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Nat Commun. 2018 Mar 23;9(1):1202. doi: 10.1038/s41467-018-03552-x.

Mice lacking the mitochondrial exonuclease MGME1 accumulate mtDNA deletions without developing progeria.

Author information

1
Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, 50931, Germany.
2
Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, 405 30, Sweden.
3
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari Aldo Moro, Bari, 70125, Italy.
4
Proteomics Core Facility, Max Planck Institute for Biology of Ageing, Cologne, 50931, Germany.
5
Harry Perkins Institute of Medical Research Centre for Medical Research and School of Molecular Sciences, The University of Western Australia, Nedlands, WA 6009, Australia.
6
Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, 50931, Germany. nils-goran.larsson@ki.se.
7
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden. nils-goran.larsson@ki.se.
8
Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, 50931, Germany. dmilenkovic@age.mpg.de.

Abstract

Replication of mammalian mitochondrial DNA (mtDNA) is an essential process that requires high fidelity and control at multiple levels to ensure proper mitochondrial function. Mutations in the mitochondrial genome maintenance exonuclease 1 (MGME1) gene were recently reported in mitochondrial disease patients. Here, to study disease pathophysiology, we generated Mgme1 knockout mice and report that homozygous knockouts develop depletion and multiple deletions of mtDNA. The mtDNA replication stalling phenotypes vary dramatically in different tissues of Mgme1 knockout mice. Mice with MGME1 deficiency accumulate a long linear subgenomic mtDNA species, similar to the one found in mtDNA mutator mice, but do not develop progeria. This finding resolves a long-standing debate by showing that point mutations of mtDNA are the main cause of progeria in mtDNA mutator mice. We also propose a role for MGME1 in the regulation of replication and transcription termination at the end of the control region of mtDNA.

PMID:
29572490
PMCID:
PMC5865154
DOI:
10.1038/s41467-018-03552-x
[Indexed for MEDLINE]
Free PMC Article

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