Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression.
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.
Pubmed ID: 9916807 RIS Download
Animals | Cardiomyopathy, Dilated | Creatine Kinase | DNA, Mitochondrial | DNA-Binding Proteins | Disease Models, Animal | Electron Transport Complex IV | Female | Gene Expression Regulation | Heart | Heart Block | High Mobility Group Proteins | Humans | Integrases | Male | Mice | Mice, Transgenic | Mitochondrial Proteins | Muscle, Skeletal | Myocardium | NAD(P)H Dehydrogenase (Quinone) | Nuclear Proteins | Trans-Activators | Transcription Factors | Viral Proteins | Xenopus Proteins