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Human Heart Mitochondrial DNA Is Organized in Complex Catenated Networks Containing Abundant Four-way Junctions and Replication Forks
Open accessAbstract
Analysis of human heart mitochondrial DNA (mtDNA) by electron microscopy and agarose gel electrophoresis revealed a complete absence of the -type replication intermediates seen abundantly in mtDNA from all other tissues. Instead only Y- and X-junctional forms were detected after restriction digestion. Uncut heart mtDNA was organized in tangled complexes of up to 20 or more genome equivalents, which could be resolved to genomic monomers, dimers, and linear fragments by treatment with the decatenating enzyme topoisomerase IV plus the cruciform-cutting T7 endonuclease I. Human and mouse brain also contained a population of such mtDNA forms, which were absent, however, from mouse, rabbit, or pig heart. Overexpression in transgenic mice of two proteins involved in mtDNA replication, namely human mitochondrial transcription factor A or the mouse Twinkle DNA helicase, generated abundant four-way junctions in mtDNA of heart, brain, and skeletal muscle. The organization of mtDNA of human heart as well as of mouse and human brain in complex junctional networks replicating via a presumed non- mechanism is unprecedented in mammals.
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“Systemic overexpression of Twinkle in mouse hearts causes an increase in complex DNA forms and recombination junctions similar to adult human hearts (Pohjoismaki et al., 2009).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Pohjoismaki et al., 2009
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“In adult human hearts however, mtDNA has been shown to exist as dimers and is organized into highly complex, branched molecules (Pohjoismaki et al., 2009).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Pohjoismaki et al., 2009
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Metadata
- Authors
- Pohjoismäki, J. L. O., Goffart, S., Tyynismaa, H., Willcox, S., Ide, T., Kang, D., Suomalainen, A., Karhunen, P. J., Griffith, J. D., Holt, I. J., & Jacobs, H. T.
- Affiliations
- Tampere University Hospital (FI)
- University of Helsinki (FI)
- University of North Carolina at Chapel Hill (US)
- Kyushu University (JP)
- University of Tampere (FI)
- MRC Mitochondrial Biology Unit (GB)
- Corresponding author
- Jacobs, Howard T.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-08
- Volume
- 284
- Issue
- 32
- Pages
- 21446-21457
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2755869
- OpenAlex
- W2014114000
- Cited by
- 122
- References
- 70
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 9 · 2023: 4 · 2022: 8 · 2021: 6 · 2020: 8 · 2019: 10 · 2018: 10 · 2017: 4 · 2016: 8 · 2015: 10 · 2014: 5 · 2013: 9 · 2012: 10
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- UNC Libraries
- Funders
- Foundation for Cardiovascular Research
- European Commission
- Academy of Finland
- Suomen Kulttuurirahasto
- Sydäntutkimussäätiö
- Tays
- National Institutes of Health
- Medical Research Council
- National Institute of General Medical Sciences (GM-31819, R01GM031819)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- mitochondrial DNA, heart, four-way junction, replication fork, topoisomerase IV, T7 endonuclease I, TFAM, Twinkle helicase, mitochondrial DNA replication, brain, skeletal muscle, species differences
- MeSH terms
- Adult, Aged, Animals, Brain, Child, Preschool, DNA, Mitochondrial, Female, Heart, Humans, Male, Mice, Transgenic, Middle Aged, Nucleic Acid Conformation, Rabbits, Species Specificity, Swine, Tissue Distribution, Mice
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