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

Stanka Matic, Min Jiang, Thomas J. Nicholls, Jay P. Uhler, Caren Dirksen-Schwanenland, Paola Loguercio Polosa, Marie-Lune Simard, Xinping Li, Ilian Atanassov, Oliver Rackham, Aleksandra Filipovska, James B. Stewart, Maria Falkenberg, Nils-Göran Larsson () and Dusanka Milenkovic ()
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Stanka Matic: Max Planck Institute for Biology of Ageing
Min Jiang: Max Planck Institute for Biology of Ageing
Thomas J. Nicholls: University of Gothenburg
Jay P. Uhler: University of Gothenburg
Caren Dirksen-Schwanenland: Max Planck Institute for Biology of Ageing
Paola Loguercio Polosa: University of Bari Aldo Moro
Marie-Lune Simard: Max Planck Institute for Biology of Ageing
Xinping Li: Max Planck Institute for Biology of Ageing
Ilian Atanassov: Max Planck Institute for Biology of Ageing
Oliver Rackham: The University of Western Australia
Aleksandra Filipovska: The University of Western Australia
James B. Stewart: Max Planck Institute for Biology of Ageing
Maria Falkenberg: University of Gothenburg
Nils-Göran Larsson: Max Planck Institute for Biology of Ageing
Dusanka Milenkovic: Max Planck Institute for Biology of Ageing

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03552-x

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