Abstract
MtDNA mutator mice exhibit marked features of premature aging. We find that these mice treated from age of ≈100 days with the mitochondria-targeted antioxidant SkQ1 showed a delayed appearance of traits of aging such as kyphosis, alopecia, lowering of body temperature, body weight loss, as well as ameliorated heart, kidney and liver pathologies. These effects of SkQ1 are suggested to be related to an alleviation of the effects of an enhanced reactive oxygen species (ROS) level in mtDNA mutator mice: the increased mitochondrial ROS released due to mitochondrial mutations probably interact with polyunsaturated fatty acids in cardiolipin, releasing malondialdehyde and 4-hydroxynonenal that form protein adducts and thus diminishes mitochondrial functions. SkQ1 counteracts this as it scavenges mitochondrial ROS. As the results, the normal mitochondrial ultrastructure is preserved in liver and heart; the phosphorylation capacity of skeletal muscle mitochondria as well as the thermogenic capacity of brown adipose tissue is also improved. The SkQ1-treated mice live significantly longer (335 versus 290 days). These data may be relevant in relation to treatment of mitochondrial diseases particularly and the process of aging in general.
Highlights
As a cause for the decreasing health status that accompanies aging, mitochondrial deterioration has been repeatedly suggested [1,2,3,4]
It has been discussed that an accumulation of errors in mitochondrial DNA replication would lead to mitochondrial dysfunction, including increased production of reactive oxygen species (ROS) that may both further deteriorate the mitochondria and affect the function of the rest of the cell [5,6,7,8,9]
We have demonstrated that treatment of mitochondrial DNA (mtDNA) mutator mice with the mitochondrial targeted antioxidant SkQ1 ameliorates most of the syndromes associated with the mitochondrial polymerase γ DNA proof-reading www.aging-us.com malfunction in these mice
Summary
As a cause for the decreasing health status that accompanies aging, mitochondrial deterioration has been repeatedly suggested [1,2,3,4]. The significance of ROS for the aging process has been doubted [10, 11], based on observations in the mtDNA mutator mice [12,13,14]. These mice accumulate errors in their mtDNA and demonstrate subsequent alterations in their respiratory chain composition [15]. There has been no convincing evidence that oxidative damage causes these problems; rather an absence of oxidative damage has been reported [13, 16,17,18,19], but see [20]
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