Role of mitochondrial fusion in cardiac energy metabolism

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. The goal of our work was to determine the importance of mitochondrial fusion on heart energy homeostasis. To decipher the link between mitochondrial dynamics and mtDNA maintenance and heart energy metabolism, we studied heart conditional knockout mouse and mouse embryonic fibroblasts (MEFs) with disruption of mitochondrial fusion. Super-resolution microscopy analyses revealed that loss of outer mitochondrial membrane (OMM) fusion, but not inner mitochondrial membrane (IMM) fusion, leads to clustering and loss of nucleoids. Remarkably, fluorescence in situ hybridization (FISH) in MEFs, bromouridine labeling of MEFs and assessment of mitochondrial transcription in tissue homogenates revealed that abolished OMM fusion does not affect transcription. The profound mtDNA depletion in 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.