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Dilated Cardiomyopathy And Atrioventricular Conduction Blocks Induced By Heart-specific Inactivation Of Mitochondrial DNA Gene Expression

J. Wang, H. Wilhelmsson, C. Graff, H. Li, A. Oldfors, P. Rustin, J. Brüning, C. Kahn, D. Clayton, G. Barsh, P. Thorén, N. Larsson
Published 1999 · Biology, Medicine

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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 (Refs 6,7). Using a loxP-flanked Tfam allele (TfamloxP; ref. 8) in combination with a cre-recombinase transgene under control of the muscle creatinine kinase promoter9,10, 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.
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