title: Maintenance of respiratory chain function in mouse hearts with severely impaired mtDNA transcription.
abstract: The basal mitochondrial transcription machinery is essential for biogenesis of the respiratory chain and consists of mitochondrial RNA polymerase, mitochondrial transcription factor A (TFAM) and mitochondrial transcription factor B2. This triad of proteins is sufficient and necessary for mtDNA transcription initiation. Abolished mtDNA transcription caused by tissue-specific knockout of TFAM in the mouse heart leads to early onset of a severe mitochondrial cardiomyopathy with lethality within the first post-natal weeks. Here, we describe a mouse model expressing human TFAM instead of the endogenous mouse TFAM in heart. These rescue mice have severe reduction in mtDNA transcription initiation, but, surprisingly, are healthy at the age of 52 weeks with near-normal steady-state levels of transcripts. In addition, we demonstrate that heavy-strand mtDNA transcription normally terminates at the termination-associated sequence in the control region. This termination is abolished in rescue animals resulting in heavy (H)-strand transcription of the entire control region. In conclusion, we demonstrate here the existence of an unexpected mtDNA transcript stabilization mechanism that almost completely compensates for the severely reduced transcription initiation in rescue hearts. Future elucidation of the underlying molecular mechanism may provide a novel pathway to treat mitochondrial dysfunction in human pathology.
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Retzius väg 8, 171 65 Solna, Sweden.
authors.forename: Christoph
authors.initials: C
authors.lastname: Freyer
authors.forename: Chan Bae
authors.initials: CB
authors.lastname: Park
authors.forename: Mats I
authors.initials: MI
authors.lastname: Ekstrand
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Shi
authors.forename: Julia
authors.initials: J
authors.lastname: Khvorostova
authors.forename: Rolf
authors.initials: R
authors.lastname: Wibom
authors.forename: Maria
authors.initials: M
authors.lastname: Falkenberg
authors.forename: Claes M
authors.initials: CM
authors.lastname: Gustafsson
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000096:biosynthesis* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D024101:Mitochondrial Proteins; C499631:TFAM protein, human; C081930:Tfam protein, mouse; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV