Shoubridge Eric A, Wai Timothy
Department of Human Genetics, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
Curr Top Dev Biol. 2007;77:87-111. doi: 10.1016/S0070-2153(06)77004-1.
In mammals, mitochondria and mitochondrial DNA (mtDNA) are transmitted through the female germ line. Mature oocytes contain at least 100,000 copies of mtDNA, organized at 1-2 copies per organelle. Despite the high genome copy number, mtDNA sequence variants are observed to segregate rapidly between generations, and this has led to the concept of a developmental bottleneck for the transmission of mtDNA. Ultrastructural investigations of primordial germ cells show that they contain approximately 10 mitochondria, suggesting that mitochondrial biogenesis is arrested during early embryogenesis, and that the mitochondria contributing to the germ cell precursors are simply apportioned from those present in the zygote. Thus, as few as 0.01% of the mitochondria in the oocyte actually contribute to the offspring of the next generation. Mitochondrial replication restarts in the migrating primordial germ cells, and mitochondrial numbers steadily increase to a few thousand in primordial oocytes. Genetic evidence from both heteroplasmic mice and human pedigrees suggests that segregation of mtDNA sequence variants is largely a stochastic process that occurs during the mitotic divisions of the germ cell precursors. This process is essentially complete by the time the primary oocyte population is differentiated in fetal life. Analysis of the distribution of pathogenic mtDNA mutations in the offspring of carrier mothers shows that risk of inheriting a pathogenic mutation increases with the proportion in the mother, but there is no bias toward transmitting more or less of the mutant mtDNAs. This implies that there is no strong selection against oocytes carrying pathogenic mutations and that atresia is not a filter for oocyte quality based on oxidative phosphorylation capacity. The large number of mitochondria and mtDNAs present in the oocyte may simply represent a genetic mechanism to ensure their distribution to the gametes and somatic cells of the next generation. If true, mtDNA copy number, and by inference mitochondrial number, may be the most important determinant of oocyte quality, not because of the effects on oocyte metabolism, but because too few would result in a maldistribution in the early embryo.
在哺乳动物中，线粒体和线粒体DNA（mtDNA）通过雌性生殖系传递。成熟的卵母细胞含有至少100,000个mtDNA拷贝，每个细胞器中组织为1 - 2个拷贝。尽管基因组拷贝数很高，但观察到mtDNA序列变异在代与代之间迅速分离，这导致了mtDNA传递存在发育瓶颈的概念。对原始生殖细胞的超微结构研究表明，它们含有大约10个线粒体，这表明线粒体生物发生在早期胚胎发育过程中停滞，并且有助于生殖细胞前体的线粒体只是从合子中存在的线粒体中分配而来。因此，卵母细胞中实际上只有0.01%的线粒体对下一代的后代有贡献。线粒体复制在迁移的原始生殖细胞中重新开始，并且线粒体数量在原始卵母细胞中稳步增加到几千个。来自异质性小鼠和人类家系的遗传证据表明，mtDNA序列变异的分离在很大程度上是一个在生殖细胞前体的有丝分裂过程中发生的随机过程。这个过程在胎儿期初级卵母细胞群体分化时基本完成。对携带致病mtDNA突变的母亲的后代中致病mtDNA突变分布的分析表明，遗传致病突变的风险随着母亲体内的比例增加而增加，但在传递更多或更少的突变mtDNA方面没有偏向。这意味着对携带致病突变的卵母细胞没有强烈的选择，并且闭锁不是基于氧化磷酸化能力对卵母细胞质量的筛选。卵母细胞中存在的大量线粒体和mtDNA可能仅仅代表一种遗传机制，以确保它们分配到下一代的配子和体细胞中。如果是这样，mtDNA拷贝数，以及由此推断的线粒体数量，可能是卵母细胞质量的最重要决定因素，不是因为对卵母细胞代谢的影响，而是因为太少会导致早期胚胎中的分布不均。
