Laboratory of Clinical Pharmacology Q7642, Rigshospitalet, DK-2100 Copenhagen, Denmark.
Free Radic Biol Med. 2012 Apr 15;52(8):1353-61. doi: 10.1016/j.freeradbiomed.2012.01.009. Epub 2012 Jan 28.
The past decade has provided exciting insights into a novel class of central (small) RNA molecules intimately involved in gene regulation. Only a small percentage of our DNA is translated into proteins by mRNA, yet 80% or more of the DNA is transcribed into RNA, and this RNA has been found to encompass various classes of novel regulatory RNAs, including, e.g., microRNAs. It is well known that DNA is constantly oxidized and repaired by complex genome maintenance mechanisms. Analogously, RNA also undergoes significant oxidation, and there are now convincing data suggesting that oxidation, and the consequent loss of integrity of RNA, is a mechanism for disease development. Oxidized RNA is found in a large variety of diseases, and interest has been especially devoted to degenerative brain diseases such as Alzheimer disease, in which up to 50-70% of specific mRNA molecules are reported oxidized, whereas other RNA molecules show virtually no oxidation. The iron-storage disease hemochromatosis exhibits the most prominent general increase in RNA oxidation ever observed. Oxidation of RNA primarily leads to strand breaks and to oxidative base modifications. Oxidized mRNA is recognized by the ribosomes, but the oxidation results in ribosomal stalling and dysfunction, followed by decreased levels of functional protein as well as the production of truncated proteins that do not undergo proper folding and may result in protein aggregation within the cell. Ribosomal dysfunction may also signal apoptosis by p53-independent pathways. There are very few reports on interventions that reduce RNA oxidation, one interesting observation being a reduction in RNA oxidation by ingestion of raw olive oil. High urinary excretion of 8-oxo-guanosine, a biomarker for RNA oxidation, is highly predictive of death in newly diagnosed type 2 diabetics; this demonstrates the clinical relevance of RNA oxidation. Taken collectively the available data suggest that RNA oxidation is a contributing factor in several diseases such as diabetes, hemochromatosis, heart failure, and β-cell destruction. The mechanism involves free iron and hydrogen peroxide from mitochondrial dysfunction that together lead to RNA oxidation that in turn gives rise to truncated proteins that may cause aggregation. Thus RNA oxidation may well be an important novel contributing mechanism for several diseases.
在过去的十年中，人们对一类新型的中枢（小）RNA 分子有了令人兴奋的认识，这类 RNA 分子与基因调控密切相关。只有一小部分 DNA 通过 mRNA 翻译成蛋白质，然而 80%或更多的 DNA 转录成 RNA，并且已经发现这种 RNA 包含各种新型的调控 RNA 类别，例如 microRNA。众所周知，DNA 会不断地通过复杂的基因组维护机制发生氧化和修复。类似地，RNA 也会发生显著的氧化，现在有令人信服的证据表明，氧化以及 RNA 完整性的丧失，是疾病发展的一种机制。氧化 RNA 存在于多种疾病中，人们特别关注退行性脑疾病，如阿尔茨海默病，据报道，在这种疾病中，多达 50-70%的特定 mRNA 分子发生氧化，而其他 RNA 分子几乎没有发生氧化。铁储存疾病血色素沉着症表现出迄今为止观察到的最显著的一般 RNA 氧化增加。RNA 的氧化主要导致链断裂和氧化碱基修饰。氧化的 mRNA 被核糖体识别，但氧化导致核糖体停滞和功能障碍，随后功能性蛋白质水平降低，以及产生未经过适当折叠的截断蛋白质，可能导致细胞内蛋白质聚集。核糖体功能障碍也可能通过 p53 非依赖性途径引发细胞凋亡。关于减少 RNA 氧化的干预措施的报告很少，一个有趣的观察结果是，通过摄入生橄榄油可以减少 RNA 氧化。新诊断的 2 型糖尿病患者尿液中 8-氧鸟苷的排泄量很高，这是 RNA 氧化的一个生物标志物，这表明 RNA 氧化具有临床相关性。综合现有数据表明，RNA 氧化是糖尿病、血色素沉着症、心力衰竭和β细胞破坏等几种疾病的一个致病因素。该机制涉及线粒体功能障碍导致的游离铁和过氧化氢，它们共同导致 RNA 氧化，进而产生可能导致聚集的截断蛋白。因此，RNA 氧化很可能是几种疾病的一个重要的新致病机制。
