Mitochondrial fusion is required for regulation of mitochondrial DNA replication

by Eduardo Silva Ramos, Elisa Motori, Christian Br üser, Inge Kühl, Assa Yeroslaviz, Benedetta Ruzzenente, Johanna H. K. Kauppila, Jakob D. Busch, Kjell Hultenby, Bianca H. Habermann, Stefan Jakobs, Nils-Göran Larsson, Arnaud Mourier 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 fusi on 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 m embrane (OMM) fusion, but not inner mitochondrial membrane (IMM) fusion, leads to nucleoid clustering. Remarkably, fluorescencein 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 rec...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research