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Article Dans Une Revue PLoS Genetics Année : 2019

Mitochondrial fusion is required for regulation of mitochondrial DNA replication

Résumé

Mitochondrial dynamics is an essential physiological process controlling mitochondrial content mixing and mobility to ensure proper function and localization of mitochondria at intra-cellular 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 muta-genesis 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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hal-02369000 , version 1 (29-11-2019)

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Eduardo Silva Ramos, Elisa Motori, Christian Brüser, Inge Kühl, Assa Yeroslaviz, et al.. Mitochondrial fusion is required for regulation of mitochondrial DNA replication. PLoS Genetics, 2019, 15 (6), pp.e1008085. ⟨10.1371/journal.pgen.1008085⟩. ⟨hal-02369000⟩
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