Altered levels of mitochondrial morphology proteins in skeletal muscle of mitochondrial DNA mutator mice

Abstract

The mitochondrial theory of aging proposes that mitochondrial DNA mutations (mtDNA) accumulate with age and this leads to mitochondrial dysfunction and/or damage that contribute to the aging process. mtDNA mutator mice (referred to as PolG) contain a deficient version of the proofreading mtDNA polymerase gamma and consequently incur high mutation rates to mtDNA that lead to mitochondrial dysfunction. As a result of these spontaneous mutations, PolG mice have an accelerated aging phenotype, allowing their use as a model of aging. The present study investigated the effect of increased mtDNA mutations on regulators of skeletal muscle mitochondrial biogenesis and morphology in young (3–6 mo) and old (8–15 mo) PolG and wild‐type (WT) mice. In old animals, mtDNA content was significantly reduced in the PolG compared to WT. Moreover, there was an age‐dependent decrease in PGC‐1α levels exhibited in both PolG and WT animals. However, young mice with the PolG mutation contained a greater level of PGC‐1α when compared to young WT mice. Age‐dependent changes were also observed in morphology proteins, including higher levels of the fusion protein Mfn2 in both WT and PolG mice, and reduced levels of the fission protein Fis1, only in WT and not in PolG mice. These data suggest that alterations in the ratio of fusion to fission proteins may contribute to the aging phenotype that is exhibited in mtDNA mutator mice.