Maintaining mitochondrial DNA copy number mitigates ROS-induced oocyte decline and female reproductive aging
Shiyun Long, Yunchao Zheng, Xiaoling Deng, Jing Guo, Zhe Xu, Karin Scharffetter‐Kochanek, Yanmei Dou, Min Jiang
Abstract
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. Elevating mitochondrial ROS induces female reproductive aging without increasing maternal mtDNA mutation load where deducing mtDNA copy numbers accelerates this phenomenon, highlighting the importance of maintaining mtDNA quantity under oxidative stress.