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

doi:10.1073/pnas.0505551102

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

^*Department of Neurology and Programme of Neurosciences, University of Helsinki, 00290, Helsinki, Finland; ^†Institute of Medical Technology and Tampere University Hospital, 33014, Tampere, Finland; ^‡Department of Molecular Medicine, National Public Health Institute, 00290, Helsinki, Finland; and ^§Department of Pathology, Helsinki University Central Hospital and Haartman Institute, University of Helsinki, 00290, Helsinki, Finland

Edited by Giuseppe Attardi, California Institute of Technology, Pasadena, CA, and approved October 12, 2005 (received for review July 1, 2005)

Abstract

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.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: anu.wartiovaara{at}helsinki.fi.
Author contributions: H.T., K.P.M., A.J., J.N.S., and A.S. designed research; H.T., K.P.M., S.W., I.L., E.Y., and A.P. performed research; H.T., K.P.M., S.W., I.L., J.N.S., A.P., and A.S. analyzed data; and H.T., A.J., J.N.S., and A.S. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: COX, cytochrome c oxidase; PEO, progressive external ophthalmoplegia; POLG, polymerase γ; SDH, succinate dehydrogenase.