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 phosphorytation(1-4) and may als o have a role in ageing and acquired diseases of old age(5). We report here that hallmarks of mtDNA mutation disorders can be reproduced in the mouse using a conditional mutation strategy tl manipulate the expression of the g ene encoding mitochondrial transcription factor A (Tfam, previously named m tTFA), which regulates transcription and replication of mtDNA (refs 6,7). U sing a loxP-flanked Tfam allele (Tfam(loxP); ref. 8) in combination with a cre-recombinase transgene under control of the muscle creatinine kinase pro moter(9,10), we have disrupted Tfam in heart and muscle. Mutant animals dev elop a mosaic cardiac-specific progressive respiratory chain deficiency, di lated cardiomyopathy, atrioventricular heart conduction blocks and die at 2 -4 weeks of age. This animal model reproduces biochemical, morphological an d physiological features of the dilated cardiomyopathy of Kearns-Sayre synd rome(1-4). Furthermore, our findings provide genetic evidence that the resp iratory chain is critical for normal heart function.