PMID- 31170154
OWN - NLM
STAT- MEDLINE
DCOM- 20191106
LR  - 20200309
IS  - 1553-7404 (Electronic)
IS  - 1553-7390 (Print)
IS  - 1553-7390 (Linking)
VI  - 15
IP  - 6
DP  - 2019 Jun
TI  - Mitochondrial fusion is required for regulation of mitochondrial DNA replication.
PG  - e1008085
LID - 10.1371/journal.pgen.1008085 [doi]
LID - e1008085
AB  - 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.
FAU - Silva Ramos, Eduardo
AU  - Silva Ramos E
AUID- ORCID: 0000-0002-8520-9107
AD  - Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 
      Cologne, Germany.
FAU - Motori, Elisa
AU  - Motori E
AD  - Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 
      Cologne, Germany.
FAU - Bruser, Christian
AU  - Bruser C
AUID- ORCID: 0000-0003-1873-5120
AD  - Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, 
      Gottingen, Germany.
FAU - Kuhl, Inge
AU  - Kuhl I
AUID- ORCID: 0000-0003-4797-0859
AD  - Institute of Integrative Biology of the Cell (I2BC) UMR9198, CEA, CNRS, Univ. 
      Paris-Sud, Universite Paris-Saclay, Gif-sur-Yvette, France.
FAU - Yeroslaviz, Assa
AU  - Yeroslaviz A
AUID- ORCID: 0000-0001-9638-4026
AD  - Computational Systems Biochemistry, Bioinformatics Core Facility, Max Planck 
      Institute of Biochemistry, Martinsried, Germany.
FAU - Ruzzenente, Benedetta
AU  - Ruzzenente B
AUID- ORCID: 0000-0001-7366-114X
AD  - INSERM U1163, Universite Paris Descartes-Sorbonne Paris Cite, Institut Imagine, 
      Paris, France.
FAU - Kauppila, Johanna H K
AU  - Kauppila JHK
AD  - Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 
      Cologne, Germany.
FAU - Busch, Jakob D
AU  - Busch JD
AD  - Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 
      Cologne, Germany.
FAU - Hultenby, Kjell
AU  - Hultenby K
AD  - Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
FAU - Habermann, Bianca H
AU  - Habermann BH
AUID- ORCID: 0000-0002-2457-7504
AD  - Aix-Marseille Universite, CNRS, IBDM UMR 7288, Marseille, France.
FAU - Jakobs, Stefan
AU  - Jakobs S
AUID- ORCID: 0000-0002-8028-3121
AD  - Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, 
      Gottingen, Germany.
FAU - Larsson, Nils-Goran
AU  - Larsson NG
AUID- ORCID: 0000-0001-5100-996X
AD  - Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 
      Cologne, Germany.
AD  - Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 
      Stockholm, Sweden.
FAU - Mourier, Arnaud
AU  - Mourier A
AUID- ORCID: 0000-0002-5413-611X
AD  - Universite de Bordeaux, IBGC UMR 5095, Bordeaux, France.
AD  - CNRS, IBGC CNRS UMR 5095, Bordeaux, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190606
PL  - United States
TA  - PLoS Genet
JT  - PLoS genetics
JID - 101239074
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (Mitochondrial Proteins)
SB  - IM
CIN - PLoS Genet. 2019 Jun 6;15(6):e1008140. PMID: 31170157
MH  - Animals
MH  - DNA Copy Number Variations/genetics
MH  - DNA Replication/genetics
MH  - DNA, Mitochondrial/*genetics
MH  - Fibroblasts
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Membrane Fusion/genetics
MH  - Mice
MH  - Mitochondria, Heart/*genetics/metabolism
MH  - Mitochondrial Dynamics/*genetics
MH  - Mitochondrial Membranes/metabolism
MH  - Mitochondrial Proteins/*genetics
MH  - Mutagenesis
MH  - Myocytes, Cardiac/metabolism
MH  - Transcription, Genetic
PMC - PMC6553695
COIS- The authors have declared that no competing interests exist.
EDAT- 2019/06/07 06:00
MHDA- 2019/11/07 06:00
PMCR- 2019/06/06
CRDT- 2019/06/07 06:00
PHST- 2018/11/27 00:00 [received]
PHST- 2019/03/11 00:00 [accepted]
PHST- 2019/06/07 06:00 [entrez]
PHST- 2019/06/07 06:00 [pubmed]
PHST- 2019/11/07 06:00 [medline]
PHST- 2019/06/06 00:00 [pmc-release]
AID - PGENETICS-D-18-02235 [pii]
AID - 10.1371/journal.pgen.1008085 [doi]
PST - epublish
SO  - PLoS Genet. 2019 Jun 6;15(6):e1008085. doi: 10.1371/journal.pgen.1008085. 
      eCollection 2019 Jun.