Metabolism and DNA repair shape a specific modification pattern in mitochondrial DNA

Tina Pawar; Magnar Bjørås; Arne Klungland; Lars Eide

doi:10.1016/j.mito.2017.09.002

Metabolism and DNA repair shape a specific modification pattern in mitochondrial DNA

Mitochondrion. 2018 May:40:16-28. doi: 10.1016/j.mito.2017.09.002. Epub 2017 Sep 8.

Authors

Tina Pawar¹, Magnar Bjørås², Arne Klungland³, Lars Eide⁴

Affiliations

¹ Department of Medical Biochemistry, University of Oslo, Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway.
² Department of Microbiology, University of Oslo, Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway; Department of clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
³ Department of Microbiology, University of Oslo, Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway.
⁴ Department of Medical Biochemistry, University of Oslo, Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway. Electronic address: lars.eide@medisin.uio.no.

PMID: 28893634
DOI: 10.1016/j.mito.2017.09.002

Abstract

The mitochondrial DNA (mtDNA) resides in the vicinity of energy-rich reactions. Thus, chemical modifications of mtDNA might mirror mitochondrial processes and could serve as biomarkers of metabolic processes in the mitochondria. This hypothesis was tested by assessing modifications at 17 different sites in the mtDNA as a function of cell type, oxidative stress and mitochondrial activity. Two mouse mutants with a metabolic phenotype were compared to wild-type (WT) mice: the ogg1^-/- mouse that lacks the 8-oxoguanine DNA glycosylase (OGG1), and the alkbh7^-/- mouse missing the ALKBH7 protein that has been implicated in fatty acid oxidation. It was found that cell type, oxidative stress and mitochondrial complex activity shaped distinct modification patterns in mtDNA, and that OGG1 and ALKBH7 independently modulated these modification patterns. The modifications included ribonucleotides, which also accumulated in mtDNA with age. Interestingly, this age-dependent accumulation most likely involves DNA repair, as mtDNA from ogg1^-/- mice did not accumulate modifications with age. On the other hand, alkbh7^-/- mtDNA accumulated more modifications with age than WT mtDNA. Our results show that mtDNA is dynamically modified with metabolic activity and imply a novel synergy between metabolism and mtDNA repair proteins.

Keywords: ALKBH7; DNA modification; Metabolism; OGG1; mtDNA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Age Factors
AlkB Enzymes / genetics
AlkB Enzymes / metabolism*
Animals
DNA Glycosylases / deficiency
DNA Methylation*
DNA Repair*
DNA, Mitochondrial / metabolism*
Mice
Mice, Knockout
Mitochondria / genetics
Mitochondria / metabolism*

Substances

DNA, Mitochondrial
ALKBH7 protein, mouse
AlkB Enzymes
DNA Glycosylases
Ogg1 protein, mouse