St John Justin C, Andreas Eryk, Penn Alexander
Experimental Mitochondrial Genetics Group, School of Biomedicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide Health and Medical Sciences Building, Adelaide, SA 5000, Australia.
Int J Mol Sci. 2025 Mar 18;26(6):2746. doi: 10.3390/ijms26062746.
The introduction of extra copies of mitochondrial DNA (mtDNA), whether autologous or heterologous, into oocytes at the time of fertilisation or through other assisted reproductive technologies, such as nuclear transfer, is a contentious issue. The primary focus has been on whether third-party mtDNA is transmitted to the offspring and if it impacts offspring health and well-being. However, little attention has focused on whether the introduction of extra copies of mtDNA will interfere with the balance established between the nuclear and mitochondrial genomes during oogenesis and as the developing embryo establishes its own epigenetic imprint that will influence mature offspring. Whilst we determined that sexually mature offspring generated through mtDNA supplementation did not inherit any-third party mtDNA, they exhibited differences in gene expression from three tissues derived from three separate embryonic lineages. This resulted in a number of pathways being affected. In each case, the differences were greater in the heterologous and autologous comparison than when comparing all supplemented offspring against non-supplemented offspring. Many of the changes in gene expression were coupled to differential DNA methylation across tissues, some of which were tissue-specific, with high levels observed in the heterologous against autologous comparison. An analysis of DNA methylation in blastocyst-stage embryos pointed to changes in patterns of DNA methylation that were transmitted through to the offspring. Our results indicated that extra copies of mtDNA may not be transmitted if introduced at low levels, but the changes induced by supplementation that occur in DNA methylation and gene expression in the blastocyst have a profound effect on tissues.
在受精时或通过其他辅助生殖技术（如核移植）将额外拷贝的线粒体DNA（mtDNA）引入卵母细胞，无论是自体的还是异体的，都是一个有争议的问题。主要关注点一直在于第三方mtDNA是否会传递给后代以及它是否会影响后代的健康和幸福。然而，很少有人关注引入额外拷贝的mtDNA是否会干扰卵子发生过程中以及发育中的胚胎建立自身表观遗传印记（这将影响成熟后代）时核基因组与线粒体基因组之间建立的平衡。虽然我们确定通过补充mtDNA产生的性成熟后代没有继承任何第三方mtDNA，但它们在来自三个不同胚胎谱系的三个组织中的基因表达存在差异。这导致许多通路受到影响。在每种情况下，异体和自体比较中的差异都比将所有补充后代与未补充后代进行比较时更大。基因表达的许多变化与跨组织的差异DNA甲基化相关，其中一些是组织特异性的，在异体与自体比较中观察到高水平。对囊胚期胚胎的DNA甲基化分析表明，DNA甲基化模式的变化会传递给后代。我们的结果表明，如果低水平引入额外拷贝的mtDNA可能不会传递，但补充mtDNA所诱导的囊胚期DNA甲基化和基因表达变化对组织有深远影响。
