Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cardiomyopathy, Dilated / genetics*
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Cardiomyopathy, Dilated / physiopathology
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Creatine Kinase / genetics
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DNA, Mitochondrial*
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DNA-Binding Proteins*
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Disease Models, Animal
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Electron Transport Complex IV / metabolism
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Female
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Gene Expression Regulation*
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Heart / physiopathology*
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Heart Block / genetics*
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Heart Block / physiopathology
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High Mobility Group Proteins*
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Humans
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Integrases / genetics
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Male
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Mice
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Mice, Transgenic
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Mitochondrial Proteins*
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Muscle, Skeletal
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Myocardium
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NAD(P)H Dehydrogenase (Quinone) / metabolism
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Nuclear Proteins*
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Trans-Activators*
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Transcription Factors / biosynthesis*
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Transcription Factors / genetics
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Viral Proteins*
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Xenopus Proteins*
Substances
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DNA, Mitochondrial
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DNA-Binding Proteins
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High Mobility Group Proteins
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Mitochondrial Proteins
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Nuclear Proteins
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TFAM protein, human
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Tfam protein, mouse
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Trans-Activators
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Transcription Factors
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Viral Proteins
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XL-MTTFA protein, Xenopus
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Xenopus Proteins
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mitochondrial transcription factor A
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NAD(P)H Dehydrogenase (Quinone)
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Electron Transport Complex IV
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Creatine Kinase
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Cre recombinase
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Integrases