Mitochondrial DNA alterations in aging postmitotic cells have been examined extensively. Aging is associated with both mtDNA deletions and mtDNA point mutations. The highest levels of age-associated multiple mtDNA deletions are observed in postmitotic tissues with high energy demands such as heart, skeletal muscle, and brain [70,71]. The search for mtDNA point mutations in tissue homogenates of aging individuals gave rather disappointing results with very low levels of specific mutations (0.04%-2.2%) .When single cells were analyzed, mtDNA point mutations were observed to accumulate to high levels in an age-dependent and tissue-specific manner [73,74]. Several of them accumulated up to 50% in single skin fibroblasts of individuals over 65 years of age . Still, there was an open question if mtDNA mutations could be a driving force of aging or are just secondary to the aging process. Recently, we have developed a mouse model that provided the first experimental evidence for a causative link between mtDNA mutations and aging phenotypes in mammals .We created homozygous knock-in mice that expressed a proofreading deficient form of the nuclear-encoded mito-
chondrial DNA polymerase (Polg). The introduced mutation was designed to create a defect in the proofreading function of Polg, leading to the progressive, random accumulation of mtDNA mutations during the course of mitochondrial biogenesis. As the proofreading in the knockin mice is efficiently prevented, these mice develop an mtDNA mutator phenotype (mtDNA mutator mice) with a three to fivefold increase in the levels of point mutations, as well as increased amounts of deleted mtDNA molecules . In contrast to the mitochondrial theory of aging, we have shown that the levels of somatic mtDNA mutations accumulate at a higher rate during the time of development from oocytes to early embryonic life of mtDNA mutator mice, than during the rest of their life when mutations accumulate in rather linear fashion . The mtDNA mutator mice display a completely normal phenotype at birth and in early adolescence but subsequently acquire many features of premature aging. The increase in somatic mtDNA mutations is associated with reduced lifespan and premature onset of aging-related phenotypes such as weight loss, reduced subcutaneous fat, alopecia, kyphosis, osteoporosis, anaemia, reduced fertility, heart diseases, sarcopenia, progressive hearing loss and decreased spontaneous activity .
Furthermore, the amount of ROS produced by embryonic fibroblasts from mtDNA mutator mice was normal, despite severe respiratory-chain dysfunction. Antioxidant defences were unaltered in adult tissues of mtDNA mutator mice. Moreover, no differences could be detected in the amount of oxidative damage to proteins and DNA and aconitase enzyme activity, a common marker for oxidative stress, was normal in mtDNA mutator mice. Our results thus challenge the direct role of ROS in the aging process, as there was no link between oxidative stress and the premature aging phe-notypes in mtDNA mutator mice .
Our results clearly show that the premature aging phenotypes in mtDNA mutator mice are not generated by a vicious cycle of massively increased oxidative stress accompanied by exponential accumulation of mtDNA mutations. We propose instead that respiratory-chain dysfunction per se is the primary inducer of premature aging in mtDNA mutator mice.
Was this article helpful?