Premature aging is associated with higher levels of 8-oxoguanine and increased DNA damage in the Polg mutator mouse.
Premature aging is associated with higher levels of 8-oxoguanine and increased DNA damage in the Polg mutator mouse.
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DOI：
10.1111/acel.13669
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发表时间：
2022-09
期刊：
影响因子：
7.8
通讯作者：
Huang, Taosheng
中科院分区：
文献类型：
--
作者：
Yu, Tenghui;Slone, Jesse;Liu, Wensheng;Barnes, Ryan;Opresko, Patricia L.;Wark, Landon;Mai, Sabine;Horvath, Steve;Huang, Taosheng
线粒体功能障碍在衰老过程中起着重要作用。然而，这种功能障碍导致衰老的机制尚未完全了解。线粒体基因组（或“mtDNA”）中突变的积累被认为是一个贡献者。支持这一假设的一个令人信服的证据来自Polg D257 A/D257 A突变小鼠（Polg mut/mut）。这些小鼠表达一种易于出错的线粒体DNA聚合酶，导致线粒体DNA突变的积累，加速衰老和过早死亡。在本文中，我们使用Polg mut/mut模型来研究在这些小鼠中观察到的与年龄相关的生物学效应是否是由DNA的氧化损伤引发的，这种氧化损伤损害了基因组的完整性。我们的研究结果表明，突变小鼠具有显著更高水平的8-氧代鸟嘌呤（8-oxoGua），这与核DNA（nDNA）链断裂和氧化性nDNA损伤增加，平均端粒长度缩短和mtDNA完整性降低相关。基于这些结果，我们提出了一个模型，其中与Polg mut/mut小鼠中mtDNA突变积累相关的活性氧（ROS）水平增加导致8-oxoGua水平升高，这反过来又导致DNA完整性受损，并通过增加DNA片段化和端粒缩短加速衰老。这些结果表明，线粒体在衰老中起着核心作用，并可能指导未来的研究开发潜在的治疗方法来缓解衰老过程。Polg mutator小鼠的mtDNA突变率增加先前已被证明与加速衰老表型相关，可能是由于氧化应激增加。这项研究提供了支持这种氧化应激模型的证据，表明Polg突变也与8-oxoGua水平增加以及端粒缩短和其他形式的DNA损伤有关。
Mitochondrial dysfunction plays an important role in the aging process. However, the mechanism by which this dysfunction causes aging is not fully understood. The accumulation of mutations in the mitochondrial genome (or “mtDNA”) has been proposed as a contributor. One compelling piece of evidence in support of this hypothesis comes from the Polg D257A/D257A mutator mouse (Polg mut/mut ). These mice express an error‐prone mitochondrial DNA polymerase that results in the accumulation of mtDNA mutations, accelerated aging, and premature death. In this paper, we have used the Polg mut/mut model to investigate whether the age‐related biological effects observed in these mice are triggered by oxidative damage to the DNA that compromises the integrity of the genome. Our results show that mutator mouse has significantly higher levels of 8‐oxoguanine (8‐oxoGua) that are correlated with increased nuclear DNA (nDNA) strand breakage and oxidative nDNA damage, shorter average telomere length, and reduced mtDNA integrity. Based on these results, we propose a model whereby the increased level of reactive oxygen species (ROS) associated with the accumulation of mtDNA mutations in Polg mut/mut mice results in higher levels of 8‐oxoGua, which in turn lead to compromised DNA integrity and accelerated aging via increased DNA fragmentation and telomere shortening. These results suggest that mitochondrial play a central role in aging and may guide future research to develop potential therapeutics for mitigating aging process. The increased mtDNA mutation rate in the Polg mutator mouse has been previously shown to be associated with an accelerated aging phenotype, likely due to increased oxidative stress. This study provides evidence in support of this oxidative stress model by showing that the Polg mutation is also associated with increased levels of 8‐oxoGua as well as telomere shortening and other forms of DNA damage.
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