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  Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression

Wang, J., Silva, J. P., Gustafsson, C. M., Rustin, P., & Larsson, N. (2001). Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression. Proc Natl Acad Sci U S A, 98(7), 4038-43. doi:10.1073/pnas.061038798.

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Wang, J., Author
Silva, J. P., Author
Gustafsson, C. M., Author
Rustin, P., Author
Larsson, N.G.1, Author           
Affiliations:
1Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society, ou_1942286              

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Free keywords: Animals Apoptosis/*genetics/physiology DNA, Mitochondrial/*genetics *DNA-Binding Proteins *Gene Expression Glutathione Peroxidase/metabolism *High Mobility Group Proteins Humans Mice Mice, Knockout *Mitochondrial Proteins Myocardium/cytology/enzymology/*metabolism *Nuclear Proteins Oxidation-Reduction Phosphorylation Reactive Oxygen Species/metabolism Signal Transduction/physiology Superoxide Dismutase/metabolism *Trans-Activators Transcription Factors/deficiency/genetics/*metabolism Tumor Cells, Cultured Up-Regulation *Xenopus Proteins
 Abstract: 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 (rho(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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 Dates: 2001-03-272001-03-22
 Publication Status: Issued
 Pages: -
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 Table of Contents: -
 Rev. Type: -
 Identifiers: Other: 11259653
DOI: 10.1073/pnas.061038798
ISSN: 0027-8424 (Print)0027-8424
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Title: Proc Natl Acad Sci U S A
  Alternative Title : Proceedings of the National Academy of Sciences of the United States of America
Source Genre: Journal
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Pages: - Volume / Issue: 98 (7) Sequence Number: - Start / End Page: 4038 - 43 Identifier: -