Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, Utrecht, 3584 CG, The Netherlands.
Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, 3584 CS, The Netherlands.
Nat Commun. 2024 Mar 28;15(1):2725. doi: 10.1038/s41467-024-47008-x.
Reactive Oxygen Species (ROS) derived from mitochondrial respiration are frequently cited as a major source of chromosomal DNA mutations that contribute to cancer development and aging. However, experimental evidence showing that ROS released by mitochondria can directly damage nuclear DNA is largely lacking. In this study, we investigated the effects of HO released by mitochondria or produced at the nucleosomes using a titratable chemogenetic approach. This enabled us to precisely investigate to what extent DNA damage occurs downstream of near- and supraphysiological amounts of localized HO. Nuclear HO gives rise to DNA damage and mutations and a subsequent p53 dependent cell cycle arrest. Mitochondrial HO release shows none of these effects, even at levels that are orders of magnitude higher than what mitochondria normally produce. We conclude that HO released from mitochondria is unlikely to directly damage nuclear genomic DNA, limiting its contribution to oncogenic transformation and aging.
活性氧（ROS）来源于线粒体呼吸，常被认为是导致癌症发展和衰老的染色体 DNA 突变的主要来源。然而，实验证据表明，线粒体释放的 ROS 可以直接损伤核 DNA，这在很大程度上是缺乏的。在这项研究中，我们使用可滴定的化学遗传学方法研究了线粒体或核小体产生的 HO 对核 DNA 的影响。这使我们能够精确地研究在局部 HO 的近生理和超生理数量水平下，DNA 损伤发生的程度。核 HO 会导致 DNA 损伤和突变，并随后导致 p53 依赖性细胞周期停滞。线粒体 HO 的释放没有这些影响，即使在比线粒体正常产生的水平高出几个数量级的水平下也是如此。我们得出结论，线粒体释放的 HO 不太可能直接损伤核基因组 DNA，从而限制了其对致癌转化和衰老的贡献。
