Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Hanzeplein 1, 9713, GZ, Groningen, The Netherlands.
Sci Rep. 2017 Mar 14;7(1):177. doi: 10.1038/s41598-017-00263-z.
Like the nucleus, mitochondria contain their own DNA and recent reports provide accumulating evidence that also the mitochondrial DNA (mtDNA) is subjective to DNA methylation. This evidence includes the demonstration of mitochondria-localised DNA methyltransferases and demethylases, and the detection of mtDNA methylation as well as hydroxymethylation. Importantly, differential mtDNA methylation has been linked to aging and diseases, including cancer and diabetes. However, functionality of mtDNA methylation has not been demonstrated. Therefore, we targeted DNA methylating enzymes (modifying cytosine in the CpG or GpC context) to the mtDNA. Unexpectedly, mtDNA gene expression remained unchanged upon induction of CpG mtDNA methylation, whereas induction of C-methylation in the GpC context decreased mtDNA gene expression. Intriguingly, in the latter case, the three mtDNA promoters were differentially affected in each cell line, while cellular function seemed undisturbed. In conclusion, this is the first study which directly addresses the potential functionality of mtDNA methylation. Giving the important role of mitochondria in health and disease, unravelling the impact of mtDNA methylation adds to our understanding of the role of mitochondria in physiological and pathophysiological processes.
与细胞核一样，线粒体也含有自己的 DNA，最近的报告提供了越来越多的证据表明，线粒体 DNA（mtDNA）也受到 DNA 甲基化的影响。这方面的证据包括线粒体定位的 DNA 甲基转移酶和去甲基酶的证明，以及 mtDNA 甲基化和羟甲基化的检测。重要的是，mtDNA 甲基化的差异与衰老和疾病有关，包括癌症和糖尿病。然而，mtDNA 甲基化的功能尚未得到证实。因此，我们将 DNA 甲基转移酶（在 CpG 或 GpC 环境中修饰胞嘧啶）靶向 mtDNA。出乎意料的是，CpG mtDNA 甲基化的诱导并没有改变 mtDNA 基因的表达，而 GpC 环境中 C 甲基化的诱导则降低了 mtDNA 基因的表达。有趣的是，在后一种情况下，三个 mtDNA 启动子在每个细胞系中受到不同的影响，而细胞功能似乎没有受到干扰。总之，这是第一项直接探讨 mtDNA 甲基化潜在功能的研究。鉴于线粒体在健康和疾病中的重要作用，揭示 mtDNA 甲基化的影响有助于我们理解线粒体在生理和病理生理过程中的作用。
