Selective mitochondrial DNA degradation following double-strand breaks

Mitochondrial DNA (mtDNA) can undergo double-strand breaks (DSBs), caused by defective replication, or by various endogenous or exogenous sources, such as reactive oxygen species, chemotherapeutic agents or ionizing radiations. MtDNA encodes for proteins involved in ATP production, and maintenance o...

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Bibliographic Details
Published in:	PloS one Vol. 12; no. 4; p. e0176795
Main Authors:	Moretton, Amandine, Morel, Frédéric, Macao, Bertil, Lachaume, Philippe, Ishak, Layal, Lefebvre, Mathilde, Garreau-Balandier, Isabelle, Vernet, Patrick, Falkenberg, Maria, Farge, Géraldine
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 28.04.2017 Public Library of Science (PLoS)
Subjects:	Aging Animal models Apoptosis Autophagy Base excision repair Biochemistry Biochemistry, Molecular Biology Biology and life sciences Biomedical materials Biotechnology Blotting, Southern Blotting, Western Cell activation Cell death Cell lines Cell proliferation cells Clinical Medicine Clonal deletion Copy number Crystal structure Cullin Cyclin-dependent kinase Cyclooxygenase 1 - genetics damage Degradation Deoxyribonuclease Deoxyribonucleic acid Depletion disease DNA DNA Breaks, Double-Stranded DNA damage DNA Repair DNA, Mitochondrial DNA-directed DNA polymerase Endonuclease Endonucleases - metabolism Enzymes Exonucleases - metabolism expression Flow Cytometry Gene expression Gene therapy Genetics Genomes Genomics HEK293 Cells Homology Humans inducible Ionizing radiation Kinetics Klinisk medicin Lesions Life Sciences Lung cancer Maintenance Mammals Mathematical analysis Millet Mitochondria Mitochondria - metabolism Mitochondrial DNA mtdna replication Mutation Neurodegenerative diseases Nuclease Nuclei Nucleic acids Organelles Oxidative phosphorylation Oxygen Proteins Quality control Reaction kinetics Reactive oxygen species Real-Time Polymerase Chain Reaction recombination removal repair Replication Sequence Analysis targeted restriction-endonuclease transcription factor-a Transfection Viability Viruses Autophagic cell death Nucleases DNA replication Mitochondria Small interfering RNAs Mitochondrial DNA DNA repair Apoptosis
ISSN:	1932-6203, 1932-6203
Online Access:	Get full text
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Summary:	Mitochondrial DNA (mtDNA) can undergo double-strand breaks (DSBs), caused by defective replication, or by various endogenous or exogenous sources, such as reactive oxygen species, chemotherapeutic agents or ionizing radiations. MtDNA encodes for proteins involved in ATP production, and maintenance of genome integrity following DSBs is thus of crucial importance. However, the mechanisms involved in mtDNA maintenance after DSBs remain unknown. In this study, we investigated the consequences of the production of mtDNA DSBs using a human inducible cell system expressing the restriction enzyme PstI targeted to mitochondria. Using this system, we could not find any support for DSB repair of mtDNA. Instead we observed a loss of the damaged mtDNA molecules and a severe decrease in mtDNA content. We demonstrate that none of the known mitochondrial nucleases are involved in the mtDNA degradation and that the DNA loss is not due to autophagy, mitophagy or apoptosis. Our study suggests that a still uncharacterized pathway for the targeted degradation of damaged mtDNA in a mitophagy/autophagy-independent manner is present in mitochondria, and might provide the main mechanism used by the cells to deal with DSBs.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Competing Interests: The authors have declared that no competing interests exist. Conceptualization: FM PL PV MF GF.Data curation: GF.Formal analysis: AM.Funding acquisition: GF PV.Investigation: AM FM BM LI ML IGB GF.Methodology: AM GF.Project administration: GF.Resources: PV MF.Supervision: GF.Validation: GF FM.Visualization: AM GF.Writing – original draft: AM GF.Writing – review & editing: FM PV MF PL BM.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0176795