Mitochondrial fusion is required for regulation of mitochondrial DNA replication.
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
Mitochondrial Dynamics
/ genetics
Mitochondrial Membranes
/ metabolism
Mitochondrial Proteins
/ genetics
Mutagenesis
Myocytes, Cardiac
/ metabolism
Transcription, Genetic
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
27
11
2018
accepted:
11
03
2019
entrez:
7
6
2019
pubmed:
7
6
2019
medline:
7
11
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31170154
doi: 10.1371/journal.pgen.1008085
pii: PGENETICS-D-18-02235
pmc: PMC6553695
doi:
Substances chimiques
DNA, Mitochondrial
0
Mitochondrial Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008085Commentaires et corrections
Type : CommentIn
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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