College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.
Commun Biol. 2024 Oct 1;7(1):1229. doi: 10.1038/s42003-024-06888-x.
Oocytes play a crucial role in transmitting maternal mitochondrial DNA (mtDNA), essential for the continuation of species. However, the effects of mitochondrial reactive oxygen species (ROS) on mammalian oocyte maturation and mtDNA maintenance remain unclear. We investigated this by conditionally knocking out the Sod2 gene in primordial follicles, elevating mitochondrial matrix ROS levels from early oocyte stages. Our data indicates that reproductive aging in Sod2 conditional knockout females begins at 6 months, with oxidative stress impairing oocyte quality, particularly affecting OXPHOS complex II and mtDNA-encoded mRNA levels. Despite unchanged mtDNA mutation load, mtDNA copy numbers exhibited significant variations. Strikingly, reducing mtDNA copy numbers by reducing mtSSB protein, crucial for mtDNA replication, accelerated reproductive aging onset to three months, underscoring the critical role of mtDNA copy number maintenance under oxidative stress conditions. This research provides new insights into the relationship among mitochondrial ROS, mtDNA, and reproductive aging, offering potential strategies for delaying aging-related fertility decline.
卵母细胞在传递母系线粒体 DNA（mtDNA）方面起着至关重要的作用，这对于物种的延续至关重要。然而，线粒体活性氧（ROS）对哺乳动物卵母细胞成熟和 mtDNA 维持的影响仍不清楚。我们通过在原始卵泡中条件性敲除 Sod2 基因来研究这一点，从而从早期卵母细胞阶段开始提高线粒体基质 ROS 水平。我们的数据表明，Sod2 条件性敲除雌性的生殖衰老始于 6 个月，氧化应激会损害卵母细胞质量，特别是影响 OXPHOS 复合物 II 和 mtDNA 编码的 mRNA 水平。尽管 mtDNA 突变负荷没有变化，但 mtDNA 拷贝数显示出显著的变化。引人注目的是，通过减少 mtDNA 复制关键蛋白 mtSSB 来降低 mtDNA 拷贝数，会加速生殖衰老的发生，使其在三个月内出现，这突显了在氧化应激条件下 mtDNA 拷贝数维持的关键作用。这项研究为线粒体 ROS、mtDNA 和生殖衰老之间的关系提供了新的见解，并为延迟与衰老相关的生育能力下降提供了潜在的策略。
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