Human Molecular Genetics Advance Access originally published online on February 9, 2005
Human Molecular Genetics 2005 14(7):893-902; doi:10.1093/hmg/ddi082
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Double-strand breaks of mouse muscle mtDNA promote large deletions similar to multiple mtDNA deletions in humans
1Department of Cell Biology and Anatomy and 2Department of Neurology, University of Miami School of Medicine, Miami, FL 33136, USA
* To whom correspondence should be addressed at: University of Miami School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA. Tel: +1 3052435858; Fax: +1 3052433914; Email: cmoraes{at}med.miami.edu
Received December 8, 2004; Accepted February 1, 2005
Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders and have been found to accumulate during normal aging. Despite the fact that hundreds of deletions have been characterized at the molecular level, their mechanisms of genesis are unknown. We tested the effect of double-strand breaks of muscle mtDNA by developing a mouse model in which a mitochondrially targeted restriction endonuclease (PstI) was expressed in skeletal muscle of mice. Because mouse mtDNA harbors two PstI sites, transgenic founders developed a mitochondrial myopathy associated with mtDNA depletion. The founders showed a chimeric pattern of transgene expression and their residual level of wild-type mtDNA in muscle was 
40% of controls. We were able to identify the formation of large mtDNA deletions in muscle of transgenic mice. A family of mtDNA deletions was identified, and most of these rearrangements involved one of the PstI sites and the 3' end of the D-loop region. The deletions had no or small direct repeats at the breakpoint region. These features are essentially identical to the ones observed in humans with multiple mtDNA deletions in muscle, suggesting that double-strand DNA breaks mediate the formation of large mtDNA deletions.
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