Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bypass Road, Bhauri, Bhopal, 462030, India.
Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Environ Sci Pollut Res Int. 2022 Oct;29(49):74133-74149. doi: 10.1007/s11356-022-21059-3. Epub 2022 May 28.
Mitochondria play a central role in maintaining cellular and metabolic homeostasis during vital development cycles of foetal growth. Optimal mitochondrial functions are important not only to sustain adequate energy production but also for regulated epigenetic programming. However, these organelles are subtle targets of environmental exposures, and any perturbance in the defined mitochondrial machinery during the developmental stage can lead to the re-programming of the foetal epigenetic landscape. As these modifications can be transferred to subsequent generations, we herein performed a cross-sectional study to have an in-depth understanding of this intricate phenomenon. The study was conducted with two arms: whereas the first group consisted of in utero pro-oxidant exposed individuals and the second group included controls. Our results showed higher levels of oxidative mtDNA damage and associated integrated stress response among the exposed individuals. These disturbances were found to be closely related to the observed discrepancies in mitochondrial biogenesis. The exposed group showed mtDNA hypermethylation and changes in allied mitochondrial functioning. Altered expression of mitomiRs and their respective target genes in the exposed group indicated the possibilities of a disturbed mitochondrial-nuclear cross talk. This was further confirmed by the modified activity of the mitochondrial stress regulators and pro-inflammatory mediators among the exposed group. Importantly, the disturbed DNMT functioning, hypermethylation of nuclear DNA, and higher degree of post-translational histone modifications established the existence of aberrant epigenetic modifications in the exposed individuals. Overall, our results demonstrate the first molecular insights of in utero pro-oxidant exposure associated changes in the mitochondrial-epigenetic axis. Although, our study might not cement an exposure-response relationship for any particular environmental pro-oxidant, but suffice to establish a dogma of mito-epigenetic reprogramming at intrauterine milieu with chronic illness, a hitherto unreported interaction.
线粒体在胎儿生长的重要发育周期中维持细胞和代谢稳态方面发挥着核心作用。最佳的线粒体功能不仅对于维持足够的能量产生很重要，而且对于调节表观遗传编程也很重要。然而，这些细胞器是环境暴露的微妙靶点，并且在发育阶段任何对定义明确的线粒体机制的干扰都可能导致胎儿表观遗传景观的重新编程。由于这些修饰可以传递到后代，因此我们在此进行了一项横断面研究，以深入了解这一复杂现象。该研究有两个分支：第一个分支包括宫内暴露于促氧化剂的个体，第二个分支包括对照组。我们的研究结果表明，暴露组个体的氧化 mtDNA 损伤和相关的综合应激反应水平更高。这些干扰与观察到的线粒体生物发生差异密切相关。暴露组显示 mtDNA 过度甲基化以及相关的线粒体功能变化。暴露组中 mitomiRs 及其各自靶基因的表达改变表明存在线粒体-核交叉对话紊乱的可能性。暴露组中线粒体应激调节剂和促炎介质的活性改变进一步证实了这一点。重要的是，受干扰的 DNMT 功能、核 DNA 的高甲基化和翻译后组蛋白修饰程度较高，证实了暴露个体中存在异常的表观遗传修饰。总的来说，我们的研究结果表明，宫内促氧化剂暴露相关的线粒体-表观遗传轴变化的第一个分子见解。尽管我们的研究可能不会为任何特定的环境促氧化剂建立暴露-反应关系，但足以在宫内环境中建立慢性疾病的线粒体-表观遗传重编程的教条，这是一个以前未报道过的相互作用。
