Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice

Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17687-92. doi: 10.1073/pnas.0505551102. Epub 2005 Nov 21.


Defects of mitochondrial DNA (mtDNA) maintenance have recently been associated with inherited neurodegenerative and muscle diseases and the aging process. Twinkle is a nuclear-encoded mtDNA helicase, dominant mutations of which cause adult-onset progressive external ophthalmoplegia (PEO) with multiple mtDNA deletions. We have generated transgenic mice expressing mouse Twinkle with PEO patient mutations. Multiple mtDNA deletions accumulate in the tissues of these mice, resulting in progressive respiratory dysfunction and chronic late-onset mitochondrial disease starting at 1 year of age. The muscles of the mice faithfully replicate all of the key histological, genetic, and biochemical features of PEO patients. Furthermore, the mice have progressive deficiency of cytochrome c oxidase in distinct neuronal populations. These "deletor" mice do not, however, show premature aging, indicating that subtle accumulation of mtDNA deletions and progressive respiratory chain dysfunction are not sufficient to accelerate aging. This model is a valuable tool for therapy development and testing for adult-onset mitochondrial disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism*
  • DNA, Mitochondrial / genetics*
  • Mice
  • Mice, Transgenic
  • Mitochondrial Myopathies / enzymology*
  • Mitochondrial Myopathies / genetics*
  • Mitochondrial Myopathies / pathology
  • Muscles / metabolism
  • Muscles / pathology
  • Mutation / genetics
  • Neurons / metabolism
  • Neurons / pathology
  • Phenotype
  • Sequence Deletion / genetics*


  • DNA, Mitochondrial
  • DNA Helicases