title: Amelioration of premature aging in mtDNA mutator mouse by exercise: the interplay of oxidative stress, PGC-1α, p53, and DNA damage. A hypothesis.
abstract: The mtDNA mutator mouse lacks the proofreading capacity of the sole mtDNA polymerase, leading to accumulation of somatic mtDNA mutations, and a profound premature aging phenotype including elevated oxidative stress and apoptosis, and reduced mitochondrial function. We have previously reported that endurance exercise alleviates the aging phenotype in the mutator mice, reduces oxidative stress, and enhances mitochondrial biogenesis. Here we summarize our findings, with the emphasis on the central role of p53 in these adaptations. We demonstrate that mtDNA in sedentary and exercised PolG mice carry similar amounts of mutations in muscle, but in addition to that sedentary mice have more non-mutational damage, which is mitigated by exercise. It follows therefore that the profound alleviation of the mtDNA mutator phenotype in muscle by exercise may not require a reduction in mtDNA mutational load, but rather a decrease of mtDNA damage and/or oxidative stress. We further hypothesize that the observed 'alleviation without a reduction of mutational load' implies that the oxidative stress in PolG muscle is maintained, at least in part, by the 'malicious cycle', a hypothetical positive feedback potentially driven by the 'transcriptional mutagenesis', that is the conversion of chemically modified nucleotides into mutant RNA bases by the mitochondrial RNA polymerase.
authors: Department of Pediatrics, McMaster University, Hamilton, ON L8N3Z5, Canada.
authors: Adeel
authors: A
authors: Safdar
authors: Department of Biology, Northeastern University, Boston, MA 02215, USA.
authors: Sofia
authors: S
authors: Annis
authors: Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors: Yevgenya
authors: Y
authors: Kraytsberg
authors: Department of Biology, Northeastern University, Boston, MA 02215, USA.
authors: Chloe
authors: C
authors: Laverack
authors: Department of Pediatrics, McMaster University, Hamilton, ON L8N3Z5, Canada.
authors: Ayesha
authors: A
authors: Saleem
authors: University of Lausanne, Switzerland.
authors: Konstantin
authors: K
authors: Popadin
authors: Department of Biology, Northeastern University, Boston, MA 02215, USA.
authors: Dori C
authors: DC
authors: Woods
authors: Department of Biology, Northeastern University, Boston, MA 02215, USA.
authors: Jonathan L
authors: JL
authors: Tilly
authors: Department of Biology, Northeastern University, Boston, MA 02215, USA. Electronic address: kkhrapko@gmail.com.
authors: Konstantin
authors: K
authors: Khrapko
mesh_terms: D019588:Aging, Premature / Q000235:genetics* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics*; D010805:Physical Conditioning, Animal; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D016159:Tumor Suppressor Protein p53; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse