A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations
Open accessAbstract
The majority of mitochondrial DNA (mtDNA) mutations that cause human disease are mild to moderately deleterious, yet many random mtDNA mutations would be expected to be severe. To determine the fate of the more severe mtDNA mutations, we introduced mtDNAs containing two mutations that affect oxidative phosphorylation into the female mouse germ line. The severe ND6 mutation was selectively eliminated during oogenesis within four generations, whereas the milder COI mutation was retained throughout multiple generations even though the offspring consistently developed mitochondrial myopathy and cardiomyopathy. Thus, severe mtDNA mutations appear to be selectively eliminated from the female germ line, thereby minimizing their impact on population fitness.
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Two heteroplasmic point mutations in MT-ND6 (m.13885insC) and MT-CO1 (m.6589T N C) resulted in myopathy and cardiomyopathy.
“Two heteroplasmic point mutations introduced in MT-ND6 (m.13885insC) and MT-CO1 (m.6589T N C) resulted in myopathy and cardiomyopathy [174]”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [174]
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- Authors
- Fan, W., Waymire, K. G., Narula, N., Li, P., Rocher, C., Coskun, P. E., Vannan, M. A., Narula, J., MacGregor, G. R., & Wallace, D. C.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Wallace, Douglas C.
- ORCID
- Venue
- Science
- Published
- 2008-02-15
- Volume
- 319
- Issue
- 5865
- Pages
- 958-962
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3049809
- OpenAlex
- W2079092251
- Cited by
- 466
- References
- 20
- Citations by year
- 2026: 16 · 2025: 18 · 2024: 18 · 2023: 14 · 2022: 20 · 2021: 30 · 2020: 32 · 2019: 32 · 2018: 29 · 2017: 17 · 2016: 23 · 2015: 16 · 2014: 31 · 2013: 22 · 2012: 40
- FWCI
- 14.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (AG 16573, AG-13154, R01AG024373, P50AG016573, AG24373, R01AG013154)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-73691, R01DK073691)
- National Institute of Neurological Disorders and Stroke (NS-21328, R01NS021328)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD45913, U01HD045913)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Keywords
- mitochondrial disease, mitochondrial DNA mutations, oogenesis, oxidative phosphorylation, mitochondrial myopathy, cardiomyopathy, mouse model, female germline
- MeSH terms
- Animals, Cell Line, Crosses, Genetic, Electron Transport Complex IV, DNA, Mitochondrial, Female, Litter Size, Male, Mitochondria, Cardiomyopathies, Myocardium, NADH Dehydrogenase, Oocytes, Oogenesis, Oxidative Phosphorylation, Oxygen Consumption, Selection, Genetic, Frameshift Mutation, Mitochondrial Myopathies, Point Mutation, Germ-Line Mutation, Mutation, Missense, Electron Transport Complex I, Mice, Embryonic Stem Cells
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