Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression.
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.
Department of Molecular Medicine, Karolinska Institutet, L8: 02, Karolinska Hospital, S-171 76 Stockholm, Sweden.
J
J
Wang
J P
JP
Silva
C M
CM
Gustafsson
P
P
Rustin
N G
NG
Larsson
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D004272:DNA, Mitochondrial / Q000235:genetics*; D004268:DNA-Binding Proteins; D015870:Gene Expression; D005979:Glutathione Peroxidase / Q000378:metabolism; D006609:High Mobility Group Proteins; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D009687:Nuclear Proteins; D010084:Oxidation-Reduction; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D029867:Xenopus Proteins
D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; C499631:TFAM protein, human; C081930:Tfam protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C097078:XL-MTTFA protein, Xenopus; D029867:Xenopus Proteins; C422562:mitochondrial transcription factor A; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase