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

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Matic, S.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Jiang, M.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Dirksen-Schwanenland, C.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Simard, Marie-Lune
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Li, X.
Proteomics, Core Facilities, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Atanassov, Ilian
Proteomics, Core Facilities, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons129358

Stewart, J.
Stewart – Mitochondrial Mutations and Genome Co-evolution, Research Groups, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Larsson, N.G.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Milenkovic, D.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Citation

Matic, S., Jiang, M., Nicholls, T. J., Uhler, J. P., Dirksen-Schwanenland, C., Polosa, P. L., et al. (2018). Mice lacking the mitochondrial exonuclease MGME1 accumulate mtDNA deletions without developing progeria. Nat Commun, 9(1), 1202. doi:10.1038/s41467-018-03552-x.

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.