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OBJECTIVE To determine whether low frequency mitochondrial DNA (mtDNA) mutations are pathogenic. METHODS We studied mice that express a proofreading-deficient mitochondrial DNA polymerase in the heart and develop cardiac mtDNA mutations. RESULTS At 4 weeks of age, when point mutation levels had risen to on average two per mitochondrial genome, these(More)
Increased frequencies of mitochondrial DNA (mtDNA) mutations characterize the aging heart and are also found in idiopathic dilated cardiomyopathy and end-stage heart failure. The pathogenic potential of such mutations is unclear. Transgenic mice showing accelerated accumulation of mtDNA mutations and dilated cardiomyopathy due to expression of an(More)
BACKGROUND Elevated mitochondrial DNA (mtDNA) mutations are associated with aging and age-related diseases, but their pathogenic potential is unclear. METHODS We performed expression profiling using an Incyte cDNA array of a mouse model of elevated mtDNA mutations wherein random mutations accumulate specifically in the heart. At frequencies of about 1(More)
Studies of transgenic mice with accelerated accumulation of mtDNA mutations specifically in the heart lead us to propose that apoptotic signaling and cell death is central to the pathogenesis of mtDNA mutations in aging. It is the cellular response to that apoptotic signaling and the organ?s compensatory response to a loss of cells that specify the(More)
The age-related accumulation of mitochondrial DNA mutations has the potential to impair organ function and contribute to disease. In support of this hypothesis, accelerated mitochondrial mutagenesis is pathogenic in the mouse heart, and there is an increase in myocyte apoptosis. The current study sought to identify functional alterations in cell death(More)
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