On August 3, Aging Cell journal published a latest research titled “Mitochondrial DNA mutation exacerbates female reproductive aging via impairment of the NADH/NAD+ redox” from Xingguo Liu’s research group in Guangzhou Institute of biomedicine and health, Chinese Academy of Sciences. The work found that the oocytes of elder female patients carried more mitochondrial DNA mutations and had lower blastocyst formation rate than those of young women. Using animal models, they demonstrated that mitochondrial DNA mutations cause fertility decline in females rather than males. The mechanism study found that mitochondrial DNA mutation caused the decrease of female fertility by reducing the NADH/NAD+ redox state of oocytes, and determined that NMN (nicotinamide mononucleotide) could improve fertility, which provided a potential candidate drug for the treatment of the infertility of elder female patients.
Childbirth of aging female is not only a basic scientific problem in the field of reproductive and regenerative medicine, but also a major national demand of China's national conditions. Aging is one of the key factors affecting the fertility of men and women, in which female fertility usually declines after the age of 30. On the other hand, rapid environmental changes may also lead to a sharp increase of infertility rate in recent years. As an energy factory containing DNA in cells, mitochondrial dysfunction is supposed to play an important role in age and environment induced infertility. However, whether and how mitochondrial DNA mutations accumulated by aging regulate fertility and its sex dependence are still unknown.
Xingguo Liu’s group revealed the age-related variation of mitochondrial DNA mutations in human female oocytes and identified the types of mutations. At the same time, mitochondrial DNA mutations are inversely proportional to oocyte quality, which provides a new potential biomarker for embryo viability in assisted reproduction. To answer the causal effect of mitochondrial DNA mutations on fertility, the research group used mitochondrial DNA mutation (mitochondrial DNA polymerase γ-Polg mutation) mice, a widely used experimental model to study the roles of mtDNA mutations in aging process.
Xingguo Liu’s group generated a series of mice with increasing levels of mtDNA mutations using Polg mutation and wild-type mice, and verified the quantitative correlation between mitochondrial DNA mutation level and fertility. In addition, through the ingenious breeding pairs using of male (or female) Polg mutation and wild-type mice, they demonstrated that mtDNA mutations mainly affect fertility of female mice and not of male ones. The group further found that accumulated mitochondrial DNA mutations during aging comprised oocyte quality by reducing the number of follicles. It did not significantly affect male fertility although it reduced sperm motility.
Further mechanism studies showed that accumulation of mtDNA mutations decreases fertility by impairing oocyte’s NADH/NAD+ redox state. NMN (nicotinamide mononucleotide), the key intermediate product of this redox state, can significantly improve the infertility of female mice by increasing the NADH/NAD+ of oocytes.
To sum up, the research answer the fundamental question of the causal effect of age accumulated mtDNA mutations on fertility and its sex dependence, and show its distinct metabolic controlling mechanism, which provides new ideas and potential drug candidates for the treatment of infertility of elder females.
This study was completed with combinations from Sun Yat-Sen University, East China University of Science and Technology and Guangdong Pharmaceutical University, and received technical support from Tsinghua University. This study was supported by National Key Research and Development projects, Chinese Academy of Sciences, National Natural Science Foundation, Guangdong Province and Guangzhou city.
Xingguo Liu’s group revealed the mechanism of female infertility caused by mtDNA mutation