Manipulation of mitochondrial DNA gene expression in the mouse.
Mitochondrial dysfunction due to impaired respiratory chain function is increasingly recognized as an important cause of human disease. Mitochondrial disorders are relatively common and have an estimated incidence of 1:10,000 live births. There are more than 100 different point mutations and numerous large rearrangements of mitochondrial DNA (mtDNA; mainly single deletions) that cause human disease. We aimed at obtaining an animal model to study physiological aspects of mtDNA mutation disorders. There are as yet unsolved technical problems associated with transfection of mammalian mitochondria. We therefore choose to manipulate mtDNA expression by targeting of the nuclear gene encoding Tfam. We utilised the cre-loxP recombination system to disrupt Tfam since this system allows manipulation of respiratory chain function in selected mouse tissues. We have found increased cell death or apoptosis induction in both germ line and tissue-specific Tfam knockouts. Our results further suggest that increased production of reactive oxygen species (ROS) is not a prominent feature in cells with impaired mtDNA expression.
Silva
José P
JP
Department of Medical Nutrition, Karolinska Institutet, Novum, Huddinge Hospital, S-141 86 Huddinge, Sweden.
Larsson
Nils-Göran
NG
D000818:Animals; D017209:Apoptosis; D004272:DNA, Mitochondrial / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005656:Fungal Proteins; D005786:Gene Expression Regulation; D018390:Gene Targeting; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006609:High Mobility Group Proteins; D007515:Islets of Langerhans / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D028361:Mitochondrial Diseases / Q000235:genetics / Q000503:physiopathology; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins / Q000235:genetics*; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D029867:Xenopus Proteins
D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D006609:High Mobility Group Proteins; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C081930:Tfam protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C097078:XL-MTTFA protein, Xenopus; D029867:Xenopus Proteins; C422562:mitochondrial transcription factor A; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases