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.

Voluntary wheel running has no impact on brain and liver mitochondrial DNA copy number or mutation measures in the PolG mouse model of aging

“…We expected exercise would ameliorate the mutant mitochondrial phenotypes in the brain as it has been reported to do so in other tissues such as liver and muscle (4,11). However, our results for the brain and liver are consistent with other PolG studies which have found no effect of forced treadmill exercise on mtDNA mutation load in muscle or oocytes (9,12). Studies which reported reduced mtDNA mutations in muscle with exercise were either unable to be duplicated or only a small portion of the mitochondrial genome was explored (4,12).…”

“…However, our results for the brain and liver are consistent with other PolG studies which have found no effect of forced treadmill exercise on mtDNA mutation load in muscle or oocytes (9,12). Studies which reported reduced mtDNA mutations in muscle with exercise were either unable to be duplicated or only a small portion of the mitochondrial genome was explored (4,12). Differences in tissue, regions of sequencing, exercise method and age at examination may explain these seemingly contrasting results.…”

“…Since the sole cause of premature aging in the PolG mouse model is an increase in mtDNA mutations, a decrease in mtDNA mutations would indicate an overall improvement and serves as a particularly relevant measure for mitochondrial health. One study reported a decreased mtDNA mutation load with short-term forced treadmill exercise in skeletal muscle; although later studies were unable to duplicate this finding (4,12). A recent study using voluntary wheel running also found a decrease in mtDNA mutation load in skeletal muscle in the PolG mouse model, but they were unable to duplicate findings of an increased mtDNA copy number with exercise (11).…”

Training Performed Above Lactate Threshold Decreases p53 and Shelterin Expression in Mice

“…Lifelong, this failure elicits telomere shortening as a result of cell divisions, leading to senescence [42]. Thus, telomere length, as a marker of cell aging, has been linked to a greater risk of devel-oping age-related diseases such as type-2 diabetes [49], cardiovascular dysfunctions [16], obesity [30] and sarcopenia [9,37].…”

Autosomal Recessive Cerebellar Ataxias: Paving the Way toward Targeted Molecular Therapies

“…Mutations in POLG, the nuclear-encoded catalytic subunit of the mtDNA polymerase (responsible for mtDNA replication and repair) ( Figure 5), can present as ARCA (Coutelier et al, 2018). Mutations in POLG thus cause mtDNA depletion that results in premature mitochondrial dysfunction with increased oxidative stress and nuclear DNA damage, leading to translocation of the tumor suppressor protein p53 into the nucleus, activation of apoptosis, and repression of PGC-1a, the master regulator of mitochondrial biogenesis and cellular antioxidant response (Safdar et al, 2016). As for FA, it is probable that, secondary to these primary dysfunctions, multiple pathways with differential cell vulnerability are involved in the complex pathogenesis, thus leading to heterogeneous phenotypic presentations (Synofzik et al, 2012).…”