Kong Minghua, Guo Lishu, Xu Weilin, He Chengpeng, Jia Xiaoyan, Zhao Zhiyao, Gu Zhenglong
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
School of Life Sciences, Westlake University, Hangzhou 310024, China.
Life Med. 2022 Aug 17;1(2):149-167. doi: 10.1093/lifemedi/lnac014. eCollection 2022 Oct.
The majority of cancer patients are among aged population, suggesting an urgent need to advance our knowledge on complicated relationship between aging and cancer. It has been hypothesized that metabolic changes during aging could act as a driver for tumorigenesis. Given the fact that mitochondrial DNA (mtDNA) mutations are common in both tumors and aged tissues, it is interesting to contemplate possible role of age-related mtDNA mutations in tumorigenesis. MtDNA encodes genes essential for mitochondrial metabolism, and mtDNA mutates at a much higher rate than nuclear genome. Random drifting of somatic mtDNA mutations, as a result of cell division or mitochondrial turnover during aging, may lead to more and more cells harboring high-frequency pathogenic mtDNA mutations, albeit at different loci, in single-cells. Such mutations can induce metabolic reprogramming, nuclear genome instability and immune response, which might increase the likelihood of tumorigenesis. In this review, we summarize current understanding of how mtDNA mutations accumulate with aging and how these mutations could mechanistically contribute to tumor origin. We also discuss potential prevention strategies for mtDNA mutation-induced tumorigenesis, and future works needed in this direction.
大多数癌症患者属于老年人群体，这表明迫切需要增进我们对衰老与癌症之间复杂关系的了解。据推测，衰老过程中的代谢变化可能是肿瘤发生的驱动因素。鉴于线粒体DNA（mtDNA）突变在肿瘤和衰老组织中都很常见，思考与年龄相关的mtDNA突变在肿瘤发生中的可能作用很有意思。mtDNA编码线粒体代谢所必需的基因，并且mtDNA的突变率比核基因组高得多。衰老过程中由于细胞分裂或线粒体更新导致的体细胞mtDNA突变的随机漂移，可能会导致越来越多的细胞在单细胞中携带高频致病性mtDNA突变，尽管这些突变位于不同的位点。此类突变可诱导代谢重编程、核基因组不稳定和免疫反应，这可能会增加肿瘤发生的可能性。在这篇综述中，我们总结了目前对mtDNA突变如何随衰老积累以及这些突变如何在机制上促进肿瘤起源的理解。我们还讨论了mtDNA突变诱导肿瘤发生的潜在预防策略，以及在这个方向上未来需要开展的工作。
