 Abstract: Mitochondrial dynamics is an essential physiological process controlling mitochondrial content mixing and mobility to ensure proper function and localization of mitochondria at intracellular sites of high-energy demand. Intriguingly, for yet unknown reasons, severe impairment of mitochondrial fusion drastically affects mtDNA copy number. To decipher the link between mitochondrial dynamics and mtDNA maintenance, we studied mouse embryonic fibroblasts (MEFs) and mouse cardiomyocytes with disruption of mitochondrial fusion. Super-resolution microscopy revealed that loss of outer mitochondrial membrane (OMM) fusion, but not inner mitochondrial membrane (IMM) fusion, leads to nucleoid clustering. Remarkably, fluorescence in situ hybridization (FISH), bromouridine labeling in MEFs and assessment of mitochondrial transcription in tissue homogenates revealed that abolished OMM fusion does not affect transcription. Furthermore, the profound mtDNA depletion in mouse hearts lacking OMM fusion is not caused by defective integrity or increased mutagenesis of mtDNA, but instead we show that mitochondrial fusion is necessary to maintain the stoichiometry of the protein components of the mtDNA replisome. OMM fusion is necessary for proliferating MEFs to recover from mtDNA depletion and for the marked increase of mtDNA copy number during postnatal heart development. Our findings thus link OMM fusion to replication and distribution of mtDNA.

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 Dates: 2019-062019-06-07
 Publication Status: Issued
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 Identifiers: Other: 31170154
DOI: 10.1371/journal.pgen.1008085
ISSN: 1553-7404 (Electronic)1553-7390 (Linking)
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Title: PLoS Genet
Source Genre: Journal
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Pages: - Volume / Issue: 15 (6) Sequence Number: - Start / End Page: e1008085 Identifier: -