Multiplicity of beneficial effects of mitochondrially targeted
plastoquinone on ageing phenotype in premature ageing mice
with increased mitochondrial DNA mutations

B. Cannon1, I. Shabalina2,
M. Vyssokikh2, R.Csikasz1,
A. Hallden-Waldermarson1,
Z. Rozhdestvenskaya1, A. Pustovidko2,
A. Trifunovic3, V. Skulachev2, J. Nedergaard1
1The Wenner-Gren Institute, the Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm
2Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 11992
3Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne

MtDNA mutator mice expressing mtDNA polymerase with reduced proof-reading activity exhibit several features of premature ageing, such as reduced lifespan, weight loss, reduced fat content, manifestation of alopecia, kyphosis and osteoporosis, anemia and reduced fertility (Trifunovic et al., 2004). A new type of mitochondrially targeted compounds (SkQs) - consisting of plastoquinone (an antioxidant moiety), triphenylphosphonium (a penetrating cation), and a decane linker - have been suggested as potential tools for treatment of senescence and age-related diseases (Skulachev et al., 2009). We have treated mtDNA mutator and wild type mice with SkQ1 added to the drinking water (0.7 - 1.0 μmol/day x kg body weight).Treated mice exhibit delayed appearance of traits of ageing phenotype such as lordokyphosis, baldness, alopecia, lowering of body temperature, torpor, body weight loss and reduced fat content. SkQ1 treatment also increased the number of estruses and the regularity of the estrous cycle in mtDNA mutator females. Notably mtDNA mutator mice treated with SkQ1 lived significantly longer than untreated littermates. However, the gross changes observed at necropsy and the main histopathological findings in tissues were identical in treated or untreated mtDNA mutator mice at death. At the end of life, the mtDNA mutator mice exhibited severe anaemia and significant leucopenia, which was not improved by SkQ1 treatment. Thus, we here demonstrate a complex of beneficial changes in ageing phenotypes in mtDNA mutator mice chronically treated with mitochondrially targeted plastoquinone that may be therefore be suggested as a promising pharmacological treatment for premature ageing and mitochondrial diseases.

Homo Sapiens Liberatus Workshop, Moscow State University, May 2010