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Freyer 2010 Nucleic Acids Res

From Bioblast
Publications in the MiPMap
Freyer C, Park CB, Ekstrand MI, Shi Y, Khvorostova J, Wibom R, Falkenberg M, Gustafsson CM, Larsson NG (2010) Maintenance of respiratory chain function in mouse hearts with severely impaired mtDNA transcription. Nucleic Acids Res 38:6577–88.

Β» PMID: 20566479 Open Access

Freyer C, Park CB, Ekstrand MI, Shi Y, Khvorostova J, Wibom R, Falkenberg M, Gustafsson CM, Larsson NG (2010) Nucleic Acids Res

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. β€’ Keywords: luminometry

β€’ O2k-Network Lab: DE Cologne Larsson NG


Labels: MiParea: Respiration, mtDNA;mt-genetics  Pathology: Cardiovascular 

Organism: Mouse  Tissue;cell: Heart  Preparation: Isolated mitochondria  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase 


Pathway: N, S, CIV