Developmental and pathological changes in the human cardiac muscle mitochondrial DNA organization, replication and copy number
Open accessAbstract
Adult human heart mitochondrial DNA (mtDNA) has recently been shown to have a complex organization with abundant dimeric molecules, branched structures and four-way junctions. In order to understand the physiological significance of the heart-specific mtDNA maintenance mode and to find conditions that modify human heart mtDNA structure and replication, we analyzed healthy human heart of various ages as well as several different heart diseases, including ischemic heart disease, dilated as well as hypertrophic cardiomyopathies, and several mitochondrial disorders. By using one- and two-dimensional agarose gel electrophoresis, various enzymatic treatments and quantitative PCR we found that in human newborns heart mtDNA has a simple organization, lacking junctional forms and dimers. The adult-type branched forms are acquired in the early childhood, correlating with an increase in mtDNA copy number. Mitochondrial disorders involving either mutations in the mtDNA polymerase gamma (PolGalpha) or mtDNA helicase Twinkle, while having no obvious cardiac manifestation, show distinct mtDNA maintenance phenotypes, which are not seen in various types of diseased heart or in mitochondrial disorders caused by point mutations or large-scale deletions of mtDNA. The findings suggest a link between cardiac muscle development, mtDNA copy number, replication mode and topological organization. Additionally, we show that Twinkle might have a direct role in the maintenance of four-way junctions in human heart mtDNA.
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Heart tissue samples from patients harboring a Twinkle duplication mutation (amino acids 352-364) that causes adPEO have mtDNA lacking these complex higher order structures.
“Heart tissue samples from patients harboring a Twinkle duplication mutation (amino acids 352–364) that causes adPEO have mtDNA that is lacking in these complex higher order structures (Pohjoismaki et al., 2010).”
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., 2010
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- Authors
- Pohjoismäki, J. L. O., Goffart, S., Taylor, R. W., Turnbull, D. M., Suomalainen, A., Jacobs, H. T., & Karhunen, P. J.
- Affiliations
- Tampere University (FI)
- University of Tampere (FI)
- Newcastle University (GB)
- University of Helsinki (FI)
- Corresponding author
- Pohjoismäki, Jaakko L. O.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-05-03
- Volume
- 5
- Issue
- 5
- Pages
- e10426
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2862702
- OpenAlex
- W2001021612
- Cited by
- 50
- References
- 37
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 2 · 2022: 4 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 3 · 2016: 4 · 2015: 5 · 2014: 4 · 2013: 5 · 2012: 4
- FWCI
- 1.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Tampere University Institutional Repository (Tampere University) (publishedVersion)
- Tampere University Institutional Repository (Tampere University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Työväentutkimus Vuosikirja (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Wellcome Trust (074454)
- Newcastle upon Tyne Hospitals NHS Foundation Trust
- Tampereen Yliopisto
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- mitochondrial DNA, human heart, mitochondrial DNA copy number, mitochondrial DNA replication, four-way junction, cardiomyopathy, ischemic heart disease, mitochondrial disease, Twinkle helicase, cardiac muscle development, mtDNA maintenance
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Animals, Child, Child, Preschool, DNA Polymerase I, DNA Replication, DNA Helicases, DNA, Mitochondrial, Female, Heart Diseases, Heart Ventricles, Humans, Infant, Infant, Newborn, Male, Middle Aged, Mutation, Myocardium, Recombination, Genetic, Case-Control Studies, Mitochondrial Proteins, Mitochondrial Diseases, Mice, DNA Copy Number Variations
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