title: Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice.
abstract: The regulation of mitochondrial DNA (mtDNA) expression is crucial for mitochondrial biogenesis during development and differentiation. We have disrupted the mouse gene for mitochondrial transcription factor A (Tfam; formerly known as m-mtTFA) by gene targetting of loxP-sites followed by cre-mediated excision in vivo. Heterozygous knockout mice exhibit reduced mtDNA copy number and respiratory chain deficiency in heart. Homozygous knockout embryos exhibit a severe mtDNA depletion with abolished oxidative phosphorylation. Mutant embryos proceed through implantation and gastrulation, but die prior to embryonic day (E)10.5. Thus, Tfam is the first mammalian protein demonstrated to regulate mtDNA copy number in vivo and is essential for mitochondrial biogenesis and embryonic development.
authors.affiliation: Department of Molecular Medicine, Center for Molecular Medicine L8:02, Stockholm, Sweden. nils-goran.larsson@cmm.ki.se
authors.forename: N G
authors.initials: NG
authors.lastname: Larsson
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Wilhelmsson
authors.forename: A
authors.initials: A
authors.lastname: Oldfors
authors.forename: P
authors.initials: P
authors.lastname: Rustin
authors.forename: M
authors.initials: M
authors.lastname: Lewandoski
authors.forename: G S
authors.initials: GS
authors.lastname: Barsh
authors.forename: D A
authors.initials: DA
authors.lastname: Clayton
mesh_terms: D000818:Animals; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D010064:Embryo Implantation; D005260:Female; D005313:Fetal Death / Q000235:genetics*; D005317:Fetal Growth Retardation / Q000235:genetics; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology; D006579:Heterozygote; D006609:High Mobility Group Proteins; D019426:Integrases / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins; D009154:Mutation; D009687:Nuclear Proteins; D010766:Phosphorylation; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014764:Viral Proteins
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; C081930:Tfam protein, mouse; D014157:Transcription Factors; D014764:Viral Proteins; C422562:mitochondrial transcription factor A; C045073:Cre recombinase; D019426:Integrases