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

Lookup NU author(s): Dr Thomas NichollsORCiD, Dr Jim StewartORCiD

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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.

Publication metadata

Author(s): Matic S, Jiang M, Nicholls TJ, Uhler JP, Dirksen-Schwanenland C, Polosa PL, Simard ML, Li X, Atanassov I, Rackham O, Filipovska A, Stewart JB, Falkenberg M, Larsson NG, Milenkovic D

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2018

Volume: 9

Issue: 1

Online publication date: 23/03/2018

Acceptance date: 21/02/2018

Date deposited: 14/03/2019

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41467-018-03552-x

DOI: 10.1038/s41467-018-03552-x

PubMed id: 29572490

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