Altered levels of mitochondrial DNA are associated with female age, aneuploidy, and provide an independent measure of embryonic implantation potential.
Altered levels of mitochondrial DNA are associated with female age, aneuploidy, and provide an independent measure of embryonic implantation potential.
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DOI：
10.1371/journal.pgen.1005241
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发表时间：
2015-06
期刊：
影响因子：
4.5
通讯作者：
Wells D
中科院分区：
文献类型：
--
作者：
Fragouli E;Spath K;Alfarawati S;Kaper F;Craig A;Michel CE;Kokocinski F;Cohen J;Munne S;Wells D
线粒体在胚胎发育中起着至关重要的作用。它们是能量产生的主要场所，并具有各种其他关键的细胞功能。尽管这种细胞器很重要，但人们对植入前个体人类胚胎之间线粒体DNA （mtDNA）的差异程度知之甚少。本研究探讨了379个胚胎中mtDNA数量的生物学和临床相关性。这些通过微阵列比较基因组杂交（aCGH）、定量PCR和下一代测序（NGS）的组合进行检测，提供了染色体状态、mtDNA数量和线粒体基因组中突变存在的信息。老年妇女胚胎的mtDNA数量明显较高（P=0.003）。此外，mtDNA水平在非整倍体胚胎中升高，与年龄无关（P=0.025）。整倍体胚胎移植到子宫后的临床结果评估显示，成功植入囊胚的mtDNA含量往往低于未植入囊胚（P=0.007）。重要的是，建立了一个mtDNA数量阈值，超过该阈值从未观察到植入。随后，该阈值的预测值在一项独立的盲法前瞻性研究中得到证实，表明30%的未着床整倍体胚胎存在mtDNA水平异常，但在形成可存活妊娠的胚胎中未见异常。NGS未显示mtDNA水平升高的囊胚突变增加。这项研究的结果表明，增加的mtDNA可能与代谢升高有关，并与生存能力降低有关，这可能与“安静胚胎”假说相一致。重要的是，这些发现表明线粒体在女性生殖衰老和非整倍体发生中的潜在作用。在临床意义上，我们提出mtDNA含量代表了一种新的生物标志物，在体外受精（IVF）治疗中具有潜在价值，揭示了染色体正常的囊胚不能产生可行的妊娠。线粒体是一种小的膜封闭结构，存在于人体细胞内。线粒体积极参与细胞生命，其主要功能是产生供细胞使用的能量。因此，线粒体被认为是细胞的动力源。与其他细胞器不同，线粒体含有自己的DNA （mtDNA）。MtDNA携带有关细胞代谢和能量产生的重要遗传信息。线粒体和mtDNA可能在胚胎早期发育过程中起重要作用。我们的研究证实了这一假设。具体来说，我们的研究结果表明线粒体及其基因组与女性生殖衰老和胚胎染色体异常的产生有关。重要的是，我们描述了mtDNA数量与胚胎成功成为婴儿的潜力之间的直接关系。我们建议，评估mtDNA的数量可能是一种识别胚胎的新方法，具有最高的能力，导致健康怀孕和活产。
Mitochondria play a vital role in embryo development. They are the principal site of energy production and have various other critical cellular functions. Despite the importance of this organelle, little is known about the extent of variation in mitochondrial DNA (mtDNA) between individual human embryos prior to implantation. This study investigated the biological and clinical relevance of the quantity of mtDNA in 379 embryos. These were examined via a combination of microarray comparative genomic hybridisation (aCGH), quantitative PCR and next generation sequencing (NGS), providing information on chromosomal status, amount of mtDNA, and presence of mutations in the mitochondrial genome. The quantity of mtDNA was significantly higher in embryos from older women (P=0.003). Additionally, mtDNA levels were elevated in aneuploid embryos, independent of age (P=0.025). Assessment of clinical outcomes after transfer of euploid embryos to the uterus revealed that blastocysts that successfully implanted tended to contain lower mtDNA quantities than those failing to implant (P=0.007). Importantly, an mtDNA quantity threshold was established, above which implantation was never observed. Subsequently, the predictive value of this threshold was confirmed in an independent blinded prospective study, indicating that abnormal mtDNA levels are present in 30% of non-implanting euploid embryos, but are not seen in embryos forming a viable pregnancy. NGS did not reveal any increase in mutation in blastocysts with elevated mtDNA levels. The results of this study suggest that increased mtDNA may be related to elevated metabolism and are associated with reduced viability, a possibility consistent with the ‘quiet embryo’ hypothesis. Importantly, the findings suggest a potential role for mitochondria in female reproductive aging and the genesis of aneuploidy. Of clinical significance, we propose that mtDNA content represents a novel biomarker with potential value for in vitro fertilisation (IVF) treatment, revealing chromosomally normal blastocysts incapable of producing a viable pregnancy. Mitochondria are small membrane-enclosed structures and are found inside the cells of the body. Mitochondria actively participate in cellular life, and their main function is to generate energy which is used by the cell. For this reason mitochondria are considered as the powerhouses of cells. Unlike other cellular organelles, mitochondria contain their own DNA (mtDNA). MtDNA carries important genetic information concerning cellular metabolism and the generation of energy. It has been suggested that mitochondria and mtDNA could be of significance during early embryo development. Our work confirms this hypothesis. Specifically, our findings implicate mitochondria and their genome in female reproductive aging and the generation of embryonic chromosome abnormalities. Importantly, we describe a direct relationship between mtDNA quantity and the potential of an embryo to successfully become a baby. We propose that assessment of mtDNA quantity could be a novel way of identifying embryos with the highest ability to lead to healthy pregnancies and live births.
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影响因子：
6.1
作者：
Christopikou, Dimitra;Tsorva, Erika;Handyside, Alan H.
通讯作者：
Handyside, Alan H.
影响因子：
4
作者：
Chan, CCW;Liu, VWS;Ho, PC
通讯作者：
Ho, PC
DOI：
10.1016/j.fsigss.2011.09.014
发表时间：
2011-12-01
期刊：
FORENSIC SCIENCE INTERNATIONAL GENETICS SUPPLEMENT SERIES
影响因子：
--
作者：
Fregel, R.;Almeida, M.;Pestano, J.
通讯作者：
Pestano, J.
DOI：
10.1093/humrep/der295
发表时间：
2011-11
期刊：
Human reproduction (Oxford, England)
影响因子：
--
作者：
Magli MC;Montag M;Köster M;Muzi L;Geraedts J;Collins J;Goossens V;Handyside AH;Harper J;Repping S;Schmutzler A;Vesela K;Gianaroli L
通讯作者：
Gianaroli L
影响因子：
6.7
作者：
Gutierrez-Mateo, Cristina;Colls, Pere;Munne, Santiago
通讯作者：
Munne, Santiago