Linear mitochondrial DNA is rapidly degraded by components of the replication machinery

Viktoriya Peeva, Daniel Blei, Genevieve Trombly, Sarah Corsi, Maciej J. Szukszto, Pedro Rebelo-Guiomar, Payam A. Gammage, Alexei P. Kudin, Christian Becker, Janine Altmüller, Michal Minczuk (), Gábor Zsurka () and Wolfram S. Kunz ()
Additional contact information
Viktoriya Peeva: University of Bonn
Daniel Blei: University of Bonn
Genevieve Trombly: University of Bonn
Sarah Corsi: University of Bonn
Maciej J. Szukszto: University of Cambridge
Pedro Rebelo-Guiomar: University of Cambridge
Payam A. Gammage: University of Cambridge
Alexei P. Kudin: University of Bonn
Christian Becker: University of Cologne
Janine Altmüller: University of Cologne
Michal Minczuk: University of Cambridge
Gábor Zsurka: University of Bonn
Wolfram S. Kunz: University of Bonn

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract Emerging gene therapy approaches that aim to eliminate pathogenic mutations of mitochondrial DNA (mtDNA) rely on efficient degradation of linearized mtDNA, but the enzymatic machinery performing this task is presently unknown. Here, we show that, in cellular models of restriction endonuclease-induced mtDNA double-strand breaks, linear mtDNA is eliminated within hours by exonucleolytic activities. Inactivation of the mitochondrial 5′-3′exonuclease MGME1, elimination of the 3′-5′exonuclease activity of the mitochondrial DNA polymerase POLG by introducing the p.D274A mutation, or knockdown of the mitochondrial DNA helicase TWNK leads to severe impediment of mtDNA degradation. We do not observe similar effects when inactivating other known mitochondrial nucleases (EXOG, APEX2, ENDOG, FEN1, DNA2, MRE11, or RBBP8). Our data suggest that rapid degradation of linearized mtDNA is performed by the same machinery that is responsible for mtDNA replication, thus proposing novel roles for the participating enzymes POLG, TWNK, and MGME1.

Date: 2018
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DOI: 10.1038/s41467-018-04131-w

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