ausblenden:
Schlagwörter:
Animals
Cardiomyopathy, Dilated/*genetics/physiopathology
Creatine Kinase/genetics
*DNA, Mitochondrial
*DNA-Binding Proteins
Disease Models, Animal
Electron Transport Complex IV/metabolism
Female
*Gene Expression Regulation
Heart/*physiopathology
Heart Block/*genetics/physiopathology
*High Mobility Group Proteins
Humans
Integrases/genetics
Male
Mice
Mice, Transgenic
*Mitochondrial Proteins
Muscle, Skeletal
Myocardium
NAD(P)H Dehydrogenase (Quinone)/metabolism
*Nuclear Proteins
*Trans-Activators
Transcription Factors/*biosynthesis/genetics
*Viral Proteins
*Xenopus Proteins
Zusammenfassung:
Mutations of mitochondrial DNA (mtDNA) cause several well-recognized human genetic syndromes with deficient oxidative phosphorylation and may also have a role in ageing and acquired diseases of old age. We report here that hallmarks of mtDNA mutation disorders can be reproduced in the mouse using a conditional mutation strategy to manipulate the expression of the gene encoding mitochondrial transcription factor A (Tfam, previously named mtTFA), which regulates transcription and replication of mtDNA. Using a loxP-flanked Tfam allele (TfamloxP) in combination with a cre-recombinase transgene under control of the muscle creatinine kinase promoter, we have disrupted Tfam in heart and muscle. Mutant animals develop a mosaic cardiac-specific progressive respiratory chain deficiency, dilated cardiomyopathy, atrioventricular heart conduction blocks and die at 2-4 weeks of age. This animal model reproduces biochemical, morphological and physiological features of the dilated cardiomyopathy of Kearns-Sayre syndrome. Furthermore, our findings provide genetic evidence that the respiratory chain is critical for normal heart function.
