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Human Molecular Genetics Advance Access published online on February 9, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi082
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© The Author 2005. Published by Oxford University Press. All rights reserved

Article

Double-strand breaks of mouse muscle mtDNA promote large-deletions similar to multiple mtDNA deletions in humans

Sarika Srivastava 1 and Carlos T. Moraes Ph.D.2*

1 Departments of Cell Biology & Anatomy, University of Miami School of Medicine, Miami, FL
2 Departments of Cell Biology & Anatomy, University of Miami School of Medicine, Miami, FL; Departments of Neurology, University of Miami School of Medicine, 1095 NW 14th Terrace, Miami, FL, 33136

* To whom correspondence should be addressed.
Carlos T. Moraes, E-mail: cmoraes{at}med.miami.edu


  Abstract

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 where 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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