title: Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice.
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.
authors.affiliation: Department of Neurology and Programme of Neurosciences, University of Helsinki, 00290, Helsinki, Finland.
authors.forename: Henna
authors.initials: H
authors.lastname: Tyynismaa
authors.forename: Katja Peltola
authors.initials: KP
authors.lastname: Mjosund
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Wanrooij
authors.forename: Ilse
authors.initials: I
authors.lastname: Lappalainen
authors.forename: Emil
authors.initials: E
authors.lastname: Ylikallio
authors.forename: Anu
authors.initials: A
authors.lastname: Jalanko
authors.forename: Johannes N
authors.initials: JN
authors.lastname: Spelbrink
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
mesh_terms: D000375:Aging; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D017240:Mitochondrial Myopathies / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D004265:DNA Helicases