Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria
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Summary: Mitochondrial defects have been found in aging and several age‐related diseases. Mice with a homozygous mutation in the exonuclease encoding domain of mitochondrial DNA polymerase gamma (Polg m/m ) are prone to age‐dependent accumulation of mitochondrial DNA mutations and have shown a broad spectrum of aging‐like phenotypes. However, the mechanism of cardiac phenotypes in relation to the role of mitochondrial DNA mutations and oxidative stress in this mouse model has not been fully addressed. We demonstrate age‐dependent cardiomyopathy in Polg m/m mice, which by 13–14 months of age displays marked cardiac hypertrophy and dilatation, impairment of systolic and diastolic function, and increased cardiac fibrosis. This age‐dependent cardiomyopathy is associated with increases in mitochondrial DNA (mtDNA) deletions and protein oxidative damage, increased expression of apoptotic and senescence markers, as well as a decline in signaling for mitochondrial biogenesis. The relationship of these changes to mitochondrial reactive oxygen species (ROS) was tested by crossing Polg m/m mice with mice that overexpress mitochondrial targeted catalase (mCAT). All of the above phenotypes were partially rescued in Polg m/m /mCAT mice. These data indicate that accumulation of mitochondrial DNA damage with age can lead to cardiomyopathy and that this phenotype is partly mediated by mitochondrial oxidative stress.
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Dysfunctional mitochondria can induce cellular senescence in culture and in vivo.
“Dysfunctional mitochondria can induce cellular senescence in culture (Moiseeva et al., 2009; Wang et al., 2003) and in vivo (Dai et al., 2010; Kang et al., 2013).”
From Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype (2016) · cites this paper as Dai et al., 2010
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Self-citation
- Authors
- Dai, D., Chen, T., Wanagat, J., Laflamme, M., Marcinek, D. J., Emond, M. J., Ngo, C. P., Prolla, T. A., & Rabinovitch, P. S.
- Affiliations
- University of Washington (US)
- University of California, Los Angeles (US)
- University of Wisconsin–Madison (US)
- Corresponding author
- Rabinovitch, Peter S.
- ORCID
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2010-07-21
- Volume
- 9
- Issue
- 4
- Pages
- 536-544
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC3265170
- OpenAlex
- W2116680700
- Cited by
- 280
- References
- 39
- Citations by year
- 2026: 16 · 2025: 10 · 2024: 13 · 2023: 16 · 2022: 16 · 2021: 22 · 2020: 24 · 2019: 13 · 2018: 23 · 2017: 21 · 2016: 17 · 2015: 20 · 2014: 28 · 2013: 8 · 2012: 19
- FWCI
- 5.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (P01AG001751, RC1AG035844, R01AG028455, P30AG013280)
- National Heart, Lung, and Blood Institute (R01HL101186)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- mitochondrial DNA deletions, mitochondrial DNA damage, mitochondrial oxidative stress, cardiac hypertrophy, cardiac dilatation, myocardial fibrosis, mitochondrial biogenesis, oxidative protein damage, apoptosis, cellular senescence, reactive oxygen species
- MeSH terms
- DNA Polymerase gamma, Aging, Animals, Catalase, DNA-Directed DNA Polymerase, DNA, Mitochondrial, Gene Expression Regulation, Cardiomegaly, Mitochondria, Mutation, Cardiomyopathies, Myocardium, Ultrasonography, Biomarkers, Cellular Senescence, Apoptosis, Sequence Deletion, Oxidative Stress, Mice
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