Mitochondrial DNA mutations activate programmed cell survival in the mouse heart
Abstract
Increased frequencies of mitochondrial DNA (mtDNA) mutations characterize the aging heart and are also found in idiopathic dilated cardiomyopathy and end-stage heart failure. The pathogenic potential of such mutations is unclear. Transgenic mice showing accelerated accumulation of mtDNA mutations and dilated cardiomyopathy due to expression of an error-prone mtDNA polymerase specifically in the heart were characterized by Western blot analysis and immunohistochemistry for the levels of pro- and antiapoptotic proteins. By 8 wk of age, when frequencies of mtDNA mutations were approximately 0.01% and all transgenic mice showed four-chamber cardiac dilation, a vigorous prosurvival response was evident. Upregulated were Bcl-2, Bcl-xl, Bfl1, heat shock protein 27, and X-linked inhibitor of apoptosis protein, all of which function to inhibit apoptosis. Although translocation of Bax to mitochondria was also seen, it was not integrated into the mitochondrial membrane. Treatment of transgenic mice with doxorubicin failed to induce apoptosis, in contrast to controls, showing that the prosurvival response protected cardiomyocytes from a death stimulus. Increased apoptosis and release of cytochrome c appeared to precede the establishment of the prosurvival state suggesting that it may reflect a response to activation of programmed cell death pathways. It has been proposed that a programmed cell survival response is activated in the failing and aging heart. We show that elevated frequencies of mtDNA mutations may serve as one trigger for the activation of such a response.
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These mice also presented with secondary effects, such as increased apoptosis and cardiomyopathy.
“These mice also presented with secondary effects, such as increased apoptosis and cardiomyopathy (Zhang et al., 2005; Zhang et al., 2003).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Zhang et al., 2005
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Self-citation
- Authors
- Zhang, D., Mott, J. L., Chang, S.-W., Stevens, M., Mikolajczak, P., & Zassenhaus, H. P.
- Affiliations
- Saint Louis University (US)
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2005-05
- Volume
- 288
- Issue
- 5
- Pages
- H2476-H2483
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- OpenAlex
- W2118984005
- Cited by
- 49
- References
- 36
- Citations by year
- 2025: 1 · 2023: 1 · 2021: 1 · 2020: 2 · 2017: 1 · 2016: 2 · 2015: 1 · 2014: 3 · 2013: 4 · 2012: 1
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ns041785-05)
- National Institute on Aging (F32AG005710, AG-5710)
- National Institute of Neurological Disorders and Stroke (NS-41785)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- mitochondrial DNA mutations, cardiomyocyte apoptosis, dilated cardiomyopathy, heart failure, aging heart, Bcl-2 family proteins, Bax translocation, cytochrome c release, doxorubicin resistance, HSP27, XIAP, transgenic mice
- MeSH terms
- Aging, Animals, Cell Survival, DNA, Mitochondrial, Heart Failure, Heat-Shock Proteins, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Signal Transduction, Up-Regulation, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Myocytes, Cardiac, Mice, HSP27 Heat-Shock Proteins
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