Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression
Open accessAbstract
We have attempted to determine whether loss of mtDNA and respiratory chain function result in apoptosis in vivo . Apoptosis was studied in embryos with homozygous disruption of the mitochondrial transcription factor A gene ( Tfam ) and tissue-specific Tfam knockout animals with severe respiratory chain deficiency in the heart. We found massive apoptosis in Tfam knockout embryos at embryonic day (E) 9.5 and increased apoptosis in the heart of the tissue-specific Tfam knockouts. Furthermore, mtDNA-less (ρ 0 ) cell lines were susceptible to apoptosis induced by different stimuli in vitro . The data presented here provide in vivo evidence that respiratory chain deficiency predisposes cells to apoptosis, contrary to previous assumptions based on in vitro studies of cultured cells. These results suggest that increased apoptosis is a pathogenic event in human mtDNA mutation disorders. The finding that respiratory chain deficiency is associated with increased in vivo apoptosis may have important therapeutic implications for human disease. Respiratory chain deficiency and cell loss and/or apoptosis have been associated with neurodegeneration, heart failure, diabetes mellitus, and aging. Furthermore, chemotherapy and radiation treatment of cancer are intended to induce apoptosis in tumor cells. It would therefore be of interest to determine whether manipulation of respiratory chain function can be used to inhibit or enhance apoptosis in these conditions.
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Mouse models with decreased mtDNA expression have increased cell death with little or no increase of oxidative stress.
“We have studied a variety of mouse models with decreased mtDNA expression (10, 12–18) and such mice have increased cell death with little or no increase of oxidative stress (18, 30).”
From Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons (2007) · cites this paper as [18]
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- Authors
- Wang, J., Silva, J. P., Gustafsson, C. M., Rustin, P., & Larsson, N.-G.
- Affiliations
- Karolinska University Hospital (SE)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-03-20
- Volume
- 98
- Issue
- 7
- Pages
- 4038-4043
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC31175
- OpenAlex
- W2057380297
- Cited by
- 245
- References
- 31
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 4 · 2022: 7 · 2021: 4 · 2020: 10 · 2019: 7 · 2018: 7 · 2017: 6 · 2016: 7 · 2015: 11 · 2014: 7 · 2013: 9 · 2012: 11
- FWCI
- 5.94
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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 › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- apoptosis, mitochondrial DNA, TFAM, respiratory chain deficiency, mitochondrial DNA deletions, rho0 cells, heart, embryonic lethality, cell death
- MeSH terms
- Animals, DNA-Binding Proteins, DNA, Mitochondrial, Glutathione Peroxidase, High Mobility Group Proteins, Humans, Myocardium, Nuclear Proteins, Oxidation-Reduction, Phosphorylation, Superoxide Dismutase, Transcription Factors, Tumor Cells, Cultured, Signal Transduction, Trans-Activators, Up-Regulation, Gene Expression, Apoptosis, Reactive Oxygen Species, Mice, Knockout, Mitochondrial Proteins, Xenopus Proteins, Mice
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