Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease
Open accessAbstract
MGME1, also known as Ddk1 or C20orf72, is a mitochondrial exonuclease found to be involved in the processing of mitochondrial DNA (mtDNA) during replication. Here, we present detailed insights on the role of MGME1 in mtDNA maintenance. Upon loss of MGME1, elongated 7S DNA species accumulate owing to incomplete processing of 5' ends. Moreover, an 11-kb linear mtDNA fragment spanning the entire major arc of the mitochondrial genome is generated. In contrast to control cells, where linear mtDNA molecules are detectable only after nuclease S1 treatment, the 11-kb fragment persists in MGME1-deficient cells. In parallel, we observed characteristic mtDNA duplications in the absence of MGME1. The fact that the breakpoints of these mtDNA rearrangements do not correspond to either classical deletions or the ends of the linear 11-kb fragment points to a role of MGME1 in processing mtDNA ends, possibly enabling their repair by homologous recombination. In agreement with its functional involvement in mtDNA maintenance, we show that MGME1 interacts with the mitochondrial replicase PolgA, suggesting that it is a constituent of the mitochondrial replisome, to which it provides an additional exonuclease activity. Thus, our results support the viewpoint that MGME1-mediated mtDNA processing is essential for faithful mitochondrial genome replication and might be required for intramolecular recombination of mtDNA.
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MGME1 has a role in mtDNA replication, likely providing 5′ → 3′ exonuclease activity.
“MGME1 interacts directly with PolG suggesting a role in mtDNA replication, likely providing 5′ → 3′ exonuclease activity (Nicholls et al., 2014).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Nicholls et al., 2014
HeLa cells and patient fibroblasts with MGME1 knocked-down have increased amounts and lengths of 7S mtDNA.
“HeLa cells and patient fibroblasts with MGME1 knocked-down have increased amounts and lengths of 7S mtDNA (Nicholls et al., 2014).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Nicholls et al., 2014
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- Authors
- Nicholls, T. J., Zsurka, G., Peeva, V., Schöler, S., Szczesny, R. J., Cysewski, D., Reyes, A., Kornblum, C., Sciacco, M., Moggio, M., Dziembowski, A., Kunz, W. S., & Minczuk, M.
- Affiliations
- MRC Mitochondrial Biology Unit (GB)
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences (PL)
- University of Bonn (DE)
- University of Milan (IT)
- Corresponding author
- Kunz, Wolfram S.
- Minczuk, Michal
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-06-30
- Volume
- 23
- Issue
- 23
- Pages
- 6147-6162
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC4222359
- OpenAlex
- W2103776029
- Cited by
- 78
- References
- 68
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 6 · 2022: 9 · 2021: 3 · 2020: 10 · 2019: 7 · 2018: 11 · 2017: 2 · 2016: 6 · 2015: 6
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Human Molecular Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- European Commission (279062)
- Deutsche Forschungsgemeinschaft (KU911/21-1, ZS 99/3-1)
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- mitochondrial DNA maintenance, mtDNA rearrangements, 5' end processing, homologous recombination, mitochondrial DNA replication, intramolecular recombination
- MeSH terms
- DNA Polymerase gamma, Cell Line, DNA-Directed DNA Polymerase, DNA Replication, DNA, Mitochondrial, Exodeoxyribonucleases, Humans, Mutation, Gene Rearrangement, Mitochondrial Diseases
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