Mitochondrial effects of prolonged treatment
of mtDNA mutator mice with SkQ

J. Nedergaard1, I. Shabalina1,
M. Vyssokikh2, N. Gibanova1, A. Trifunovic3,
V. Skulachev1, B. Cannon1
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

We have demonstrated that chronic treatment of mtDNA mutator mice with drinking water containing SkQ1 increases their lifespan and causes delayed and less manifest appearance of ageing traits. To explore the molecular mechanism behind these improvements, we have here studied mitochondrial effects of SkQ1.The oxygen consumption rate of skeletal muscle mitochondria isolated from mtDNA mutator mice was analysed. ADP-stimulated respiration was increased in SkQ1-treated mtDNA mutator mice. Consistently with this improved function of skeletal muscle mitochondria isolated from treated animals, a restored hydrogen peroxide production rate (stimulated by a complex II substrate (succinate) or by mixed complex I and complex II substrates (pyruvate + malate + succinate)) was observed after treatment with SkQ1. Interestingly, SkQ1 treatment increased the concentration of the mitochondrial marker VDAC in skeletal muscle homogenates. Thus, SkQ1 treatment improved the function and increased the number of mitochondria in skeletal muscle. Similarly, an increased VDAC concentration per mg of brown adipose tissue (BAT) indicated an increased number of mitochondria in BAT from SkQ1-treated mice. There was a significant positive effect of SkQ treatment on interscapular BAT mass and on total protein content in BAT. Estimation of the total content of the thermogenic protein UCP1 and of VDAC per mouse implied a significant improvement in BAT thermogenic potential. The positive effects of in vivo treatment with SkQ1 could also be attributed to its antioxidant properties, revealed as a delayed spontaneous formation of MDA (in all 3 tissues examined: liver, kidney, brain). A lowered content of endogenously formed HNE-adducts was observed in the kidney of treated animals (in liver and brain, the content of HNE-adducts was not different between treated and untreated mice). A decreased cardiolipin content, with markedly altered fatty acid composition, in mitochondria from mtDNA mutator mice was normalised after treatment with SkQ1. These features may at least in part explain the beneficial effects of SkQ1 in-vivo. Thus, mitochondrially targeted plastoquinone may be suggested as a pharmacological treatment for premature ageing and mitochondrial diseases.

Homo Sapiens Liberatus Workshop, Moscow State University, May 2010